diff --git a/.eslintignore b/.eslintignore new file mode 100644 index 0000000..dc28728 --- /dev/null +++ b/.eslintignore @@ -0,0 +1,4 @@ +backup/ +.next/ +node_modules/ +out/ diff --git a/.github/workflows/deploy.yml b/.github/workflows/deploy.yml new file mode 100644 index 0000000..1674618 --- /dev/null +++ b/.github/workflows/deploy.yml @@ -0,0 +1,66 @@ +name: Deploy Next.js site to Pages + +on: + push: + branches: ["master", "feature/nextjs-redesign"] + workflow_dispatch: + +permissions: + contents: read + pages: write + id-token: write + +concurrency: + group: "pages" + cancel-in-progress: false + +jobs: + build: + runs-on: ubuntu-latest + steps: + - name: Checkout + uses: actions/checkout@v4 + + - name: Setup Node + uses: actions/setup-node@v4 + with: + node-version: "20" + cache: "npm" + + - name: Install dependencies + run: npm ci + + - name: Build with Next.js + run: npx next build + + - name: Debug Output + run: | + echo "Current directory:" + pwd + ls -la + if [ -d "out" ]; then + echo "'out' directory found. Contents:" + ls -la out + else + echo "'out' directory NOT found." + if [ -d ".next" ]; then + echo "'.next' directory found. Contents:" + ls -la .next + fi + fi + + - name: Upload artifact + uses: actions/upload-pages-artifact@v3 + with: + path: ./out + + deploy: + environment: + name: github-pages + url: ${{ steps.deployment.outputs.page_url }} + runs-on: ubuntu-latest + needs: build + steps: + - name: Deploy to GitHub Pages + id: deployment + uses: actions/deploy-pages@v4 diff --git a/.gitignore b/.gitignore index 5f99b9b..5ef6a52 100644 --- a/.gitignore +++ b/.gitignore @@ -1,3 +1,41 @@ +# See https://help.github.com/articles/ignoring-files/ for more about ignoring files. + +# dependencies +/node_modules +/.pnp +.pnp.* +.yarn/* +!.yarn/patches +!.yarn/plugins +!.yarn/releases +!.yarn/versions + +# testing +/coverage + +# next.js +/.next/ +/out/ + +# production +/build + +# misc .DS_Store -node_modules/ -build/ +*.pem + +# debug +npm-debug.log* +yarn-debug.log* +yarn-error.log* +.pnpm-debug.log* + +# env files (can opt-in for committing if needed) +.env* + +# vercel +.vercel + +# typescript +*.tsbuildinfo +next-env.d.ts diff --git a/AGENTS.md b/AGENTS.md new file mode 100644 index 0000000..8bd0e39 --- /dev/null +++ b/AGENTS.md @@ -0,0 +1,5 @@ + +# This is NOT the Next.js you know + +This version has breaking changes — APIs, conventions, and file structure may all differ from your training data. Read the relevant guide in `node_modules/next/dist/docs/` before writing any code. Heed deprecation notices. + diff --git a/CLAUDE.md b/CLAUDE.md new file mode 100644 index 0000000..43c994c --- /dev/null +++ b/CLAUDE.md @@ -0,0 +1 @@ +@AGENTS.md diff --git a/README.md b/README.md index de41edd..66bb426 100644 --- a/README.md +++ b/README.md @@ -1,34 +1,36 @@ -# Lab Website +This is a [Next.js](https://nextjs.org) project bootstrapped with [`create-next-app`](https://github.com/vercel/next.js/tree/canary/packages/create-next-app). -## Contributing -To modify the content just edit one of the three JSON files in the `src/data` directory. Layout or styling modifications can be made via a pull request or by reaching out to Michael. +## Getting Started -## Development +First, run the development server: -### Installation - -``` -git clone https://github.com/veg/LabSite -cd LabSite -yarn +```bash +npm run dev +# or +yarn dev +# or +pnpm dev +# or +bun dev ``` -### Dev Server +Open [http://localhost:3000](http://localhost:3000) with your browser to see the result. -Start the development server: +You can start editing the page by modifying `app/page.js`. The page auto-updates as you edit the file. -``` -yarn start -``` +This project uses [`next/font`](https://nextjs.org/docs/app/building-your-application/optimizing/fonts) to automatically optimize and load [Geist](https://vercel.com/font), a new font family for Vercel. -## Deployment -Make/pull appropriate changes, then: +## Learn More -``` -yarn run build -``` +To learn more about Next.js, take a look at the following resources: -To serve (only necessary if `pm2` is not already provisioning this process): -``` -supervisor server.js -``` +- [Next.js Documentation](https://nextjs.org/docs) - learn about Next.js features and API. +- [Learn Next.js](https://nextjs.org/learn) - an interactive Next.js tutorial. + +You can check out [the Next.js GitHub repository](https://github.com/vercel/next.js) - your feedback and contributions are welcome! + +## Deploy on Vercel + +The easiest way to deploy your Next.js app is to use the [Vercel Platform](https://vercel.com/new?utm_medium=default-template&filter=next.js&utm_source=create-next-app&utm_campaign=create-next-app-readme) from the creators of Next.js. + +Check out our [Next.js deployment documentation](https://nextjs.org/docs/app/building-your-application/deploying) for more details. diff --git a/.babelrc b/backup/.babelrc similarity index 100% rename from .babelrc rename to backup/.babelrc diff --git a/backup/README.md b/backup/README.md new file mode 100644 index 0000000..de41edd --- /dev/null +++ b/backup/README.md @@ -0,0 +1,34 @@ +# Lab Website + +## Contributing +To modify the content just edit one of the three JSON files in the `src/data` directory. Layout or styling modifications can be made via a pull request or by reaching out to Michael. + +## Development + +### Installation + +``` +git clone https://github.com/veg/LabSite +cd LabSite +yarn +``` + +### Dev Server + +Start the development server: + +``` +yarn start +``` + +## Deployment +Make/pull appropriate changes, then: + +``` +yarn run build +``` + +To serve (only necessary if `pm2` is not already provisioning this process): +``` +supervisor server.js +``` diff --git a/backup/package-lock.json b/backup/package-lock.json new file mode 100644 index 0000000..a7c20d1 --- /dev/null +++ b/backup/package-lock.json @@ -0,0 +1,11589 @@ +{ + "name": "LabSite", + "version": "0.1.0", + "lockfileVersion": 1, + "requires": true, + "dependencies": { + "@babel/runtime": { + "version": "7.10.5", + "resolved": "https://registry.npmjs.org/@babel/runtime/-/runtime-7.10.5.tgz", + "integrity": "sha512-otddXKhdNn7d0ptoFRHtMLa8LqDxLYwTjB4nYgM1yy5N6gU/MUf8zqyyLltCH3yAVitBzmwK4us+DD0l/MauAg==", + 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src/papers_method.jsx rename to backup/src/papers_method.jsx diff --git a/src/projects.jsx b/backup/src/projects.jsx similarity index 100% rename from src/projects.jsx rename to backup/src/projects.jsx diff --git a/src/registerServiceWorker.js b/backup/src/registerServiceWorker.js similarity index 100% rename from src/registerServiceWorker.js rename to backup/src/registerServiceWorker.js diff --git a/data/extracted_pubs.json b/data/extracted_pubs.json new file mode 100644 index 0000000..b104c40 --- /dev/null +++ b/data/extracted_pubs.json @@ -0,0 +1,1807 @@ +[ + { + "id": "Selberg:2026aa", + "title": "MoleRate: comparing molecular relative evolutionary rates to detect convergent evolution", + "abstract": "In comparative evolutionary genomics, faster or slower evolution of a particular gene, site, or branch in a phylogenetic tree, when compared to the appropriate average, has been interpreted as evidence of conservation, functional importance, or adaptation. With large consortia generating hundreds of genomes, there is an opportunity to interrogate these datasets for evidence of accelerated or reduced evolutionary rates in protein-coding genes associated with the presence or absence of a given phenotype (e.g., marine vs. terrestrial, nocturnal vs. diurnal). Such rate shifts can reflect the molecular basis of convergent phenotypic adaptation when they occur repeatedly across independent lineages. Here, we introduce an explicit phylogenetic rate test, MoleRate, for acceleration or reduction of nucleotide or protein evolutionary rates in focal lineages vs. the rest of the phylogeny. Compared to existing methods, MoleRate offers execution, explicit likelihood-based hypothesis testing, and the ability to detect and filter out potentially aberrant signal from single lineages. We demonstrate MoleRate's performance on simulated and empirical data, and apply it to several mammalian phenotypes. We also highlight its visualization capabilities, which enable exploration and communication of results. These analyses show that MoleRate detects biologically significant enrichments in selective pressure on specific functions related to the given phenotype, and that enrichments in selective pressure related to the given phenotype, absent when random lineages are tested.", + "year": "2026", + "author": "Selberg, Avery G and Clark, Nathan and Nekrutenko, Anton and Chikina, Maria and Kosakovsky Pond, Sergei L", + "journal": "Evolution" + }, + { + "id": "Havens:2026aa", + "title": "Dynamics of natural selection preceding human viral epidemics and pandemics", + "abstract": "Using a phylogenetic framework to characterize natural selection, we investigate the hypothesis that zoonotic viruses require adaptation prior to zoonosis to sustain human-to-human transmission. Examining the zoonotic emergence of Ebola virus, Marburg virus, mpox virus, influenza A virus, and SARS-CoV-2, we find no evidence of a change in selection intensity immediately prior to outbreaks in humans compared with typical selection within reservoir hosts. We found a change in selection on SARS-CoV in an intermediate host. We conclude that extensive pre-zoonotic adaptation is not necessary for human-to-human transmission of zoonotic viruses. In contrast, the reemergence of H1N1 influenza A virus in 1977 was preceded by a shift in selection intensity, consistent with the hypothesis of passage in a laboratory setting. Holistic phylogenetic analysis of selection regimes can be used to detect evolutionary signals of host switching or laboratory passage, providing insight into the circumstances of past and future viral emergence.", + "year": "2026", + "author": "Havens, Jennifer L and Kosakovsky Pond, Sergei L and Zehr, Jordan D and Pekar, Jonathan E and Parker, Edyth and Worobey, Michael and Andersen, Kristian G and Wertheim, Joel O", + "journal": "Cell" + }, + { + "id": "Melendez-Vazquez:2025aa", + "title": "Ecological interactions and genomic innovation fueled the evolution of ray-finned fish endothermy", + "abstract": "Endothermy has independently evolved in several vertebrate lineages but remains rare among fishes. Using an integrated approach combining phylogenomic and ecomorphological data for 1051 ray-finned fishes, a time-dependent evolutionary model, and comparative genomic analyses of 205 marine vertebrates, we show that ecological interactions with modern cetaceans coincided with the evolution of endothermy in ray-finned fishes during the Eocene-Miocene. This result is supported by evidence of temporal and geographical overlap between cetaceans and endothermic fish lineages in the fossil record, as well as correlations between cetacean diversification and the origin of endothermy in fishes. Phylogenetic comparative analyses identified correlations between endothermy, large body sizes, and specialized swimming modes while challenging diet specialization and depth range expansion hypotheses. Comparative genomic analyses identified several genes under selection in endothermic lineages, including carnmt1 (involved in fatty acid metabolism) and dcaf6 (associated with development). Our findings advance the understanding of how ecological interactions and genomic factors shape key adaptations.", + "year": "2025", + "author": "Melendez-Vazquez, Fernando and Lucaci, Alexander G and Selberg, Avery and Clavel, Julien and Rincon-Sandoval, Melissa and Santaquiteria, Aintzane and White, William T and Drabeck, Danielle and Carnevale, Giorgio and Duarte-Ribeiro, Emanuell and Miya, Masaki and Westneat, Mark W and Baldwin, Carole C and Hughes, Lily C and Ort{\\'\\i}, Guillermo and Kosakovsky Pond, Sergei L and Betancur-R, Ricardo and Arcila, Dahiana", + "journal": "Sci Adv" + }, + { + "id": "Selberg:2025aa", + "title": "Minus the Error: Testing for Positive Selection in the Presence of Residual Alignment Errors", + "abstract": "Positive selection is an evolutionary process which increases the frequency of advantageous mutations because they confer a fitness benefit. Inferring the past action of positive selection on protein-coding sequences is fundamental for deciphering phenotypic diversity and the emergence of novel traits. With the advent of genome-wide comparative genomic datasets, researchers can analyze selection not only at the level of individual genes but also globally, delivering systems-level insights into evolutionary dynamics. However, genome-scale datasets are generated with automated pipelines and imperfect curation that does not eliminate all sequencing, annotation, and alignment errors. Positive selection inference methods are highly sensitive to such errors. We present BUSTED-E: a method designed to detect positive selection for amino acid diversification while concurrently identifying some alignment errors. This method builds on the flexible branch-site random effects model (BUSTED) for fitting distributions of dN/dS, with a critical modification: it incorporates an \"error-sink\" component to represent an abiological evolutionary regime. Using several genome-scale biological datasets that were extensively filtered using state-of-the art automated alignment tools, we show that BUSTED-E identifies pervasive residual alignment errors, produces more realistic estimates of positive selection, reduces bias, and improves biological interpretation. The BUSTED-E model promises to be a more stringent filter to identify positive selection in genome-wide contexts, thus enabling further characterization and validation of the most biologically relevant cases.", + "year": "2025", + "author": "Selberg, Avery and Clark, Nathan L and Sackton, Timothy B and Muse, Spencer V and Lucaci, Alexander G and Weaver, Steven and Nekrutenko, Anton and Chikina, Maria and Pond, Sergei L Kosakovsky", + "journal": "bioRxiv" + }, + { + "id": "Makova:2024aa", + "title": "The complete sequence and comparative analysis of ape sex chromosomes", + "abstract": "Apes possess two sex chromosomes-the male-specific Y chromosome and the X chromosome, which is present in both males and females. The Y chromosome is crucial for male reproduction, with deletions being linked to infertility1. The X chromosome is vital for reproduction and cognition2. Variation in mating patterns and brain function among apes suggests corresponding differences in their sex chromosomes. However, owing to their repetitive nature and incomplete reference assemblies, ape sex chromosomes have been challenging to study. Here, using the methodology developed for the telomere-to-telomere (T2T) human genome, we produced gapless assemblies of the X and Y chromosomes for five great apes (bonobo (Pan paniscus), chimpanzee (Pan troglodytes), western lowland gorilla (Gorilla gorilla gorilla), Bornean orangutan (Pongo pygmaeus) and Sumatran orangutan (Pongo abelii)) and a lesser ape (the siamang gibbon (Symphalangus syndactylus)), and untangled the intricacies of their evolution. Compared with the X chromosomes, the ape Y chromosomes vary greatly in size and have low alignability and high levels of structural rearrangements-owing to the accumulation of lineage-specific ampliconic regions, palindromes, transposable elements and satellites. Many Y chromosome genes expand in multi-copy families and some evolve under purifying selection. Thus, the Y chromosome exhibits dynamic evolution, whereas the X chromosome is more stable. Mapping short-read sequencing data to these assemblies revealed diversity and selection patterns on sex chromosomes of more than 100 individual great apes. These reference assemblies are expected to inform human evolution and conservation genetics of non-human apes, all of which are endangered species.", + "year": "2024", + "author": "Makova, Kateryna D and Pickett, Brandon D and Harris, Robert S and Hartley, Gabrielle A and Cechova, Monika and Pal, Karol and Nurk, Sergey and Yoo, DongAhn and Li, Qiuhui and Hebbar, Prajna and McGrath, Barbara C and Antonacci, Francesca and Aubel, Margaux and Biddanda, Arjun and Borchers, Matthew and Bornberg-Bauer, Erich and Bouffard, Gerard G and Brooks, Shelise Y and Carbone, Lucia and Carrel, Laura and Carroll, Andrew and Chang, Pi-Chuan and Chin, Chen-Shan and Cook, Daniel E and Craig, Sarah J C and de Gennaro, Luciana and Diekhans, Mark and Dutra, Amalia and Garcia, Gage H and Grady, Patrick G S and Green, Richard E and Haddad, Diana and Hallast, Pille and Harvey, William T and Hickey, Glenn and Hillis, David A and Hoyt, Savannah J and Jeong, Hyeonsoo and Kamali, Kaivan and Pond, Sergei L Kosakovsky and LaPolice, Troy M and Lee, Charles and Lewis, Alexandra P and Loh, Yong-Hwee E and Masterson, Patrick and McGarvey, Kelly M and McCoy, Rajiv C and Medvedev, Paul and Miga, Karen H and Munson, Katherine M and Pak, Evgenia and Paten, Benedict and Pinto, Brendan J and Potapova, Tamara and Rhie, Arang and Rocha, Joana L and Ryabov, Fedor and Ryder, Oliver A and Sacco, Samuel and Shafin, Kishwar and Shepelev, Valery A and Slon, Viviane and Solar, Steven J and Storer, Jessica M and Sudmant, Peter H and Sweetalana and Sweeten, Alex and Tassia, Michael G and Thibaud-Nissen, Fran{\\c c}oise and Ventura, Mario and Wilson, Melissa A and Young, Alice C and Zeng, Huiqing and Zhang, Xinru and Szpiech, Zachary A and Huber, Christian D and Gerton, Jennifer L and Yi, Soojin V and Schatz, Michael C and Alexandrov, Ivan A and Koren, Sergey and O'Neill, Rachel J and Eichler, Evan E and Phillippy, Adam M", + "journal": "Nature" + }, + { + "id": "Council:2025aa", + "title": "The persistent pool of HIV-1-infected cells is formed episodically during untreated infection", + "abstract": "Previous studies have shown that the majority of long-lived cells harboring persistent HIV-1 proviral genomes originates from viruses circulating in the year prior to antiretroviral therapy (ART) initiation, but a smaller proportion originates from viruses circulating much earlier in untreated infection. These observations suggest that discrete biological factors influence the entry and persistence of viruses into the persistent proviral pool, and there may be periods earlier in untreated infection with increased seeding. Therefore, we examined the timing of formation of the long-lived pool of infected cells that persists during ART in seven women (after a median of 5.1 years of suppressive ART) by comparing the phylogenetic distance between unique 3' half genome on-ART proviral sequences and longitudinally sampled pre-ART viral RNA sequences, focusing on the period >1 year prior to ART initiation (i.e., the \"early\" proviral pool). We constructed models of continuous entry into the persistent proviral pool prior to ART initiation and analyzed the fit of our experimentally derived data to these models. We found that the pattern of persistent proviral pool formation in five of seven participants is incongruent with a model of continuous entry, implying that persistent proviral pool formation can occur episodically during untreated infection. Notably, increased entry into the persistent proviral pool was not universally observed during acute infection, and the timing of enhanced early entry differed across the participants.IMPORTANCECells harboring HIV-1 proviruses that persist on antiretroviral therapy (ART) constitute the main barrier to an HIV-1 cure. Recent work has elucidated that the majority of persisting proviruses harbor HIV-1 variants circulating near the time of ART initiation, whether the proviruses are intact or defective, though a portion forms earlier in untreated infection. We examined the formation of the \"early-forming\" persistent proviral pool and found that in 5/7 participants, persistent proviral pool formation was episodic, rather than continuous, suggesting that there are host/biological factors that periodically enhance the formation of the persistent proviral pool. Further characterization of these factors will aid in the development of methods to abrogate their effect, thereby reducing the size of the persistent proviral pool.", + "year": "2025", + "author": "Council, Olivia D and Tyers, Lynn and Moeser, Matthew and Sondgeroth, Amy and Spielvogel, Ean and Richardson, Brian D and Doolabh, Deelan and Zhou, Shuntai and Emery, Ann and Archin, Nancie M and Shook-Sa, Bonnie and Margolis, David M and Abdool Karim, Salim S and Kosakovsky Pond, Sergei and Garrett, Nigel and Abrahams, Melissa-Rose and Joseph, Sarah B and Williamson, Carolyn and Swanstrom, Ronald", + "journal": "J Virol" + }, + { + "id": "Tyers:2025aa", + "title": "HIV-1 Rebound Virus Consists of a Small Number of Lineages That Entered the Reservoir Close to ART Initiation", + "abstract": "HIV-1 persists as a latent reservoir during suppressive antiretroviral therapy (ART). Viral rebound occurs upon ART interruption, posing a challenge to cure efforts. Characterizing viral populations fuelling rebound is imperative to curing HIV-1. We used longitudinal samples collected pretherapy from women in the CAPRISA 002 cohort to create an evolutionary timeline to determine the pretherapy timepoint when the rebound virus originally entered the long-lived reservoir. Participants (N=10) were untreated for an average of 5 years then on ART for an average of 2 years before viral rebound (defined as >1000 RNA copies/ml). env sequences were used to characterize the longitudinal pre-ART evolving viral RNA population, the proviral DNA reservoir during ART, and viral RNA in the plasma during rebound. For each participant, between 1 and 3 major viral lineages were identified in the plasma during rebound. A total of 20 rebound virus lineages were examined for the 10 participants, and 19 were found to have entered the reservoir around the time of therapy initiation. The one lineage estimated to enter the reservoir more than a year before therapy was observed in a participant who was untreated for more than 8 years, yet retained moderate CD4 T cell counts. Analysis of the viral DNA reservoir, from which the rebound viruses emanated, revealed that while 95% of rebounding lineages dated to the year before ART initiation, only 61% of unique proviruses dated to that time period. Strikingly, for three participants with DNA reservoirs dominated by viruses from earlier in untreated infection, only 33% of unique proviruses dated to the year before ART initiation, yet 83% of rebounding lineages dated to that time. Our results show that rebound virus almost exclusively comes from the portion of the latent reservoir that formed around the time of therapy initiation, even when the reservoir is composed of diverse sequences from across the pre-ART time period.", + "year": "2025", + "author": "Tyers, Lynn and Moeser, Matthew and Ntuli, Jean and Council, Olivia and Zhou, Shuntai and Spielvogel, Ean and Sondgeroth, Amy and Adams, Craig and Thebus, Ruwayhida and Yssel, Anna and Karim, Salim Abdool and Garrett, Nigel and Pond, Sergei Kosakovsky and Williamson, Carolyn and Swanstrom, Ronald and Abrahams, Melissa-Rose and Joseph, Sarah B", + "journal": "bioRxiv" + }, + { + "id": "Verdonk:2025aa", + "title": "A New Comparative Framework for Estimating Selection on Synonymous Substitutions", + "abstract": "Selection on synonymous codon usage is a well-known and widespread phenomenon, yet existing models often do not account for it or its effect on synonymous substitution rates. In this article, we develop and expand the capabilities of multiclass synonymous substitution (MSS) models, which account for such selection by partitioning synonymous substitutions into 2 or more classes and estimating a relative substitution rate for each class, while accounting for important confounders like mutation bias. We identify extensive heterogeneity among relative synonymous substitution rates in an empirical dataset of ∼12,000 gene alignments from 12 Drosophila species. We validate model performance using data simulated under a forward population genetic simulation, demonstrating that MSS models are robust to model misspecification. MSS rates are significantly correlated with other covariates of selection on codon usage (population-level polymorphism data and tRNA abundance data), suggesting that models can detect weak signatures of selection on codon usage. With the MSS model, we can now study selection on synonymous substitutions in diverse taxa, independent of any a priori assumptions about the forces driving that selection.", + "year": "2025", + "author": "Verdonk, Hannah and Pivirotto, Alyssa and Pavinato, Vitor and Hey, Jody and Pond, Sergei L K", + "journal": "Mol Biol Evol" + }, + { + "id": "France:2025aa", + "title": "Nationwide Implementation of HIV Molecular Cluster Detection by Centers for Disease Control and Prevention and State and Local Health Departments, United States", + "abstract": "Detecting and responding to clusters of rapid HIV transmission is a core HIV prevention strategy in the United States, guiding public health interventions and identifying gaps in prevention and care services. In 2016, the Centers for Disease Control and Prevention (CDC) initiated molecular cluster detection using data from 27 jurisdictions. During 2016-2023, CDC expanded sequence reporting nationwide and deployed Secure HIV-TRACE, an application supporting health department (HD) molecular cluster detection. CDC conducts molecular cluster detection quarterly; state and local HDs analyze local data monthly. HDs began routinely reporting clusters to CDC by using cluster report forms in 2020. During 2018-2023, CDC identified 404 molecular clusters of rapid HIV transmission; 325 (80%) involved multiple jurisdictions. During 2020-2023, HDs reported 298 molecular clusters to CDC; 249 were first detected by HDs. Expanding molecular cluster detection has provided a foundation for improving service delivery to networks experiencing rapid HIV transmission.", + "year": "2025", + "author": "France, Anne Marie and Hallmark, Camden J and Panneer, Nivedha and Billock, Rachael and Russell, Olivia O and Plaster, Mary and Alberti, Jessica and Nuthan, Fathima and Saduvala, Neeraja and Philpott, David and Ocfemia, M Cheryl Ba{\\~n}ez and Cope, Scott and Hernandez, Angela L and Pond, Sergei L Kosakovsky and Wertheim, Joel O and Weaver, Steven and Khader, Saja and Johnson, Kevin and Oster, Alexandra M", + "journal": "Emerg Infect Dis" + }, + { + "id": "Rincon-Sandoval:2024aa", + "title": "Ecological diversification of sea catfishes is accompanied by genome-wide signatures of positive selection", + "abstract": "Habitat transitions have shaped the evolutionary trajectory of many clades. Sea catfishes (Ariidae) have repeatedly undergone ecological transitions, including colonizing freshwaters from marine environments, leading to an adaptive radiation in Australia and New Guinea alongside non-radiating freshwater lineages elsewhere. Here, we generate and analyze one long-read reference genome and 66 short-read whole genome assemblies, in conjunction with genomic data for 54 additional species. We investigate how three major ecological transitions have shaped genomic variation among ariids over their ~ 50 million-year evolutionary history. Our results show that relatively younger freshwater lineages exhibit a higher incidence of positive selection than their more ancient marine counterparts. They also display a larger disparity in body shapes, a trend that correlates with a heightened occurrence of positive selection on genes associated with body size and elongation. Although positive selection in the Australia and New Guinea radiation does not stand out compared to non-radiating lineages overall, selection across the prolactin gene family during the marine-to-freshwater transition suggests that strong osmoregulatory adaptations may have facilitated their colonization and radiation. Our findings underscore the significant role of selection in shaping the genome and organismal traits in response to habitat shifts across macroevolutionary scales.", + "year": "2024", + "author": "Rincon-Sandoval, Melissa and De-Kayne, Rishi and Shank, Stephen D and Pirro, Stacy and Ko'ou, Alfred and Abueg, Linelle and Tracey, Alan and Mountcastle, Jackie and O'Toole, Brian and Balacco, Jennifer and Formenti, Giulio and Jarvis, Erich D and Arcila, Dahiana and Kosakovsky Pond, Sergei L and Davis, Aaron and Bloom, Devin D and Betancur-R, Ricardo", + "journal": "Nat Commun" + }, + { + "id": "Zarate:2024aa", + "title": "Phylogenomic Signatures of a Lineage of Vesicular Stomatitis Indiana Virus Circulating During the 2019-2020 Epidemic in the United States", + "abstract": "For the first time, we describe phylogenomic signatures of an epidemic lineage of vesicular stomatitis Indiana virus (VSIV). We applied multiple evolutionary analyses to a dataset of 87 full-length genome sequences representing the circulation of an epidemic VSIV lineage in the US between 2019 and 2020. Based on phylogenetic analyses, we predicted the ancestral relationship of this lineage with a specific group of isolates circulating in the endemic zone of Chiapas, Mexico. Subsequently, our findings indicate that the lineage diversified into at least four different subpopulations during its circulation in the US. We identified single nucleotide polymorphisms (SNPs) that differentiate viral subpopulations and assessed their potential relevance using comparative phylogenetic methods, highlighting the preponderance of synonymous mutations during the differentiation of these populations. Purifying selection was the main evolutionary force favoring the conservation of this epidemic phenotype, with P and G genes as the main drivers of the evolution of this lineage. Our analyses identified multiple codon sites under positive selection and the association of these sites with specific functional domains at P, M, G, and L proteins. Based on ancestral reconstruction analyses, we showed the potential relevance of some of the sites identified under positive selection to the adaptation of the epidemic lineage at the population level. Finally, using a representative group of viruses from Colorado, we established a positive correlation between genetic and geographical distances, suggesting that positive selection on specific codon positions might have favored the adaptation of different subpopulations to circulation in specific geographical settings. Collectively, our study reveals the complex dynamics that accompany the evolution of an epidemic lineage of VSIV in nature. Our analytical framework provides a model for conducting future evolutionary analyses. The ultimate goal is to support the implementation of an early warning system for vesicular stomatitis virus in the US, enabling early detection of epidemic precursors from Mexico.", + "year": "2024", + "author": "Zarate, Selene and Bertram, Miranda and Rodgers, Case and Reed, Kirsten and Pelzel-McCluskey, Angela and Gomez-Romero, Ninnet and Rodriguez, Luis L and Mayo, Christie and Mire, Chad and Pond, Sergei L Kosakovsky and Velazquez-Salinas, Lauro", + "journal": "Viruses" + }, + { + "id": "Lucaci:2024aa", + "title": "The evolution of mammalian Rem2: unraveling the impact of purifying selection and coevolution on protein function, and implications for human disorders", + "abstract": "Rad And Gem-Like GTP-Binding Protein 2 (Rem2), a member of the RGK family of Ras-like GTPases, is implicated in Huntington's disease and Long QT Syndrome and is highly expressed in the brain and endocrine cells. We examine the evolutionary history of Rem2 identified in various mammalian species, focusing on the role of purifying selection and coevolution in shaping its sequence and protein structural constraints. Our analysis of Rem2 sequences across 175 mammalian species found evidence for strong purifying selection in 70% of non-invariant codon sites which is characteristic of essential proteins that play critical roles in biological processes and is consistent with Rem2's role in the regulation of neuronal development and function. We inferred epistatic effects in 50 pairs of codon sites in Rem2, some of which are predicted to have deleterious effects on human health. Additionally, we reconstructed the ancestral evolutionary history of mammalian Rem2 using protein structure prediction of extinct and extant sequences which revealed the dynamics of how substitutions that change the gene sequence of Rem2 can impact protein structure in variable regions while maintaining core functional mechanisms. By understanding the selective pressures, protein- and gene - interactions that have shaped the sequence and structure of the Rem2 protein, we gain a stronger understanding of its biological and functional constraints.", + "year": "2024", + "author": "Lucaci, Alexander G and Brew, William E and Lamanna, Jason and Selberg, Avery and Carnevale, Vincenzo and Moore, Anna R and Kosakovsky Pond, Sergei L", + "journal": "Front Bioinform" + }, + { + "id": "Weaver:2024aa", + "title": "AUTO-TUNE: selecting the distance threshold for inferring HIV transmission clusters", + "abstract": "Molecular surveillance of viral pathogens and inference of transmission networks from genomic data play an increasingly important role in public health efforts, especially for HIV-1. For many methods, the genetic distance threshold used to connect sequences in the transmission network is a key parameter informing the properties of inferred networks. Using a distance threshold that is too high can result in a network with many spurious links, making it difficult to interpret. Conversely, a distance threshold that is too low can result in a network with too few links, which may not capture key insights into clusters of public health concern. Published research using the HIV-TRACE software package frequently uses the default threshold of 0.015 substitutions/site for HIV pol gene sequences, but in many cases, investigators heuristically select other threshold parameters to better capture the underlying dynamics of the epidemic they are studying. Here, we present a general heuristic scoring approach for tuning a distance threshold adaptively, which seeks to prevent the formation of giant clusters. We prioritize the ratio of the sizes of the largest and the second largest cluster, maximizing the number of clusters present in the network. We apply our scoring heuristic to outbreaks with different characteristics, such as regional or temporal variability, and demonstrate the utility of using the scoring mechanism's suggested distance threshold to identify clusters exhibiting risk factors that would have otherwise been more difficult to identify. For example, while we found that a 0.015 substitutions/site distance threshold is typical for US-like epidemics, recent outbreaks like the CRF07_BC subtype among men who have sex with men (MSM) in China have been found to have a lower optimal threshold of 0.005 to better capture the transition from injected drug use (IDU) to MSM as the primary risk factor. Alternatively, in communities surrounding Lake Victoria in Uganda, where there has been sustained heterosexual transmission for many years, we found that a larger distance threshold is necessary to capture a more risk factor-diverse population with sparse sampling over a longer period of time. Such identification may allow for more informed intervention action by respective public health officials.", + "year": "2024", + "author": "Weaver, Steven and D{\\'a}vila Conn, Vanessa M and Ji, Daniel and Verdonk, Hannah and {\\'A}vila-R{\\'\\i}os, Santiago and Leigh Brown, Andrew J and Wertheim, Joel O and Kosakovsky Pond, Sergei L", + "journal": "Front Bioinform" + }, + { + "id": "Zehr:2024aa", + "title": "Positive selection, genetic recombination, and intra-host evolution in novel equine coronavirus genomes and other members of the Embecovirus subgenus", + "abstract": "There are several examples of coronaviruses in the Betacoronavirus subgenus Embecovirus that have jumped from an animal to the human host. Studying how evolutionary factors shape coronaviruses in non-human hosts may provide insight into the coronavirus host-switching potential. Equids, such as horses and donkeys, are susceptible to equine coronaviruses (ECoVs). With increased testing prevalence, several ECoV genome sequences have become available for molecular evolutionary analyses, especially those from the United States of America (USA). To date, no analyses have been performed to characterize evolution within coding regions of the ECoV genome. Here, we obtain and describe four new ECoV genome sequences from infected equines from across the USA presenting clinical symptoms of ECoV, and infer ECoV-specific and Embecovirus-wide patterns of molecular evolution. Within two of the four data sets analyzed, we find evidence of intra-host evolution within the nucleocapsid (N) gene, suggestive of quasispecies development. We also identify 12 putative genetic recombination events within the ECoV genome, 11 of which fall in ORF1ab. Finally, we infer and compare sites subject to positive selection on the ancestral branch of each major Embecovirus member clade. Specifically, for the two currently identified human coronavirus (HCoV) embecoviruses that have spilled from animals to humans (HCoV-OC43 and HCoV-HKU1), we find that there are 42 and 2 such sites, respectively, perhaps reflective of the more complex ancestral evolutionary history of HCoV-OC43, which involves several different animal hosts.IMPORTANCEThe Betacoronavirus subgenus Embecovirus contains coronaviruses that not only pose a health threat to animals and humans, but also have jumped from animal to human host. Equids, such as horses and donkeys are susceptible to equine coronavirus (ECoV) infections. No studies have systematically examined evolutionary patterns within ECoV genomes. Our study addresses this gap and provides insight into intra-host ECoV evolution from infected horses. Further, we identify and report natural selection pattern differences between two embecoviruses that have jumped from animals to humans [human coronavirus OC43 and HKU1 (HCoV-OC43 and HCoV-HKU1, respectively)], and hypothesize that the differences observed may be due to the different animal host(s) that each virus circulated in prior to its jump into humans. Finally, we contribute four novel, high-quality ECoV genomes to the scientific community.", + "year": "2024", + "author": "Zehr, Jordan D and Kosakovsky Pond, Sergei L and Shank, Stephen D and McQueary, Holly and Grenier, Jennifer K and Whittaker, Gary R and Stanhope, Michael J and Goodman, Laura B", + "journal": "Microbiol Spectr" + }, + { + "id": "Inzaule:2023aa", + "title": "Recommendations on data sharing in HIV drug resistance research", + "abstract": " * Human immunodeficiency virus (HIV) drug resistance has implications for antiretroviral treatment strategies and for containing the HIV pandemic because the development of HIV drug resistance leads to the requirement for antiretroviral drugs that may be less effective, less well-tolerated, and more expensive than those used in first-line regimens.  * HIV drug resistance studies are designed to determine which HIV mutations are selected by antiretroviral drugs and, in turn, how these mutations affect antiretroviral drug susceptibility and response to future antiretroviral treatment regimens.  * Such studies collectively form a vital knowledge base essential for monitoring global HIV drug resistance trends, interpreting HIV genotypic tests, and updating HIV treatment guidelines.  * Although HIV drug resistance data are collected in many studies, such data are often not publicly shared, prompting the need to recommend best practices to encourage and standardize HIV drug resistance data sharing.  * In contrast to other viruses, sharing HIV sequences from phylogenetic studies of transmission dynamics requires additional precautions as HIV transmission is criminalized in many countries and regions.  * Our recommendations are designed to ensure that the data that contribute to HIV drug resistance knowledge will be available without undue hardship to those publishing HIV drug resistance studies and without risk to people living with HIV.", + "year": "2023", + "author": "Inzaule, Seth C and Siedner, Mark J and Little, Susan J and Avila-Rios, Santiago and Ayitewala, Alisen and Bosch, Ronald J and Calvez, Vincent and Ceccherini-Silberstein, Francesca and Charpentier, Charlotte and Descamps, Diane and Eshleman, Susan H and Fokam, Joseph and Frenkel, Lisa M and Gupta, Ravindra K and Ioannidis, John P A and Kaleebu, Pontiano and Kantor, Rami and Kassaye, Seble G and Pond, Sergei L Kosakovsky and Kouamou, Vinie and Kouyos, Roger D and Kuritzkes, Daniel R and Lessells, Richard and Marcelin, Anne-Genevieve and Mbuagbaw, Lawrence and Minalga, Brian and Ndembi, Nicaise and Neher, Richard A and Paredes, Roger and Pillay, Deenan and Raizes, Elliot G and Rhee, Soo-Yon and Richman, Douglas D and Ruxrungtham, Kiat and Sabeti, Pardis C and Schapiro, Jonathan M and Sirivichayakul, Sunee and Steegen, Kim and Sugiura, Wataru and van Zyl, Gert U and Vandamme, Anne-Mieke and Wensing, Annemarie M J and Wertheim, Joel O and Gunthard, Huldrych F and Jordan, Michael R and Shafer, Robert W", + "journal": "PLoS Med" + }, + { + "id": "Kosakovsky-Pond:2023aa", + "title": "Anti-COVID drug accelerates viral evolution", + "year": "2023", + "author": "Pond, Sergei L Kosakovsky and Martin, Darren", + "journal": "Nature" + }, + { + "id": "Elli:2023aa", + "title": "Molecular modeling and phylogenetic analyses highlight the role of amino acid 347 of the {N1} subtype neuraminidase in influenza virus host range and interspecies adaptation", + "abstract": "The N1 neuraminidases (NAs) of avian and pandemic human influenza viruses contain tyrosine and asparagine, respectively, at position 347 on the rim of the catalytic site; the biological significance of this difference is not clear. Here, we used molecular dynamics simulation to model the effects of amino acid 347 on N1 NA interactions with sialyllacto-N-tetraoses 6'SLN-LC and 3'SLN-LC, which represent NA substrates in humans and birds, respectively. Our analysis predicted that Y347 plays an important role in the NA preference for the avian-type substrates. The Y347N substitution facilitates hydrolysis of human-type substrates by resolving steric conflicts of the Neu5Ac2-6Gal moiety with the bulky side chain of Y347, decreasing the free energy of substrate binding, and increasing the solvation of the Neu5Ac2-6Gal bond. Y347 was conserved in all N1 NA sequences of avian influenza viruses in the GISAID EpiFlu database with two exceptions. First, the Y347F substitution was present in the NA of a specific H6N1 poultry virus lineage and was associated with the substitutions G228S and/or E190V/L in the receptor-binding site (RBS) of the hemagglutinin (HA). Second, the highly pathogenic avian H5N1 viruses of the Gs/Gd lineage contained sporadic variants with the NA substitutions Y347H/D, which were frequently associated with substitutions in the HA RBS. The Y347N substitution occurred following the introductions of avian precursors into humans and pigs with N/D347 conserved during virus circulation in these hosts. Comparative evolutionary analysis of site 347 revealed episodic positive selection across the entire tree and negative selection within most host-specific groups of viruses, suggesting that substitutions at NA position 347 occurred during host switches and remained under pervasive purifying selection thereafter. Our results elucidate the role of amino acid 347 in NA recognition of sialoglycan substrates and emphasize the significance of substitutions at position 347 as a marker of host range and adaptive evolution of influenza viruses.", + "year": "2023", + "author": "Elli, Stefano and Raffaini, Giuseppina and Guerrini, Marco and Pond, Sergei L Kosakovsky and Matrosovich, Mikhail", + "journal": "Front Microbiol" + }, + { + "id": "Maurer-Alcala:2024aa", + "title": "Somatic genome architecture and molecular evolution are decoupled in \"young\" linage-specific gene families in ciliates", + "abstract": "The evolution of lineage-specific gene families remains poorly studied across the eukaryotic tree of life, with most analyses focusing on the recent evolution of de novo genes in model species. Here we explore the origins of lineage-specific genes in ciliates, a ~1 billion year old clade of microeukaryotes that are defined by their division of somatic and germline functions into distinct nuclei. Previous analyses on conserved gene families have shown the effect of ciliates' unusual genome architecture on gene family evolution: extensive genome processing-the generation of thousands of gene-sized somatic chromosomes from canonical germline chromosomes-is associated with larger and more diverse gene families. To further study the relationship between ciliate genome architecture and gene family evolution, we analyzed lineage specific gene families from a set of 46 transcriptomes and 12 genomes representing x species from eight ciliate classes. We assess how the evolution lineage-specific gene families occurs among four groups of ciliates: extensive fragmenters with gene-size somatic chromosomes, non-extensive fragmenters with \"large'' multi-gene somatic chromosomes, Heterotrichea with highly polyploid somatic genomes and Karyorelictea with 'paradiploid' somatic genomes. Our analyses demonstrate that: 1) most lineage-specific gene families are found at shallow taxonomic scales; 2) extensive genome processing (i.e., gene unscrambling) during development likely influences the size and number of young lineage-specific gene families; and 3) the influence of somatic genome architecture on molecular evolution is increasingly apparent in older gene families. Altogether, these data highlight the influences of genome architecture on the evolution of lineage-specific gene families in eukaryotes.", + "year": "2024", + "author": "Maurer-Alcal{\\'a}, Xyrus X and Cote-L'Heureux, Auden and Pond, Sergei L Kosakovsky and Katz, Laura A", + "journal": "PLoS One" + }, + { + "id": "Joseph:2024aa", + "title": "The timing of HIV-1 infection of cells that persist on therapy is not strongly influenced by replication competency or cellular tropism of the provirus", + "abstract": "People with HIV-1 (PWH) on antiretroviral therapy (ART) can maintain undetectable virus levels, but a small pool of infected cells persists. This pool is largely comprised of defective proviruses that may produce HIV-1 proteins but are incapable of making infectious virus, with only a fraction (~10%) of these cells harboring intact viral genomes, some of which produce infectious virus following ex vivo stimulation (i.e. inducible intact proviruses). A majority of the inducible proviruses that persist on ART are formed near the time of therapy initiation. Here we compared proviral DNA (assessed here as 3' half genomes amplified from total cellular DNA) and inducible replication competent viruses in the pool of infected cells that persists during ART to determine if the original infection of these cells occurred at comparable times prior to therapy initiation. Overall, the average percent of proviruses that formed late (i.e. around the time of ART initiation, 60%) did not differ from the average percent of replication competent inducible viruses that formed late (69%), and this was also true for proviral DNA that was hypermutated (57%). Further, there was no evidence that entry into the long-lived infected cell pool was impeded by the ability to use the CXCR4 coreceptor, nor was the formation of long-lived infected cells enhanced during primary infection, when viral loads are exceptionally high. We observed that infection of cells that transitioned to be long-lived was enhanced among people with a lower nadir CD4+ T cell count. Together these data suggest that the timing of infection of cells that become long-lived is impacted more by biological processes associated with immunodeficiency before ART than the replication competency and/or cellular tropism of the infecting virus or the intactness of the provirus. Further research is needed to determine the mechanistic link between immunodeficiency and the timing of infected cells transitioning to the long-lived pool, particularly whether this is due to differences in infected cell clearance, turnover rates and/or homeostatic proliferation before and after ART.", + "year": "2024", + "author": "Joseph, Sarah B and Abrahams, Melissa-Rose and Moeser, Matthew and Tyers, Lynn and Archin, Nancie M and Council, Olivia D and Sondgeroth, Amy and Spielvogel, Ean and Emery, Ann and Zhou, Shuntai and Doolabh, Deelan and Ismail, Sherazaan D and Karim, Salim Abdool and Margolis, David M and Pond, Sergei Kosakovsky and Garrett, Nigel and Swanstrom, Ronald and Williamson, Carolyn", + "journal": "PLoS Pathog" + }, + { + "id": "Wirthlin:2024aa", + "title": "Vocal learning-associated convergent evolution in mammalian proteins and regulatory elements", + "abstract": "Vocal production learning (\"vocal learning\") is a convergently evolved trait in vertebrates. To identify brain genomic elements associated with mammalian vocal learning, we integrated genomic, anatomical, and neurophysiological data from the Egyptian fruit bat (Rousettus aegyptiacus) with analyses of the genomes of 215 placental mammals. First, we identified a set of proteins evolving more slowly in vocal learners. Then, we discovered a vocal motor cortical region in the Egyptian fruit bat, an emergent vocal learner, and leveraged that knowledge to identify active cis-regulatory elements in the motor cortex of vocal learners. Machine learning methods applied to motor cortex open chromatin revealed 50 enhancers robustly associated with vocal learning whose activity tended to be lower in vocal learners. Our research implicates convergent losses of motor cortex regulatory elements in mammalian vocal learning evolution.", + "year": "2024", + "author": "Wirthlin, Morgan E and Schmid, Tobias A and Elie, Julie E and Zhang, Xiaomeng and Kowalczyk, Amanda and Redlich, Ruby and Shvareva, Varvara A and Rakuljic, Ashley and Ji, Maria B and Bhat, Ninad S and Kaplow, Irene M and Sch{\\\"a}ffer, Daniel E and Lawler, Alyssa J and Wang, Andrew Z and Phan, BaDoi N and Annaldasula, Siddharth and Brown, Ashley R and Lu, Tianyu and Lim, Byung Kook and Azim, Eiman and {Zoonomia Consortium} and Clark, Nathan L and Meyer, Wynn K and Pond, Sergei L Kosakovsky and Chikina, Maria and Yartsev, Michael M and Pfenning, Andreas R and Andrews, Gregory and Armstrong, Joel C and Bianchi, Matteo and Birren, Bruce W and Bredemeyer, Kevin R and Breit, Ana M and Christmas, Matthew J and Clawson, Hiram and Damas, Joana and Di Palma, Federica and Diekhans, Mark and Dong, Michael X and Eizirik, Eduardo and Fan, Kaili and Fanter, Cornelia and Foley, Nicole M and Forsberg-Nilsson, Karin and Garcia, Carlos J and Gatesy, John and Gazal, Steven and Genereux, Diane P and Goodman, Linda and Grimshaw, Jenna and Halsey, Michaela K and Harris, Andrew J and Hickey, Glenn and Hiller, Michael and Hindle, Allyson G and Hubley, Robert M and Hughes, Graham M and Johnson, Jeremy and Juan, David and Kaplow, Irene M and Karlsson, Elinor K and Keough, Kathleen C and Kirilenko, Bogdan and Koepfli, Klaus-Peter and Korstian, Jennifer M and Kowalczyk, Amanda and Kozyrev, Sergey V and Lawler, Alyssa J and Lawless, Colleen and Lehmann, Thomas and Levesque, Danielle L and Lewin, Harris A and Li, Xue and Lind, Abigail and Lindblad-Toh, Kerstin and Mackay-Smith, Ava and Marinescu, Voichita D and Marques-Bonet, Tomas and Mason, Victor C and Meadows, Jennifer R S and Meyer, Wynn K and Moore, Jill E and Moreira, Lucas R and Moreno-Santillan, Diana D and Morrill, Kathleen M and Muntan{\\'e}, Gerard and Murphy, William J and Navarro, Arcadi and Nweeia, Martin and Ortmann, Sylvia and Osmanski, Austin and Paten, Benedict and Paulat, Nicole S and Pfenning, Andreas R and Phan, BaDoi N and Pollard, Katherine S and Pratt, Henry E and Ray, David A and Reilly, Steven K and Rosen, Jeb R and Ruf, Irina and Ryan, Louise and Ryder, Oliver A and Sabeti, Pardis C and Sch{\\\"a}ffer, Daniel E and Serres, Aitor and Shapiro, Beth and Smit, Arian F A and Springer, Mark and Srinivasan, Chaitanya and Steiner, Cynthia and Storer, Jessica M and Sullivan, Kevin A M and Sullivan, Patrick F and Sundstr{\\\"o}m, Elisabeth and Supple, Megan A and Swofford, Ross and Talbot, Joy-El and Teeling, Emma and Turner-Maier, Jason and Valenzuela, Alejandro and Wagner, Franziska and Wallerman, Ola and Wang, Chao and Wang, Juehan and Weng, Zhiping and Wilder, Aryn P and Wirthlin, Morgan E and Xue, James R and Zhang, Xiaomeng", + "journal": "Science" + }, + { + "id": "Langedijk:2024aa", + "title": "The genomic evolutionary dynamics and global circulation patterns of respiratory syncytial virus", + "abstract": "Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection in young children and the second leading cause of infant death worldwide. While global circulation has been extensively studied for respiratory viruses such as seasonal influenza, and more recently also in great detail for SARS-CoV-2, a lack of global multi-annual sampling of complete RSV genomes limits our understanding of RSV molecular epidemiology. Here, we capitalise on the genomic surveillance by the INFORM-RSV study and apply phylodynamic approaches to uncover how selection and neutral epidemiological processes shape RSV diversity. Using complete viral genome sequences, we show similar patterns of site-specific diversifying selection among RSVA and RSVB and recover the imprint of non-neutral epidemic processes on their genealogies. Using a phylogeographic approach, we provide evidence for air travel governing the global patterns of RSVA and RSVB spread, which results in a considerable degree of phylogenetic mixing across countries. Our findings highlight the potential of systematic global RSV genomic surveillance for transforming our understanding of global RSV spread.", + "year": "2024", + "author": "Langedijk, Annefleur C and Vrancken, Bram and Lebbink, Robert Jan and Wilkins, Deidre and Kelly, Elizabeth J and Baraldi, Eugenio and Mascare{\\~n}as de Los Santos, Abiel Homero and Danilenko, Daria M and Choi, Eun Hwa and Palomino, Mar{\\'\\i}a Ang{\\'e}lica and Chi, Hsin and Keller, Christian and Cohen, Robert and Papenburg, Jesse and Pernica, Jeffrey and Greenough, Anne and Richmond, Peter and Martin{\\'o}n-Torres, Federico and Heikkinen, Terho and Stein, Renato T and Hosoya, Mitsuaki and Nunes, Marta C and Verwey, Charl and Evers, Anouk and Kragten-Tabatabaie, Leyla and Suchard, Marc A and Pond, Sergei L Kosakovsky and Poletto, Chiara and Colizza, Vittoria and Lemey, Philippe and Bont, Louis J and {INFORM-RSV Study Group}", + "journal": "Nat Commun" + }, + { + "id": "Amendola:2022aa", + "title": "Molecular evidence for SARS-CoV-2 in samples collected from patients with morbilliform eruptions since late 2019 in Lombardy, northern Italy", + "abstract": "As a reference laboratory for measles and rubella surveillance in Lombardy, we evaluated the association between SARS-CoV-2 infection and measles-like syndromes, providing preliminary evidence for undetected early circulation of SARS-CoV-2. Overall, 435 samples from 156 cases were investigated. RNA from oropharyngeal swabs (N = 148) and urine (N = 141) was screened with four hemi-nested PCRs and molecular evidence for SARS-CoV-2 infection was found in 13 subjects. Two of the positive patients were from the pandemic period (2/12, 16.7%, March 2020-March 2021) and 11 were from the pre-pandemic period (11/44, 25%, August 2019-February 2020). Sera (N = 146) were tested for anti-SARS-CoV-2 IgG, IgM, and IgA antibodies. Five of the RNA-positive individuals also had detectable anti-SARS-CoV-2 antibodies. No strong evidence of infection was found in samples collected between August 2018 and July 2019 from 100 patients. The earliest sample with evidence of SARS-CoV-2 RNA was from September 12, 2019, and the positive patient was also positive for anti-SARS-CoV-2 antibodies (IgG and IgM). Mutations typical of B.1 strains previously reported to have emerged in January 2020 (C3037T, C14408T, and A23403G), were identified in samples collected as early as October 2019 in Lombardy. One of these mutations (C14408T) was also identified among sequences downloaded from public databases that were obtained by others from samples collected in Brazil in November 2019. We conclude that a SARS-CoV-2 progenitor capable of producing a measles-like syndrome may have emerged in late June-late July 2019 and that viruses with mutations characterizing B.1 strain may have been spreading globally before the first Wuhan outbreak. Our findings should be complemented by high-throughput sequencing to obtain additional sequence information. We highlight the importance of retrospective surveillance studies in understanding the early dynamics of COVID-19 spread and we encourage other groups to perform retrospective investigations to seek confirmatory proofs of early SARS-CoV-2 circulation.", + "year": "2022", + "author": "Amendola, Antonella and Canuti, Marta and Bianchi, Silvia and Kumar, Sudhir and Fappani, Clara and Gori, Maria and Colzani, Daniela and Kosakovsky Pond, Sergei L and Miura, Sayaka and Baggieri, Melissa and Marchi, Antonella and Borghi, Elisa and Zuccotti, Gianvincenzo and Raviglione, Mario C and Magurano, Fabio and Tanzi, Elisabetta", + "journal": "Environ Res" + }, + { + "id": "Lucaci:2022aa", + "title": "RASCL: Rapid Assessment of Selection in CLades through molecular sequence analysis", + "abstract": "An important unmet need revealed by the COVID-19 pandemic is the near-real-time identification of potentially fitness-altering mutations within rapidly growing SARS-CoV-2 lineages. Although powerful molecular sequence analysis methods are available to detect and characterize patterns of natural selection within modestly sized gene-sequence datasets, the computational complexity of these methods and their sensitivity to sequencing errors render them effectively inapplicable in large-scale genomic surveillance contexts. Motivated by the need to analyze new lineage evolution in near-real time using large numbers of genomes, we developed the Rapid Assessment of Selection within CLades (RASCL) pipeline. RASCL applies state of the art phylogenetic comparative methods to evaluate selective processes acting at individual codon sites and across whole genes. RASCL is scalable and produces automatically updated regular lineage-specific selection analysis reports: even for lineages that include tens or hundreds of thousands of sampled genome sequences. Key to this performance is (i) generation of automatically subsampled high quality datasets of gene/ORF sequences drawn from a selected \"query\" viral lineage; (ii) contextualization of these query sequences in codon alignments that include high-quality \"background\" sequences representative of global SARS-CoV-2 diversity; and (iii) the extensive parallelization of a suite of computationally intensive selection analysis tests. Within hours of being deployed to analyze a novel rapidly growing lineage of interest, RASCL will begin yielding JavaScript Object Notation (JSON)-formatted reports that can be either imported into third-party analysis software or explored in standard web-browsers using the premade RASCL interactive data visualization dashboard. By enabling the rapid detection of genome sites evolving under different selective regimes, RASCL is well-suited for near-real-time monitoring of the population-level selective processes that will likely underlie the emergence of future variants of concern in measurably evolving pathogens with extensive genomic surveillance.", + "year": "2022", + "author": "Lucaci, Alexander G and Zehr, Jordan D and Shank, Stephen D and Bouvier, Dave and Ostrovsky, Alexander and Mei, Han and Nekrutenko, Anton and Martin, Darren P and Kosakovsky Pond, Sergei L", + "journal": "PLoS One" + }, + { + "id": "Tzou:2022aa", + "title": "Sierra SARS-CoV-2 sequence and antiviral resistance analysis program", + "abstract": "Although most laboratories are capable of employing established protocols to perform full-genome SARS-CoV-2 sequencing, many are unable to assess sequence quality, select appropriate mutation-detection thresholds, or report on the potential clinical significance of mutations in the targets of antiviral therapy METHODS: We describe the technical aspects and benchmark the performance of Sierra SARS-CoV-2, a program designed to perform these functions on user-submitted FASTQ and FASTA sequence files and lists of Spike mutations. Sierra SARS-CoV-2 indicates which sequences contain an unexpectedly large number of unusual mutations and which mutations are associated with reduced susceptibility to clinical stage mAbs, the RdRP inhibitor remdesivir, or the Mpro inhibitor nirmatrelvir RESULTS: To assess the performance of Sierra SARS-CoV-2 on FASTQ files, we applied it to 600 representative FASTQ sequences and compared the results to the COVID-19 EDGE program. To assess its performance on FASTA files, we applied it to nearly one million representative FASTA sequences and compared the results to the GISAID mutation annotation. To assess its performance on mutations lists, we applied it to 13,578 distinct Spike RBD mutation patterns and showed that exactly or partially matching annotations were available for 88% of patterns CONCLUSION: Sierra SARS-CoV-2 leverages previously published data to improve the quality control of submitted viral genomic data and to provide functional annotation on the impact of mutations in the targets of antiviral SARS-CoV-2 therapy. The program can be found at https://covdb.stanford.edu/sierra/sars2/ and its source code at https://github.com/hivdb/sierra-sars2.", + "year": "2022", + "author": "Tzou, Philip L and Tao, Kaiming and Sahoo, Malaya K and Kosakovsky Pond, Sergei L and Pinsky, Benjamin A and Shafer, Robert W", + "journal": "J Clin Virol" + }, + { + "id": "Zehr:2023aa", + "title": "Natural selection differences detected in key protein domains between non-pathogenic and pathogenic feline coronavirus phenotypes", + "abstract": "Feline coronaviruses (FCoVs) commonly cause mild enteric infections in felines worldwide (termed feline enteric coronavirus [FECV]), with around 12 per cent developing into deadly feline infectious peritonitis (FIP; feline infectious peritonitis virus [FIPV]). Genomic differences between FECV and FIPV have been reported, yet the putative genotypic basis of the highly pathogenic phenotype remains unclear. Here, we used state-of-the-art molecular evolutionary genetic statistical techniques to identify and compare differences in natural selection pressure between FECV and FIPV sequences, as well as to identify FIPV- and FECV-specific signals of positive selection. We analyzed full-length FCoV protein coding genes thought to contain mutations associated with FIPV (Spike, ORF3abc, and ORF7ab). We identified two sites exhibiting differences in natural selection pressure between FECV and FIPV: one within the S1/S2 furin cleavage site (FCS) and the other within the fusion domain of Spike. We also found fifteen sites subject to positive selection associated with FIPV within Spike, eleven of which have not previously been suggested as possibly relevant to FIP development. These sites fall within Spike protein subdomains that participate in host cell receptor interaction, immune evasion, tropism shifts, host cellular entry, and viral escape. There were fourteen sites (twelve novel sites) within Spike under positive selection associated with the FECV phenotype, almost exclusively within the S1/S2 FCS and adjacent to C domain, along with a signal of relaxed selection in FIPV relative to FECV, suggesting that furin cleavage functionality may not be needed for FIPV. Positive selection inferred in ORF7b was associated with the FECV phenotype and included twenty-four positively selected sites, while ORF7b had signals of relaxed selection in FIPV. We found evidence of positive selection in ORF3c in FCoV-wide analyses, but no specific association with the FIPV or FECV phenotype. We hypothesize that some combination of mutations in FECV may contribute to FIP development, and that it is unlikely to be one singular 'switch' mutational event. This work expands our understanding of the complexities of FIP development and provides insights into how evolutionary forces may alter pathogenesis in coronavirus genomes.", + "year": "2023", + "author": "Zehr, Jordan D and Kosakovsky Pond, Sergei L and Millet, Jean K and Olarte-Castillo, Ximena A and Lucaci, Alexander G and Shank, Stephen D and Ceres, Kristina M and Choi, Annette and Whittaker, Gary R and Goodman, Laura B and Stanhope, Michael J", + "journal": "Virus Evol" + }, + { + "id": "Tao:2023aa", + "title": "HIV-1 Group M Capsid Amino Acid Variability: Implications for Sequence Quality Control of Genotypic Resistance Testing", + "abstract": "BACKGROUND: With the approval of the HIV-1 capsid inhibitor, lenacapavir, capsid sequencing will be required for managing lenacapavir-experienced individuals with detectable viremia. Successful sequence interpretation will require examining new capsid sequences in the context of previously published sequence data.\nMETHODS: We analyzed published HIV-1 group M capsid sequences from 21,012 capsid-inhibitor na{\\\"\\i}ve individuals to characterize amino acid variability at each position and influence of subtype and cytotoxic T lymphocyte (CTL) selection pressure. We determined the distributions of usual mutations, defined as amino acid differences from the group M consensus, with a prevalence ≥ 0.1%. Co-evolving mutations were identified using a phylogenetically-informed Bayesian graphical model method.\nRESULTS: 162 (70.1%) positions had no usual mutations (45.9%) or only conservative usual mutations with a positive BLOSUM62 score (24.2%). Variability correlated independently with subtype-specific amino acid occurrence (Spearman rho = 0.83; p < 1 × 10-9) and the number of times positions were reported to contain an HLA-associated polymorphism, an indicator of CTL pressure (rho = 0.43; p = 0.0002).\nCONCLUSIONS: Knowing the distribution of usual capsid mutations is essential for sequence quality control. Comparing capsid sequences from lenacapavir-treated and lenacapavir-na{\\\"\\i}ve individuals will enable the identification of additional mutations potentially associated with lenacapavir therapy.", + "year": "2023", + "author": "Tao, Kaiming and Rhee, Soo-Yon and Tzou, Philip L and Osman, Zachary A and Pond, Sergei L Kosakovsky and Holmes, Susan P and Shafer, Robert W", + "journal": "Viruses" + }, + { + "id": "Escalera-Zamudio:2023aa", + "title": "Identification of Evolutionary Trajectories Shared across Human Betacoronaviruses", + "abstract": "Comparing the evolution of distantly related viruses can provide insights into common adaptive processes related to shared ecological niches. Phylogenetic approaches, coupled with other molecular evolution tools, can help identify mutations informative on adaptation, although the structural contextualization of these to functional sites of proteins may help gain insight into their biological properties. Two zoonotic betacoronaviruses capable of sustained human-to-human transmission have caused pandemics in recent times (SARS-CoV-1 and SARS-CoV-2), although a third virus (MERS-CoV) is responsible for sporadic outbreaks linked to animal infections. Moreover, two other betacoronaviruses have circulated endemically in humans for decades (HKU1 and OC43). To search for evidence of adaptive convergence between established and emerging betacoronaviruses capable of sustained human-to-human transmission (HKU1, OC43, SARS-CoV-1, and SARS-CoV-2), we developed a methodological pipeline to classify shared nonsynonymous mutations as putatively denoting homoplasy (repeated mutations that do not share direct common ancestry) or stepwise evolution (sequential mutations leading towards a novel genotype). In parallel, we look for evidence of positive selection and draw upon protein structure data to identify potential biological implications. We find 30 candidate mutations, from which 4 (codon sites 18121 [nsp14/residue 28], 21623 [spike/21], 21635 [spike/25], and 23948 [spike/796]; SARS-CoV-2 genome numbering) further display evolution under positive selection and proximity to functional protein regions. Our findings shed light on potential mechanisms underlying betacoronavirus adaptation to the human host and pinpoint common mutational pathways that may occur during establishment of human endemicity.", + "year": "2023", + "author": "Escalera-Zamudio, Marina and Kosakovsky Pond, Sergei L and Mart{\\'\\i}nez de la Vi{\\~n}a, Natalia and Guti{\\'e}rrez, Bernardo and Inward, Rhys P D and Th{\\'e}z{\\'e}, Julien and van Dorp, Lucy and Castel{\\'a}n-S{\\'a}nchez, Hugo G and Bowden, Thomas A and Pybus, Oliver G and Hulswit, Ruben J G", + "journal": "Genome Biol Evol" + }, + { + "id": "Joyce:2023aa", + "title": "Antigen pressure from two founder viruses induces multiple insertions at a single antibody position to generate broadly neutralizing HIV antibodies", + "abstract": "Vaccination strategies aimed at maturing broadly neutralizing antibodies (bnAbs) from na{\\\"\\i}ve precursors are hindered by unusual features that characterize these Abs, including insertions and deletions (indels). Longitudinal studies of natural HIV infection cases shed light on the complex processes underlying bnAb development and have suggested a role for superinfection as a potential enhancer of neutralization breadth. Here we describe the development of a potent bnAb lineage that was elicited by two founder viruses to inform vaccine design. The V3-glycan targeting bnAb lineage (PC39-1) was isolated from subtype C-infected IAVI Protocol C elite neutralizer, donor PC39, and is defined by the presence of multiple independent insertions in CDRH1 that range from 1-11 amino acids in length. Memory B cell members of this lineage are predominantly atypical in phenotype yet also span the class-switched and antibody-secreting cell compartments. Development of neutralization breadth occurred concomitantly with extensive recombination between founder viruses before each virus separated into two distinct population \"arms\" that evolved independently to escape the PC39-1 lineage. Ab crystal structures show an extended CDRH1 that can help stabilize the CDRH3. Overall, these findings suggest that early exposure of the humoral system to multiple related Env molecules could promote the induction of bnAbs by focusing Ab responses to conserved epitopes.", + "year": "2023", + "author": "Joyce, Collin and Murrell, Sasha and Murrell, Ben and Omorodion, Oluwarotimi and Ver, Lorena S and Carrico, Nancy and Bastidas, Raiza and Nedellec, Rebecca and Bick, Michael and Woehl, Jordan and Zhao, Fangzhu and Burns, Alison and Barman, Shawn and Appel, Michael and Ramos, Alejandra and Wickramasinghe, Lalinda and Eren, Kemal and Vollbrecht, Thomas and Smith, Davey M and Kosakovsky Pond, Sergei L and McBride, Ryan and Worth, Charli and Batista, Facundo and Sok, Devin and {IAVI Protocol C Investigators \\& The IAVI African HIV Research Network} and Poignard, Pascal and Briney, Bryan and Wilson, Ian A and Landais, Elise and Burton, Dennis R", + "journal": "PLoS Pathog" + }, + { + "id": "Lucaci:2023aa", + "title": "Evolutionary Shortcuts via Multinucleotide Substitutions and Their Impact on Natural Selection Analyses", + "abstract": "Inference and interpretation of evolutionary processes, in particular of the types and targets of natural selection affecting coding sequences, are critically influenced by the assumptions built into statistical models and tests. If certain aspects of the substitution process (even when they are not of direct interest) are presumed absent or are modeled with too crude of a simplification, estimates of key model parameters can become biased, often systematically, and lead to poor statistical performance. Previous work established that failing to accommodate multinucleotide (or multihit, MH) substitutions strongly biases dN/dS-based inference towards false-positive inferences of diversifying episodic selection, as does failing to model variation in the rate of synonymous substitution (SRV) among sites. Here, we develop an integrated analytical framework and software tools to simultaneously incorporate these sources of evolutionary complexity into selection analyses. We found that both MH and SRV are ubiquitous in empirical alignments, and incorporating them has a strong effect on whether or not positive selection is detected (1.4-fold reduction) and on the distributions of inferred evolutionary rates. With simulation studies, we show that this effect is not attributable to reduced statistical power caused by using a more complex model. After a detailed examination of 21 benchmark alignments and a new high-resolution analysis showing which parts of the alignment provide support for positive selection, we show that MH substitutions occurring along shorter branches in the tree explain a significant fraction of discrepant results in selection detection. Our results add to the growing body of literature which examines decades-old modeling assumptions (including MH) and finds them to be problematic for comparative genomic data analysis. Because multinucleotide substitutions have a significant impact on natural selection detection even at the level of an entire gene, we recommend that selection analyses of this type consider their inclusion as a matter of routine. To facilitate this procedure, we developed, implemented, and benchmarked a simple and well-performing model testing selection detection framework able to screen an alignment for positive selection with two biologically important confounding processes: site-to-site synonymous rate variation, and multinucleotide instantaneous substitutions.", + "year": "2023", + "author": "Lucaci, Alexander G and Zehr, Jordan D and Enard, David and Thornton, Joseph W and Kosakovsky Pond, Sergei L", + "journal": "Mol Biol Evol" + }, + { + "id": "Lucaci:2022wo", + "title": "RASCL: Rapid Assessment Of SARS-CoV-2 Clades Through Molecular Sequence Analysis", + "abstract": "An important component of efforts to manage the ongoing COVID19 pandemic is the R apid A ssessment of how natural selection contributes to the emergence and proliferation of potentially dangerous S ARS-CoV-2 lineages and CL ades (RASCL). The RASCL pipeline enables continuous comparative phylogenetics-based selection analyses of rapidly growing clade-focused genome surveillance datasets, such as those produced following the initial detection of potentially dangerous variants. From such datasets RASCL automatically generates down-sampled codon alignments of individual genes/ORFs containing contextualizing background reference sequences, analyzes these with a battery of selection tests, and outputs results as both machine readable JSON files, and interactive notebook-based visualizations.\nAVAILABILITY: RASCL is available from a dedicated repository at https://github.com/veg/RASCL and as a Galaxy workflow https://usegalaxy.eu/u/hyphy/w/rascl . Existing clade/variant analysis results are available here: https://observablehq.com/@aglucaci/rascl .\nCONTACT: Dr. Sergei L Kosakovsky Pond ( spond@temple.edu ).\nSUPPLEMENTARY INFORMATION: N/A.", + "year": "2022", + "author": "Lucaci, Alexander G and Zehr, Jordan D and Shank, Stephen D and Bouvier, Dave and Mei, Han and Nekrutenko, Anton and Martin, Darren P and Pond, Sergei L Kosakovsky", + "journal": "bioRxiv" + }, + { + "id": "Wertheim:2022tz", + "title": "Detection of SARS-CoV-2 intra-host recombination during superinfection with Alpha and Epsilon variants in New York City", + "abstract": "Recombination is an evolutionary process by which many pathogens generate diversity and acquire novel functions. Although a common occurrence during coronavirus replication, detection of recombination is only feasible when genetically distinct viruses contemporaneously infect the same host. Here, we identify an instance of SARS-CoV-2 superinfection, whereby an individual was infected with two distinct viral variants: Alpha (B.1.1.7) and Epsilon (B.1.429). This superinfection was first noted when an Alpha genome sequence failed to exhibit the classic S gene target failure behavior used to track this variant. Full genome sequencing from four independent extracts reveals that Alpha variant alleles comprise around 75% of the genomes, whereas the Epsilon variant alleles comprise around 20% of the sample. Further investigation reveals the presence of numerous recombinant haplotypes spanning the genome, specifically in the spike, nucleocapsid, and ORF 8 coding regions. These findings support the potential for recombination to reshape SARS-CoV-2 genetic diversity.", + "year": "2022", + "author": "Wertheim, Joel O and Wang, Jade C and Leelawong, Mindy and Martin, Darren P and Havens, Jennifer L and Chowdhury, Moinuddin A and Pekar, Jonathan E and Amin, Helly and Arroyo, Anthony and Awandare, Gordon A and Chow, Hoi Yan and Gonzalez, Edimarlyn and Luoma, Elizabeth and Morang'a, Collins M and Nekrutenko, Anton and Shank, Stephen D and Silver, Stefan and Quashie, Peter K and Rakeman, Jennifer L and Ruiz, Victoria and Torian, Lucia V and Vasylyeva, Tetyana I and Pond, Sergei L Kosakovsky and Hughes, Scott", + "journal": "Nat Commun" + }, + { + "id": "Tegally:2022wf", + "title": "Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa", + "abstract": "Three lineages (BA.1, BA.2 and BA.3) of the SARS-CoV-2 Omicron variant of concern predominantly drove South Africa's fourth COVID-19 wave. We have now identified two new lineages, BA.4 and BA.5, responsible for a fifth wave of infections. The spike proteins of BA.4 and BA.5 are identical, and comparable to BA.2 except for the addition of 69-70del (present in the Alpha variant and the BA.1 lineage), L452R (present in the Delta variant), F486V and the wild type amino acid at Q493.The two lineages only differ outside of the spike region. The 69-70 deletion in spike allows these lineages to be identified by the proxy marker of S-gene target failure, on the background of variants not possessing this feature . BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50% of sequenced cases in South Africa by the first week of April 2022. Using a multinomial logistic regression model, we estimate growth advantages for BA.4 and BA.5 of 0.08 (95% CI: 0.08 - 0.09) and 0.10 (95% CI: 0.09 - 0.11) per day respectively over BA.2 in South Africa. The continued discovery of genetically diverse Omicron lineages points to the hypothesis that a discrete reservoir, such as human chronic infections and/or animal hosts, is potentially contributing to further evolution and dispersal of the virus.", + "year": "2022", + "author": "Tegally, Houriiyah and Moir, Monika and Everatt, Josie and Giovanetti, Marta and Scheepers, Cathrine and Wilkinson, Eduan and Subramoney, Kathleen and Makatini, Zinhle and Moyo, Sikhulile and Amoako, Daniel G and Baxter, Cheryl and Althaus, Christian L and Anyaneji, Ugochukwu J and Kekana, Dikeledi and Viana, Raquel and Giandhari, Jennifer and Lessells, Richard J and Maponga, Tongai and Maruapula, Dorcas and Choga, Wonderful and Matshaba, Mogomotsi and Mbulawa, Mpaphi B and Msomi, Nokukhanya and {NGS-SA consortium} and Naidoo, Yeshnee and Pillay, Sureshnee and Sanko, Tomasz Janusz and San, James E and Scott, Lesley and Singh, Lavanya and Magini, Nonkululeko A and Smith-Lawrence, Pamela and Stevens, Wendy and Dor, Graeme and Tshiabuila, Derek and Wolter, Nicole and Preiser, Wolfgang and Treurnicht, Florette K and Venter, Marietjie and Chiloane, Georginah and McIntyre, Caitlyn and O'Toole, Aine and Ruis, Christopher and Peacock, Thomas P and Roemer, Cornelius and Pond, Sergei L Kosakovsky and Williamson, Carolyn and Pybus, Oliver G and Bhiman, Jinal N and Glass, Allison and Martin, Darren P and Jackson, Ben and Rambaut, Andrew and Laguda-Akingba, Oluwakemi and Gaseitsiwe, Simani and von Gottberg, Anne and de Oliveira, Tulio", + "journal": "Nat Med" + }, + { + "id": "Lucaci:2022wa", + "title": "The evolution of BDNF is defined by strict purifying selection and prodomain spatial coevolution, but what does it mean for human brain disease?", + "abstract": "Brain-Derived Neurotrophic Factor (BDNF) is an essential mediator of brain assembly, development, and maturation. BDNF has been implicated in a variety of brain disorders such as neurodevelopmental disorders (e.g., autism spectrum disorder), neuropsychiatric disorders (e.g., anxiety, depression, PTSD, and schizophrenia), and various neurodegenerative disorders (e.g., Parkinson's, Alzheimer's, etc.). To better understand the role of BDNF in disease, we sought to define the evolution of BDNF within Mammalia. We conducted sequence alignment and phylogenetic reconstruction of BDNF across a diverse selection of >160 mammalian species spanning ~177 million years of evolution. The selective evolutionary change was examined via several independent computational models of codon evolution including FEL (pervasive diversifying selection), MEME (episodic selection), and BGM (structural coevolution of sites within a single molecule). We report strict purifying selection in the main functional domain of BDNF (NGF domain, essentially comprising the mature BDNF protein). Additionally, we discover six sites in our homologous alignment which are under episodic selection in early regulatory regions (i.e. the prodomain) and 23 pairs of coevolving sites that are distributed across the entirety of BDNF. Coevolving BDNF sites exhibited complex spatial relationships and geometric features including triangular relations, acyclic graph networks, double-linked sites, and triple-linked sites, although the most notable pattern to emerge was that changes in the mature region of BDNF tended to coevolve along with sites in the prodomain. Thus, we propose that the discovery of both local and distal sites of coevolution likely reflects 'evolutionary fine-tuning' of BDNF's underlying regulation and function in mammals. This tracks with the observation that BDNF's mature domain (which encodes mature BDNF protein) is largely conserved, while the prodomain (which is linked to regulation and its own unique functionality) exhibits more pervasive and diversifying evolutionary selection. That said, the fact that negative purifying selection also occurs in BDNF's prodomain also highlights that this region also contains critical sites of sensitivity which also partially explains its disease relevance (via Val66Met and other prodomain variants). Taken together, these computational evolutionary analyses provide important context as to the origins and sensitivity of genetic changes within BDNF that may help to deconvolute the role of BDNF polymorphisms in human brain disorders.", + "year": "2022", + "author": "Lucaci, Alexander G and Notaras, Michael J and Pond, Sergei L Kosakovsky and Colak, Dilek", + "journal": "Transl Psychiatry" + }, + { + "id": "Tao:2022wu", + "title": "Susceptibility of SARS-CoV-2 Omicron Variants to Therapeutic Monoclonal Antibodies: Systematic Review and Meta-analysis", + "abstract": "SARS-CoV-2 Omicron variants contain many mutations in its spike receptor-binding domain, the target of all authorized monoclonal antibodies (MAbs). Determining the extent to which Omicron variants reduced MAb susceptibility is critical to preventing and treating COVID-19. We systematically reviewed PubMed and three preprint servers, last updated 11 April 2022, for the in vitro activity of authorized MAbs against the Omicron variants. Fifty-one studies were eligible, including 50 containing Omicron BA.1 susceptibility data and 17 containing Omicron BA.2 susceptibility data. The first two authorized MAb combinations, bamlanivimab/etesevimab and casirivimab/imdevimab, were largely inactive against the Omicron BA.1 and BA.2 variants. In 34 studies, sotrovimab displayed a median 4.0-fold (interquartile range [IQR]: 2.6 to 6.9) reduction in activity against Omicron BA.1, and in 12 studies, it displayed a median 17-fold (IQR: 13 to 30) reduction in activity against Omicron BA.2. In 15 studies, the combination cilgavimab/tixagevimab displayed a median 86-fold (IQR: 27 to 151) reduction in activity against Omicron BA.1, and in six studies, it displayed a median 5.4-fold (IQR: 3.7 to 6.9) reduction in activity against Omicron BA.2. In eight studies against Omicron BA.1 and six studies against Omicron BA.2, bebtelovimab displayed no reduction in activity. Disparate results between assays were common. For authorized MAbs, 51/268 (19.0%) results for wild-type control variants and 78/348 (22.4%) results for Omicron BA.1 and BA.2 variants were more than 4-fold below or 4-fold above the median result for that MAb. Highly disparate results between published assays indicate a need for improved MAb susceptibility test standardization or interassay calibration. IMPORTANCE Monoclonal antibodies (MAbs) targeting the SARS-CoV-2 spike protein are among the most effective measures for preventing and treating COVID-19. However, SARS-CoV-2 Omicron variants contain many mutations in their spike receptor-binding domains, the target of all authorized MAbs. Therefore, determining the extent to which Omicron variants reduced MAb susceptibility is critical to preventing and treating COVID-19. We identified 51 studies that reported the in vitro susceptibility of the two main Omicron variants BA.1 and BA.2 to therapeutic MAbs in advanced clinical development, including eight authorized individual MAbs and three authorized MAb combinations. We estimated the degree to which different MAbs displayed reduced activity against Omicron variants. The marked loss of activity of many MAbs against Omicron variants underscores the importance of developing MAbs that target conserved regions of spike. Highly disparate results between assays indicate the need for improved MAb susceptibility test standardization.", + "year": "2022", + "author": "Tao, Kaiming and Tzou, Philip L and Pond, Sergei L Kosakovsky and Ioannidis, John P A and Shafer, Robert W", + "journal": "Microbiol Spectr" + }, + { + "id": "Benndorf:2022wd", + "title": "Human HspB1, HspB3, HspB5 and HspB8: Shaping these disease factors during vertebrate evolution", + "abstract": "Small heat shock proteins (sHSPs) emerged early in evolution and occur in all domains of life and nearly in all species, including humans. Mutations in four sHSPs (HspB1, HspB3, HspB5, HspB8) are associated with neuromuscular disorders. The aim of this study is to investigate the evolutionary forces shaping these sHSPs during vertebrate evolution. We performed comparative evolutionary analyses on a set of orthologous sHSP sequences, based on the ratio of non-synonymous: synonymous substitution rates for each codon. We found that these sHSPs had been historically exposed to different degrees of purifying selection, decreasing in this order: HspB8 > HspB1, HspB5 > HspB3. Within each sHSP, regions with different degrees of purifying selection can be discerned, resulting in characteristic selective pressure profiles. The conserved α-crystallin domains were exposed to the most stringent purifying selection compared to the flanking regions, supporting a 'dimorphic pattern' of evolution. Thus, during vertebrate evolution the different sequence partitions were exposed to different and measurable degrees of selective pressures. Among the disease-associated mutations, most are missense mutations primarily in HspB1 and to a lesser extent in the other sHSPs. Our data provide an explanation for this disparate incidence. Contrary to the expectation, most missense mutations cause dominant disease phenotypes. Theoretical considerations support a connection between the historic exposure of these sHSP genes to a high degree of purifying selection and the unusual prevalence of genetic dominance of the associated disease phenotypes. Our study puts the genetics of inheritable sHSP-borne diseases into the context of vertebrate evolution.", + "year": "2022", + "author": "Benndorf, Rainer and Velazquez, Ryan and Zehr, Jordan D and Pond, Sergei L Kosakovsky and Martin, Jody L and Lucaci, Alexander G", + "journal": "Cell Stress Chaperones" + }, + { + "id": "Zehr:2022tj", + "title": "Recent Zoonotic Spillover and Tropism Shift of a Canine Coronavirus Is Associated with Relaxed Selection and Putative Loss of Function in NTD Subdomain of Spike Protein", + "abstract": "A canine coronavirus (CCoV) has now been reported from two independent human samples from Malaysia (respiratory, collected in 2017-2018; CCoV-HuPn-2018) and Haiti (urine, collected in 2017); these two viruses were nearly genetically identical. In an effort to identify any novel adaptations associated with this apparent shift in tropism we carried out detailed evolutionary analyses of the spike gene of this virus in the context of related Alphacoronavirus 1 species. The spike 0-domain retains homology to CCoV2b (enteric infections) and Transmissible Gastroenteritis Virus (TGEV; enteric and respiratory). This domain is subject to relaxed selection pressure and an increased rate of molecular evolution. It contains unique amino acid substitutions, including within a region important for sialic acid binding and pathogenesis in TGEV. Overall, the spike gene is extensively recombinant, with a feline coronavirus type II strain serving a prominent role in the recombinant history of the virus. Molecular divergence time for a segment of the gene where temporal signal could be determined, was estimated at around 60 years ago. We hypothesize that the virus had an enteric origin, but that it may be losing that particular tropism, possibly because of mutations in the sialic acid binding region of the spike 0-domain.", + "year": "2022", + "author": "Zehr, Jordan D and Pond, Sergei L Kosakovsky and Martin, Darren P and Ceres, Kristina and Whittaker, Gary R and Millet, Jean K and Goodman, Laura B and Stanhope, Michael J", + "journal": "Viruses" + }, + { + "id": "Caraballo-Ortiz:2022aa", + "title": "TopHap: rapid inference of key phylogenetic structures from common haplotypes in large genome collections with limited diversity", + "abstract": "MOTIVATION: Building reliable phylogenies from very large collections of sequences with a limited number of phylogenetically informative sites is challenging because sequencing errors and recurrent/backward mutations interfere with the phylogenetic signal, confounding true evolutionary relationships. Massive global efforts of sequencing genomes and reconstructing the phylogeny of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains exemplify these difficulties since there are only hundreds of phylogenetically informative sites but millions of genomes. For such datasets, we set out to develop a method for building the phylogenetic tree of genomic haplotypes consisting of positions harboring common variants to improve the signal-to-noise ratio for more accurate and fast phylogenetic inference of resolvable phylogenetic features.\nRESULTS: We present the TopHap approach that determines spatiotemporally common haplotypes of common variants and builds their phylogeny at a fraction of the computational time of traditional methods. We develop a bootstrap strategy that resamples genomes spatiotemporally to assess topological robustness. The application of TopHap to build a phylogeny of 68 057 SARS-CoV-2 genomes (68KG) from the first year of the pandemic produced an evolutionary tree of major SARS-CoV-2 haplotypes. This phylogeny is concordant with the mutation tree inferred using the co-occurrence pattern of mutations and recovers key phylogenetic relationships from more traditional analyses. We also evaluated alternative roots of the SARS-CoV-2 phylogeny and found that the earliest sampled genomes in 2019 likely evolved by four mutations of the most recent common ancestor of all SARS-CoV-2 genomes. An application of TopHap to more than 1 million SARS-CoV-2 genomes reconstructed the most comprehensive evolutionary relationships of major variants, which confirmed the 68KG phylogeny and provided evolutionary origins of major and recent variants of concern.\nAVAILABILITY AND IMPLEMENTATION: TopHap is available at https://github.com/SayakaMiura/TopHap.\nSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", + "year": "2022", + "author": "Caraballo-Ortiz, Marcos A and Miura, Sayaka and Sanderford, Maxwell and Dolker, Tenzin and Tao, Qiqing and Weaver, Steven and Pond, Sergei L K and Kumar, Sudhir", + "journal": "Bioinformatics" + }, + { + "id": "Martin:2022ui", + "title": "Selection Analysis Identifies Clusters of Unusual Mutational Changes in Omicron Lineage BA.1 That Likely Impact Spike Function", + "abstract": "Among the 30 nonsynonymous nucleotide substitutions in the Omicron S-gene are 13 that have only rarely been seen in other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of the S-gene at sites that will likely impact (1) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (2) interactions of Spike with ACE2 receptors, and (3) the priming of Spike for membrane fusion. We show here that, based on both the rarity of these 13 mutations in intrapatient sequencing reads and patterns of selection at the codon sites where the mutations occur in SARS-CoV-2 and related sarbecoviruses, prior to the emergence of Omicron the mutations would have been predicted to decrease the fitness of any virus within which they occurred. We further propose that the mutations in each of the three clusters therefore cooperatively interact to both mitigate their individual fitness costs, and, in combination with other mutations, adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron overall previously known SARS-CoV-2 lineages, it is crucial to determine both how such complex and highly adaptive mutation constellations were assembled within the Omicron S-gene, and why, despite unprecedented global genomic surveillance efforts, the early stages of this assembly process went completely undetected.", + "year": "2022", + "author": "Martin, Darren P and Lytras, Spyros and Lucaci, Alexander G and Maier, Wolfgang and Gr{\\\"u}ning, Bj{\\\"o}rn and Shank, Stephen D and Weaver, Steven and MacLean, Oscar A and Orton, Richard J and Lemey, Philippe and Boni, Maciej F and Tegally, Houriiyah and Harkins, Gordon W and Scheepers, Cathrine and Bhiman, Jinal N and Everatt, Josie and Amoako, Daniel G and San, James Emmanuel and Giandhari, Jennifer and Sigal, Alex and {NGS-SA} and Williamson, Carolyn and Hsiao, Nei-Yuan and von Gottberg, Anne and De Klerk, Arne and Shafer, Robert W and Robertson, David L and Wilkinson, Robert J and Sewell, B Trevor and Lessells, Richard and Nekrutenko, Anton and Greaney, Allison J and Starr, Tyler N and Bloom, Jesse D and Murrell, Ben and Wilkinson, Eduan and Gupta, Ravindra K and de Oliveira, Tulio and Pond, Sergei L Kosakovsky", + "journal": "Mol Biol Evol" + }, + { + "id": "Canuti:2022wv", + "title": "Waiting for the truth: is reluctance in accepting an early origin hypothesis for SARS-CoV-2 delaying our understanding of viral emergence?", + "abstract": "Two years after the start of the COVID-19 pandemic, key questions about the emergence of its aetiological agent (SARS-CoV-2) remain a matter of considerable debate. Identifying when SARS-CoV-2 began spreading among people is one of those questions. Although the current canonically accepted timeline hypothesises viral emergence in Wuhan, China, in November or December 2019, a growing body of diverse studies provides evidence that the virus may have been spreading worldwide weeks, or even months, prior to that time. However, the hypothesis of earlier SARS-CoV-2 circulation is often dismissed with prejudicial scepticism and experimental studies pointing to early origins are frequently and speculatively attributed to false-positive tests. In this paper, we critically review current evidence that SARS-CoV-2 had been circulating prior to December of 2019, and emphasise how, despite some scientific limitations, this hypothesis should no longer be ignored and considered sufficient to warrant further larger-scale studies to determine its veracity.", + "year": "2022", + "author": "Canuti, Marta and Bianchi, Silvia and Kolbl, Otto and Pond, Sergei L Kosakovsky and Kumar, Sudhir and Gori, Maria and Fappani, Clara and Colzani, Daniela and Borghi, Elisa and Zuccotti, Gianvincenzo and Raviglione, Mario C and Tanzi, Elisabetta and Amendola, Antonella", + "journal": "BMJ Glob Health" + }, + { + "id": "Tzou:2022wj", + "title": "Coronavirus Resistance Database (CoV-RDB): SARS-CoV-2 susceptibility to monoclonal antibodies, convalescent plasma, and plasma from vaccinated persons", + "abstract": "As novel SARS-CoV-2 variants with different patterns of spike protein mutations have emerged, the susceptibility of these variants to neutralization by antibodies has been rapidly assessed. However, neutralization data are generated using different approaches and are scattered across different publications making it difficult for these data to be located and synthesized. The Stanford Coronavirus Resistance Database (CoV-RDB; https://covdb.stanford.edu) is designed to house comprehensively curated published data on the neutralizing susceptibility of SARS-CoV-2 variants and spike mutations to monoclonal antibodies (mAbs), convalescent plasma (CP), and vaccinee plasma (VP). As of December 31, 2021, CoV-RDB encompassed 257 publications including 91 (35%) containing 9,070 neutralizing mAb susceptibility results, 131 (51%) containing 16,773 neutralizing CP susceptibility results, and 178 (69%) containing 33,540 neutralizing VP results. The database also records which spike mutations are selected during in vitro passage of SARS-CoV-2 in the presence of mAbs and which emerge in persons receiving mAbs as treatment. The CoV-RDB interface interactively displays neutralizing susceptibility data at different levels of granularity by filtering and/or aggregating query results according to one or more experimental conditions. The CoV-RDB website provides a companion sequence analysis program that outputs information about mutations present in a submitted sequence and that also assists users in determining the appropriate mutation-detection thresholds for identifying non-consensus amino acids. The most recent data underlying the CoV-RDB can be downloaded in its entirety from a GitHub repository in a documented machine-readable format.", + "year": "2022", + "author": "Tzou, Philip L and Tao, Kaiming and Pond, Sergei L Kosakovsky and Shafer, Robert W", + "journal": "PLoS One" + }, + { + "id": "Lytras:2022tz", + "title": "Exploring the Natural Origins of SARS-CoV-2 in the Light of Recombination", + "abstract": "The lack of an identifiable intermediate host species for the proximal animal ancestor of SARS-CoV-2, and the large geographical distance between Wuhan and where the closest evolutionary related coronaviruses circulating in horseshoe bats (members of the Sarbecovirus subgenus) have been identified, is fueling speculation on the natural origins of SARS-CoV-2. We performed a comprehensive phylogenetic study on SARS-CoV-2 and all the related bat and pangolin sarbecoviruses sampled so far. Determining the likely recombination events reveals a highly reticulate evolutionary history within this group of coronaviruses. Distribution of the inferred recombination events is nonrandom with evidence that Spike, the main target for humoral immunity, is beside a recombination hotspot likely driving antigenic shift events in the ancestry of bat sarbecoviruses. Coupled with the geographic ranges of their hosts and the sampling locations, across southern China, and into Southeast Asia, we confirm that horseshoe bats, Rhinolophus, are the likely reservoir species for the SARS-CoV-2 progenitor. By tracing the recombinant sequence patterns, we conclude that there has been relatively recent geographic movement and cocirculation of these viruses' ancestors, extending across their bat host ranges in China and Southeast Asia over the last 100 years. We confirm that a direct proximal ancestor to SARS-CoV-2 has not yet been sampled, since the closest known relatives collected in Yunnan shared a common ancestor with SARS-CoV-2 approximately 40 years ago. Our analysis highlights the need for dramatically more wildlife sampling to: 1) pinpoint the exact origins of SARS-CoV-2's animal progenitor, 2) the intermediate species that facilitated transmission from bats to humans (if there is one), and 3) survey the extent of the diversity in the related sarbecoviruses' phylogeny that present high risk for future spillovers.", + "year": "2022", + "author": "Lytras, Spyros and Hughes, Joseph and Martin, Darren and Swanepoel, Phillip and de Klerk, Arn{\\'e} and Lourens, Rentia and Pond, Sergei L Kosakovsky and Xia, Wei and Jiang, Xiaowei and Robertson, David L", + "journal": "Genome Biol Evol" + }, + { + "id": "VIR", + "title": "Predicting the mutational drivers of future SARS-CoV-2 variants of concern", + "abstract": "[Figure: see text].", + "year": "2022", + "author": "Maher, M Cyrus and Bartha, Istvan and Weaver, Steven and di Iulio, Julia and Ferri, Elena and Soriaga, Leah and Lempp, Florian A and Hie, Brian L and Bryson, Bryan and Berger, Bonnie and Robertson, David L and Snell, Gyorgy and Corti, Davide and Virgin, Herbert W and Pond, Sergei L Kosakovsky and Telenti, Amalio", + "journal": "Sci Transl Med" + }, + { + "id": "matrosovichH3N2", + "title": "Characterization of changes in the hemagglutinin that accompanied the emergence of H3N2/1968 pandemic influenza viruses", + "abstract": "The hemagglutinin (HA) of A/H3N2 pandemic influenza viruses (IAVs) of 1968 differed from its inferred avian precursor by eight amino acid substitutions. To determine their phenotypic effects, we studied recombinant variants of A/Hong Kong/1/1968 virus containing either human-type or avian-type amino acids in the corresponding positions of HA. The precursor HA displayed receptor binding profile and high conformational stability typical for duck IAVs. Substitutions Q226L and G228S, in addition to their known effects on receptor specificity and replication, marginally decreased HA stability. Substitutions R62I, D63N, D81N and N193S reduced HA binding avidity. Substitutions R62I, D81N and A144G promoted viral replication in human airway epithelial cultures. Analysis of HA sequences revealed that substitutions D63N and D81N accompanied by the addition of N-glycans represent common markers of avian H3 HA adaptation to mammals. Our results advance understanding of genotypic and phenotypic changes in IAV HA required for avian-to-human adaptation and pandemic emergence.", + "year": "2021", + "author": "West, Johanna and R{\\\"o}der, Juliane and Matrosovich, Tatyana and Beicht, Jana and Baumann, Jan and Mounogou Kouassi, Nancy and Doedt, Jennifer and Bovin, Nicolai and Zamperin, Gianpiero and Gastaldelli, Michele and Salviato, Annalisa and Bonfante, Francesco and Kosakovsky Pond, Sergei and Herfst, Sander and Fouchier, Ron and Wilhelm, Jochen and Klenk, Hans-Dieter and Matrosovich, Mikhail", + "journal": "PLoS Pathog" + }, + { + "id": "GalaxyCOVID", + "title": "Ready-to-use public infrastructure for global SARS-CoV-2 monitoring", + "year": "2021", + "author": "Maier, Wolfgang and Bray, Simon and van den Beek, Marius and Bouvier, Dave and Coraor, Nathan and Miladi, Milad and Singh, Babita and De Argila, Jordi Rambla and Baker, Dannon and Roach, Nathan and Gladman, Simon and Coppens, Frederik and Martin, Darren P and Lonie, Andrew and Gr{\\\"u}ning, Bj{\\\"o}rn and Pond, Sergei L Kosakovsky and Nekrutenko, Anton", + "journal": "Nat Biotechnol" + }, + { + "id": "N501Y", + "title": "The emergence and ongoing convergent evolution of the SARS-CoV-2 N501Y lineages", + "abstract": "The independent emergence late in 2020 of the B.1.1.7, B.1.351, and P.1 lineages of SARS-CoV-2 prompted renewed concerns about the evolutionary capacity of this virus to overcome public health interventions and rising population immunity. Here, by examining patterns of synonymous and non-synonymous mutations that have accumulated in SARS-CoV-2 genomes since the pandemic began, we find that the emergence of these three \"501Y lineages\" coincided with a major global shift in the selective forces acting on various SARS-CoV-2 genes. Following their emergence, the adaptive evolution of 501Y lineage viruses has involved repeated selectively favored convergent mutations at 35 genome sites, mutations we refer to as the 501Y meta-signature. The ongoing convergence of viruses in many other lineages on this meta-signature suggests that it includes multiple mutation combinations capable of promoting the persistence of diverse SARS-CoV-2 lineages in the face of mounting host immune recognition.", + "year": "2021", + "author": "Martin, Darren P and Weaver, Steven and Tegally, Houriiyah and San, James Emmanuel and Shank, Stephen D and Wilkinson, Eduan and Lucaci, Alexander G and Giandhari, Jennifer and Naidoo, Sureshnee and Pillay, Yeshnee and Singh, Lavanya and Lessells, Richard J and {NGS-SA} and {COVID-19 Genomics UK (COG-UK)} and Gupta, Ravindra K and Wertheim, Joel O and Nekturenko, Anton and Murrell, Ben and Harkins, Gordon W and Lemey, Philippe and MacLean, Oscar A and Robertson, David L and de Oliveira, Tulio and Pond, Sergei L Kosakovsky", + "journal": "Cell" + }, + { + "id": "Tao:2021vv", + "title": "The biological and clinical significance of emerging SARS-CoV-2 variants", + "abstract": "The past several months have witnessed the emergence of SARS-CoV-2 variants with novel spike protein mutations that are influencing the epidemiological and clinical aspects of the COVID-19 pandemic. These variants can increase rates of virus transmission and/or increase the risk of reinfection and reduce the protection afforded by neutralizing monoclonal antibodies and vaccination. These variants can therefore enable SARS-CoV-2 to continue its spread in the face of rising population immunity while maintaining or increasing its replication fitness. The identification of four rapidly expanding virus lineages since December 2020, designated variants of concern, has ushered in a new stage of the pandemic. The four variants of concern, the Alpha variant (originally identified in the UK), the Beta variant (originally identified in South Africa), the Gamma variant (originally identified in Brazil) and the Delta variant (originally identified in India), share several mutations with one another as well as with an increasing number of other recently identified SARS-CoV-2 variants. Collectively, these SARS-CoV-2 variants complicate the COVID-19 research agenda and necessitate additional avenues of laboratory, epidemiological and clinical research.", + "year": "2021", + "author": "Tao, Kaiming and Tzou, Philip L and Nouhin, Janin and Gupta, Ravindra K and de Oliveira, Tulio and Pond, Sergei L Kosakovsky and Fera, Daniela and Shafer, Robert W", + "journal": "Nat Rev Genet" + }, + { + "id": "Mei:2021uw", + "title": "Stepwise evolution and exceptional conservation of ORF1a/b overlap in coronaviruses", + "abstract": "The programmed frameshift element (PFE) rerouting translation from ORF1a to ORF1b is essential for propagation of coronaviruses. The combination of genomic features that make up PFE-the overlap between the two reading frames, a slippery sequence, as well as an ensemble of complex secondary structure elements-places severe constraints on this region as most possible nucleotide substitution may disrupt one or more of these elements. The vast amount of SARS-CoV-2 sequencing data generated within the past year provides an opportunity to assess evolutionary dynamics of PFE in great detail. Here we performed a comparative analysis of all available coronaviral genomic data available to date. We show that the overlap between ORF1a and ORF1b evolved as a set of discrete 7, 16, 22, 25, and 31 nucleotide stretches with a well defined phylogenetic specificity. We further examined sequencing data from over 1,500,000 complete genomes and 55,000 raw read datasets to demonstrate exceptional conservation and detect signatures of selection within the PFE region.", + "year": "2021", + "author": "Mei, Han and Pond, Sergei L Kosakovsky and Nekrutenko, Anton", + "journal": "Mol Biol Evol" + }, + { + "id": "Maier:2021un", + "title": "Freely accessible ready to use global infrastructure for SARS-CoV-2 monitoring", + "abstract": "The COVID-19 pandemic is the first global health crisis to occur in the age of big genomic data.Although data generation capacity is well established and sufficiently standardized, analytical capacity is not. To establish analytical capacity it is necessary to pull together global computational resources and deliver the best open source tools and analysis workflows within a ready to use, universally accessible resource. Such a resource should not be controlled by a single research group, institution, or country. Instead it should be maintained by a community of users and developers who ensure that the system remains operational and populated with current tools. A community is also essential for facilitating the types of discourse needed to establish best analytical practices. Bringing together public computational research infrastructure from the USA, Europe, and Australia, we developed a distributed data analysis platform that accomplishes these goals. It is immediately accessible to anyone in the world and is designed for the analysis of rapidly growing collections of deep sequencing datasets. We demonstrate its utility by detecting allelic variants in high-quality existing SARS-CoV-2 sequencing datasets and by continuous reanalysis of COG-UK data. All workflows, data, and documentation is available at https://covid19.galaxyproject.org .", + "year": "2021", + "author": "Maier, Wolfgang and Bray, Simon and van den Beek, Marius and Bouvier, Dave and Coraor, Nathaniel and Miladi, Milad and Singh, Babita and De Argila, Jordi Rambla and Baker, Dannon and Roach, Nathan and Gladman, Simon and Coppens, Frederik and Martin, Darren P and Lonie, Andrew and Gr{\\\"u}ning, Bj{\\\"o}rn and Pond, Sergei L Kosakovsky and Nekrutenko, Anton", + "journal": "bioRxiv" + }, + { + "id": "Cui:2021ui", + "title": "Ancestral transoceanic colonization and recent population reduction in a nonannual killifish from the Seychelles archipelago", + "abstract": "Whether freshwater fish colonize remote islands following tectonic or transoceanic dispersal remains an evolutionary puzzle. Integrating dating of known tectonic events with phylogenomics and current species distribution, we find that killifish species distribution is not explained by species dispersal by tectonic drift only. Investigating the colonization of a nonannual killifish (golden panchax, Pachypanchax playfairii) on the Seychelle islands, we found genetic support for transoceanic dispersal and experimentally discovered an adaptation to complete tolerance to seawater. At the macroevolutionary scale, despite their long-lasting isolation, nonannual golden panchax show stronger genome-wide purifying selection than annual killifishes from continental Africa. However, progressive decline in effective population size over a more recent timescale has probably led to the segregation of slightly deleterious mutations across golden panchax populations, which represents a potential threat for species preservation in the long term.", + "year": "2021", + "author": "Cui, Rongfeng and Tyers, Alexandra M and Malubhoy, Zahabiya Juzar and Wisotsky, Sadie and Valdesalici, Stefano and Henriette, Elvina and Pond, Sergei L Kosakovsky and Valenzano, Dario Riccardo", + "journal": "Mol Ecol" + }, + { + "id": "Escalera-Zamudio:2021vw", + "title": "Identification of site-specific evolutionary trajectories shared across human betacoronaviruses", + "abstract": "Comparison of evolution among related viruses can provide insights into shared adaptive processes, for example following host switching to a mutual host species. Whilst phylogenetic methods can help identify mutations that may be important for evolutionary processes such as adaptation to a new host, these can be enhanced by positioning candidate mutations to known functional sites on protein structures. Over the past two decades, three zoonotic betacoronaviruses have significantly impacted human public health: SARS-CoV-1, MERS-CoV and SARS-CoV-2, whilst two other betacoronaviruses, HKU1 and OC43, have circulated endemically in the human population for over 100 years. In this study, we use a comparative approach to prospectively search for potentially evolutionarily-relevant mutations within the Orf1ab and S genes across betacoronavirus species that have demonstrated sustained human-to-human transmission (HKU1, OC43, SARS-CoV-1 and SARS-CoV-2). We used a combination of molecular evolution methods to identify 30 sites that display evidence of homoplasy and/or stepwise evolution, that may be suggestive of adaptation across emerging and endemic betacoronaviruses. Of these, seven sites also display evidence of being selectively relevant. Drawing upon known protein structure data, we find that four of the identified mutations [18121 (exonuclease/27), 21623 (spike/21), 21635 (spike/25) and 23948 (spike/796), in SARS-CoV-2 genome coordinates] are proximal to regions of known functionality. Our results provide a molecular-level context for common evolutionary pathways that betacoronaviruses may undergo during adaptation to the human host.", + "year": "2021", + "author": "Escalera-Zamudio, Marina and Pond, Sergei L Kosakovsky and de la Vi{\\~n}a, Natalia Mart{\\'\\i}nez and Guti{\\'e}rrez, Bernardo and Th{\\'e}z{\\'e}, Julien and Bowden, Thomas A and Pybus, Oliver G and Hulswit, Ruben J G", + "journal": "bioRxiv" + }, + { + "id": "Radke:2021us", + "title": "Diversity of Functionally Distinct Clonal Sets of Human Conventional Memory B Cells That Bind Staphylococcal Protein A", + "abstract": "Staphylococcus aureus, a common cause of serious and often fatal infections, is well-armed with secreted factors that disarm host immune defenses. Highly expressed in vivo during infection, Staphylococcal protein A (SpA) is reported to also contribute to nasal colonization that can be a prelude to invasive infection. Co-evolution with the host immune system has provided SpA with an Fc-antibody binding site, and a Fab-binding site responsible for non-immune superantigen interactions via germline-encoded surfaces expressed on many human BCRs. We wondered whether the recurrent exposures to S. aureus commonly experienced by adults, result in the accumulation of memory B-cell responses to other determinants on SpA. We therefore isolated SpA-specific class-switched memory B cells, and characterized their encoding VH : VL antibody genes. In SpA-reactive memory B cells, we confirmed a striking bias in usage for VH genes, which retain the surface that mediates the SpA-superantigen interaction. We postulate these interactions reflect co-evolution of the host immune system and SpA, which during infection results in immune recruitment of an extraordinarily high prevalence of B cells in the repertoire that subverts the augmentation of protective defenses. Herein, we provide the first evidence that human memory responses are supplemented by B-cell clones, and circulating-antibodies, that bind to SpA determinants independent of the non-immune Fc- and Fab-binding sites. In parallel, we demonstrate that healthy individuals, and patients recovering from S. aureus infection, both have circulating antibodies with these conventional binding specificities. These findings rationalize the potential utility of incorporating specially engineered SpA proteins into a protective vaccine.", + "year": "2021", + "author": "Radke, Emily E and Li, Zhi and Hernandez, David N and El Bannoudi, Hanane and Pond, Sergei L Kosakovsky and Shopsin, Bo and Lopez, Peter and Feny{\\\"o}, David and Silverman, Gregg J", + "journal": "Front Immunol" + }, + { + "id": "Cui:2021wq", + "title": "Ancestral transoceanic colonization and recent population reduction in a non-annual killifish from the Seychelles archipelago", + "abstract": "Whether freshwater fish colonize remote islands following tectonic or transoceanic dispersal remains an evolutionary puzzle. Integrating dating of known tectonic events with phylogenomics and current species distribution, we find that killifish species distribution eludes species dispersal by tectonic drift only. Investigating the colonization of a non-annual killifish (Pachypanchax playfairii) on the Seychelle islands, we found genetic support for trans-oceanic dispersal and experimentally discovered an adaptation to complete tolerance to seawater. At the macroevolutionary scale, despite their long-lasting isolation, non-annual golden panchax show stronger genome-wide purifying selection than annual killifishes from continental Africa. However, progressive decline in effective population size in a more recent time-scale likely led to the segregation of slightly deleterious mutations across golden panchax populations, which represents a potential threat for species preservation on the long run.", + "year": "2021", + "author": "Cui, Rongfeng and Tyers, Alexandra M and Malubhoy, Zahabiya Juzar and Wisotsky, Sadie and Valdesalici, Stefano and Henriette, Elvina and Pond, Sergei L Kosakovsky and Valenzano, Dario Riccardo", + "journal": "Mol Ecol" + }, + { + "id": "MacLean:2021aa", + "title": "Natural selection in the evolution of SARS-CoV-2 in bats created a generalist virus and highly capable human pathogen", + "abstract": "Virus host shifts are generally associated with novel adaptations to exploit the cells of the new host species optimally. Surprisingly, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has apparently required little to no significant adaptation to humans since the start of the Coronavirus Disease 2019 (COVID-19) pandemic and to October 2020. Here we assess the types of natural selection taking place in Sarbecoviruses in horseshoe bats versus the early SARS-CoV-2 evolution in humans. While there is moderate evidence of diversifying positive selection in SARS-CoV-2 in humans, it is limited to the early phase of the pandemic, and purifying selection is much weaker in SARS-CoV-2 than in related bat Sarbecoviruses. In contrast, our analysis detects evidence for significant positive episodic diversifying selection acting at the base of the bat virus lineage SARS-CoV-2 emerged from, accompanied by an adaptive depletion in CpG composition presumed to be linked to the action of antiviral mechanisms in these ancestral bat hosts. The closest bat virus to SARS-CoV-2, RmYN02 (sharing an ancestor about 1976), is a recombinant with a structure that includes differential CpG content in Spike; clear evidence of coinfection and evolution in bats without involvement of other species. While an undiscovered \"facilitating\" intermediate species cannot be discounted, collectively, our results support the progenitor of SARS-CoV-2 being capable of efficient human-human transmission as a consequence of its adaptive evolutionary history in bats, not humans, which created a relatively generalist virus.", + "year": "2021", + "author": "MacLean, Oscar A and Lytras, Spyros and Weaver, Steven and Singer, Joshua B and Boni, Maciej F and Lemey, Philippe and Pond, Sergei L Kosakovsky and Robertson, David L", + "journal": "PLoS Biol" + }, + { + "id": "Lucaci:2021aa", + "title": "Extra base hits: Widespread empirical support for instantaneous multiple-nucleotide changes", + "abstract": "Despite many attempts to introduce evolutionary models that permit substitutions to instantly alter more than one nucleotide in a codon, the prevailing wisdom remains that such changes are rare and generally negligible or are reflective of non-biological artifacts, such as alignment errors. Codon models continue to posit that only single nucleotide change have non-zero rates. Here, we develop and test a simple hierarchy of codon-substitution models with non-zero evolutionary rates for only one-nucleotide (1H), one- and two-nucleotide (2H), or any (3H) codon substitutions. Using over 42, 000 empirical alignments, we find widespread statistical support for multiple hits: 61% of alignments prefer models with 2H allowed, and 23%-with 3H allowed. Analyses of simulated data suggest that these results are not likely to be due to simple artifacts such as model misspecification or alignment errors. Further modeling reveals that synonymous codon island jumping among codons encoding serine, especially along short branches, contributes significantly to this 3H signal. While serine codons were prominently involved in multiple-hit substitutions, there were other common exchanges contributing to better model fit. It appears that a small subset of sites in most alignments have unusual evolutionary dynamics not well explained by existing model formalisms, and that commonly estimated quantities, such as dN/dS ratios may be biased by model misspecification. Our findings highlight the need for continued evaluation of assumptions underlying workhorse evolutionary models and subsequent evolutionary inference techniques. We provide a software implementation for evolutionary biologists to assess the potential impact of extra base hits in their data in the HyPhy package and in the Datamonkey.org server.", + "year": "2021", + "author": "Lucaci, Alexander G and Wisotsky, Sadie R and Shank, Stephen D and Weaver, Steven and Pond, Sergei L Kosakovsky", + "journal": "PLoS One" + }, + { + "id": "Martin:2021te", + "title": "The emergence and ongoing convergent evolution of the N501Y lineages coincides with a major global shift in the SARS-CoV-2 selective landscape", + "abstract": "The emergence and rapid rise in prevalence of three independent SARS-CoV-2 \"501Y lineages'', B.1.1.7, B.1.351 and P.1, in the last three months of 2020 has prompted renewed concerns about the evolutionarily capacity of SARS-CoV-2 to adapt to both rising population immunity, and public health interventions such as vaccines and social distancing. Viruses giving rise to the different 501Y lineages have, presumably under intense natural selection following a shift in host environment, independently acquired multiple unique and convergent mutations. As a consequence all have gained epidemiological and immunological properties that will likely complicate the control of COVID-19. Here, by examining patterns of mutations that arose in SARS-CoV-2 genomes during the pandemic we find evidence of a major change in the selective forces acting on immunologically important SARS-CoV-2 genes (such as N and S) that likely coincided with the emergence of the 501Y lineages. In addition to involving continuing sequence diversification, we find evidence that a significant portion of the ongoing adaptive evolution of the 501Y lineages also involves further convergence between the lineages. Our findings highlight the importance of monitoring how members of these known 501Y lineages, and others still undiscovered, are convergently evolving similar strategies to ensure their persistence in the face of mounting infection and vaccine induced host immune recognition.", + "year": "2021", + "author": "Martin, Darren P and Weaver, Steven and Tegally, Houryiah and San, Emmanuel James and Shank, Stephen D and Wilkinson, Eduan and Giandhari, Jennifer and Naidoo, Sureshnee and Pillay, Yeshnee and Singh, Lavanya and Lessells, Richard J and {NGS-SA} and {COVID-19 Genomics UK (COG-UK)} and Gupta, Ravindra K and Wertheim, Joel O and Nekturenko, Anton and Murrell, Ben and Harkins, Gordon W and Lemey, Philippe and MacLean, Oscar A and Robertson, David L and de Oliveira, Tulio and Pond, Sergei L Kosakovsky", + "journal": "medRxiv" + }, + { + "id": "Tegally:2021aa", + "title": "Detection of a SARS-CoV-2 variant of concern in South Africa", + "abstract": "Continued uncontrolled transmission of SARS-CoV-2 in many parts of the world is creating conditions for substantial evolutionary changes to the virus1,2. Here we describe a newly arisen lineage of SARS-CoV-2 (designated 501Y.V2; also known as B.1.351 or 20H) that is defined by eight mutations in the spike protein, including three substitutions (K417N, E484K and N501Y) at residues in its receptor-binding domain that may have functional importance3-5. This lineage was identified in South Africa after the first wave of the epidemic in a severely affected metropolitan area (Nelson Mandela Bay) that is located on the coast of the Eastern Cape province. This lineage spread rapidly, and became dominant in Eastern Cape, Western Cape and KwaZulu-Natal provinces within weeks. Although the full import of the mutations is yet to be determined, the genomic data-which show rapid expansion and displacement of other lineages in several regions-suggest that this lineage is associated with a selection advantage that most plausibly results from increased transmissibility or immune escape6-8.", + "year": "2021", + "author": "Tegally, Houriiyah and Wilkinson, Eduan and Giovanetti, Marta and Iranzadeh, Arash and Fonseca, Vagner and Giandhari, Jennifer and Doolabh, Deelan and Pillay, Sureshnee and San, Emmanuel James and Msomi, Nokukhanya and Mlisana, Koleka and von Gottberg, Anne and Walaza, Sibongile and Allam, Mushal and Ismail, Arshad and Mohale, Thabo and Glass, Allison J and Engelbrecht, Susan and Van Zyl, Gert and Preiser, Wolfgang and Petruccione, Francesco and Sigal, Alex and Hardie, Diana and Marais, Gert and Hsiao, Nei-Yuan and Korsman, Stephen and Davies, Mary-Ann and Tyers, Lynn and Mudau, Innocent and York, Denis and Maslo, Caroline and Goedhals, Dominique and Abrahams, Shareef and Laguda-Akingba, Oluwakemi and Alisoltani-Dehkordi, Arghavan and Godzik, Adam and Wibmer, Constantinos Kurt and Sewell, Bryan Trevor and Louren{\\c c}o, Jos{\\'e} and Alcantara, Luiz Carlos Junior and Pond, Sergei L Kosakovsky and Weaver, Steven and Martin, Darren and Lessells, Richard J and Bhiman, Jinal N and Williamson, Carolyn and de Oliveira, Tulio", + "journal": "Nature" + }, + { + "id": "Rahman:2021vk", + "title": "Weak selection on synonymous codons substantially inflates dN/dS estimates in bacteria", + "abstract": "Synonymous codon substitutions are not always selectively neutral as revealed by several types of analyses, including studies of codon usage patterns among genes. We analyzed codon usage in 13 bacterial genomes sampled from across a large order of bacteria, Enterobacterales, and identified presumptively neutral and selected classes of synonymous substitutions. To estimate substitution rates, given a neutral/selected classification of synonymous substitutions, we developed a flexible [Formula: see text] substitution model that allows multiple classes of synonymous substitutions. Under this multiclass synonymous substitution (MSS) model, the denominator of [Formula: see text] includes only the strictly neutral class of synonymous substitutions. On average, the value of [Formula: see text] under the MSS model was 80% of that under the standard codon model in which all synonymous substitutions are assumed to be neutral. The indication is that conventional [Formula: see text] analyses overestimate these values and thus overestimate the frequency of positive diversifying selection and underestimate the strength of purifying selection. To quantify the strength of selection necessary to explain this reduction, we developed a model of selected compensatory codon substitutions. The reduction in synonymous substitution rate, and thus the contribution that selection makes to codon bias variation among genes, can be adequately explained by very weak selection, with a mean product of population size and selection coefficient, [Formula: see text].", + "year": "2021", + "author": "Rahman, Shakibur and Pond, Sergei L Kosakovsky and Webb, Andrew and Hey, Jody", + "journal": "Proc Natl Acad Sci U S A" + }, + { + "id": "Kumar:2021wx", + "title": "An evolutionary portrait of the progenitor SARS-CoV-2 and its dominant offshoots in COVID-19 pandemic", + "abstract": "Global sequencing of hundreds of thousands of genomes of Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, has continued to reveal new genetic variants that are the key to unraveling its early evolutionary history and tracking its global spread over time. Here, we present the heretofore cryptic mutational history and spatiotemporal dynamics of SARS-CoV-2 from an analysis of thousands of high-quality genomes. We report the likely most recent common ancestor of SARS-CoV-2, reconstructed through a novel application and advancement of computational methods initially developed to infer the mutational history of tumor cells in a patient. This progenitor genome differs from genomes of the first coronaviruses sampled in China by three variants, implying that none of the earliest patients represent the index case or gave rise to all the human infections. However, multiple coronavirus infections in China and the USA harbored the progenitor genetic fingerprint in January 2020 and later, suggesting that the progenitor was spreading worldwide months before and after the first reported cases of COVID-19 in China. Mutations of the progenitor and its offshoots have produced many dominant coronavirus strains, which have spread episodically over time. Fingerprinting based on common mutations reveals that the same coronavirus lineage has dominated North America for most of the pandemic in 2020. There have been multiple replacements of predominant coronavirus strains in Europe and Asia and the continued presence of multiple high-frequency strains in Asia and North America. We have developed a continually updating dashboard of global evolution and spatiotemporal trends of SARS-CoV-2 spread (http://sars2evo.datamonkey.org/).", + "year": "2021", + "author": "Kumar, Sudhir and Tao, Qiqing and Weaver, Steven and Sanderford, Maxwell and Caraballo-Ortiz, Marcos A and Sharma, Sudip and Pond, Sergei L K and Miura, Sayaka", + "journal": "Mol Biol Evol" + }, + { + "id": "Faria:2021wv", + "title": "Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil", + "abstract": "Cases of SARS-CoV-2 infection in Manaus, Brazil, resurged in late 2020, despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1, acquired 17 mutations, including a trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.7-2.4-fold more transmissible, and that previous (non-P.1) infection provides 54-79% of the protection against infection with P.1 that it provides against non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness.", + "year": "2021", + "author": "Faria, Nuno R and Mellan, Thomas A and Whittaker, Charles and Claro, Ingra M and Candido, Darlan da S and Mishra, Swapnil and Crispim, Myuki A E and Sales, Flavia C S and Hawryluk, Iwona and McCrone, John T and Hulswit, Ruben J G and Franco, Lucas A M and Ramundo, Mariana S and de Jesus, Jaqueline G and Andrade, Pamela S and Coletti, Thais M and Ferreira, Giulia M and Silva, Camila A M and Manuli, Erika R and Pereira, Rafael H M and Peixoto, Pedro S and Kraemer, Moritz U G and Gaburo, Jr, Nelson and Camilo, Cecilia da C and Hoeltgebaum, Henrique and Souza, William M and Rocha, Esmenia C and de Souza, Leandro M and de Pinho, Mariana C and Araujo, Leonardo J T and Malta, Frederico S V and de Lima, Aline B and Silva, Joice do P and Zauli, Danielle A G and Ferreira, Alessandro C de S and Schnekenberg, Ricardo P and Laydon, Daniel J and Walker, Patrick G T and Schl{\\\"u}ter, Hannah M and Dos Santos, Ana L P and Vidal, Maria S and Del Caro, Valentina S and Filho, Rosinaldo M F and Dos Santos, Helem M and Aguiar, Renato S and Proen{\\c c}a-Modena, Jos{\\'e} L and Nelson, Bruce and Hay, James A and Monod, M{\\'e}lodie and Miscouridou, Xenia and Coupland, Helen and Sonabend, Raphael and Vollmer, Michaela and Gandy, Axel and Prete, Jr, Carlos A and Nascimento, Vitor H and Suchard, Marc A and Bowden, Thomas A and Pond, Sergei L K and Wu, Chieh-Hsi and Ratmann, Oliver and Ferguson, Neil M and Dye, Christopher and Loman, Nick J and Lemey, Philippe and Rambaut, Andrew and Fraiji, Nelson A and Carvalho, Maria do P S S and Pybus, Oliver G and Flaxman, Seth and Bhatt, Samir and Sabino, Ester C", + "journal": "Science" + }, + { + "id": "Li:2021up", + "title": "Molecular Evolution of Human Norovirus GII.2 Clusters", + "abstract": "Background: The human norovirus GII.2 outbreak during the 2016-2017 winter season was of unprecedented scale and geographic distribution.\nMethods: We analyzed 519 complete VP1 gene sequences of the human norovirus GII.2 genotype sampled during the 2016-2017 winter season, as well as prior (dating back to 1976) from 7 countries. Phylodynamic analyses of these sequences were performed using maximum likelihood and Bayesian statistical frameworks in order to estimate viral evolutionary and population dynamics associated with the outbreak.\nResults: Our results revealed an increase in the genetic diversity of human norovirus GII.2 during the recent Asian outbreak and diversification was characterized by at least eight distinct clusters. Bayesian estimation of viral population dynamics revealed a highly fluctuating effective population size, increasing in frequency during the past 15 years.\nConclusion: Despite an increasing viral diversity, we found no evidence of an elevated evolutionary rate or significant selection pressure in human norovirus GII.2, indicating viral evolutionary adaptation was not responsible for the volatility of or spread of the virus during this time.", + "year": "2021", + "author": "Li, Xingguang and Liu, Haizhou and Rife Magalis, Brittany and Pond, Sergei L Kosakovsky and Volz, Erik M", + "journal": "Front Microbiol" + }, + { + "id": "Tagliamonte:2020th", + "title": "Multiple Recombination Events and Strong Purifying Selection at the Origin of SARS-CoV-2 Spike Glycoprotein Increased Correlated Dynamic Movements", + "abstract": "Our evolutionary and structural analyses revealed that the severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) spike gene is a complex mosaic resulting from several recombination events. Additionally, the fixation of variants has mainly been driven by purifying selection, suggesting the presence of conserved structural features. Our dynamic simulations identified two main long-range covariant dynamic movements of the novel glycoprotein, and showed that, as a result of the evolutionary duality, they are preserved. The first movement involves the receptor binding domain with the N-terminal domain and the C-terminal domain 2 and is maintained across human, bat and pangolin coronaviruses. The second is a complex network of long-range dynamics specific to SARS-CoV-2 involving the novel PRRA and the conserved KR*SF cleavage sites, as well as conserved segments in C-terminal domain 3. These movements, essential for host cell binding, are maintained by hinges conserved across human, bat, and pangolin coronaviruses glycoproteins. The hinges, located around Threonine 333 and Proline 527 within the N-terminal domain and C-terminal domain 2, represent candidate targets for the future development of novel pan-coronavirus inhibitors. In summary, we show that while recombination created a new configuration that increased the covariant dynamic movements of the SARS-CoV-2 glycoprotein, negative selection preserved its inter-domain structure throughout evolution in different hosts and inter-species transmissions.", + "year": "2020", + "author": "Tagliamonte, Massimiliano S and Abid, Nabil and Borocci, Stefano and Sangiovanni, Elisa and Ostrov, David A and Pond, Sergei L Kosakovsky and Salemi, Marco and Chillemi, Giovanni and Mavian, Carla", + "journal": "Int J Mol Sci" + }, + { + "id": "Little:2021ts", + "title": "Effective HIV Molecular Surveillance Requires Identification of Incident Cases of Infection", + "abstract": "BACKGROUND: Ending the HIV epidemic requires knowledge of key drivers of spread of HIV infection.\nMETHODS: Between 1996 and 2018, 1119 newly and previously diagnosed, therapy-na{\\\"\\i}ve persons with HIV (PWH) from San Diego were followed. A genetic distance-based network was inferred using pol sequences, and genetic clusters grew over time through linkage of sequences from newly observed infections. Cox proportional hazards models were used to identify factors associated with the rate of growth. These results were used to predict the impact of a hypothetical intervention targeting PWH with incident infection. Comparison was made to the CDC EHE molecular surveillance strategy, which prioritizes clusters recently linked to all new HIV diagnoses and does not incorporate data on incident infections.\nRESULTS: Overall, 219 genetic linkages to incident infections were identified over a median follow-up of 8.8 years. Incident cluster growth was strongly associated with proportion of PWH in the cluster who themselves had incident infection. (HR 44.09; 95% CI: 17.09, 113.78). The CDC EHE molecular surveillance strategy identified 11 linkages to incident infections a genetic distance threshold of 0.5%, and 24 linkages at 1.5%.\nCONCLUSIONS: Over the past two decades, incident infections drove incident HIV cluster growth in San Diego. The current CDC EHE molecular detection and response strategy would not have identified most transmission events arising from those with incident infection in San Diego. Molecular surveillance that includes detection of incident cases will provide a more effective strategy for EHE.", + "year": "2021", + "author": "Little, Susan J and Chen, Tom and Wang, Rui and Anderson, Christy and Kosakovsky Pond, Sergei and Nakazawa, Masato and Mathews, William C and DeGruttola, Victor and Smith, Davey M", + "journal": "Clin Infect Dis" + }, + { + "id": "Council:2020aa", + "title": "Deep Sequencing Reveals Compartmentalized HIV-1 in the Semen of Men with and without Sexually Transmitted Infection-Associated Urethritis", + "abstract": "Concurrent sexually transmitted infections (STI) can increase the probability of HIV-1 transmission primarily by increasing the viral load present in semen. In this study, we explored the relationship of HIV-1 in blood and seminal plasma in the presence and absence of urethritis and after treatment of the concurrent STI. Primer ID deep sequencing of the V1/V3 region of the HIV-1 env gene was done for paired blood and semen samples from antiretroviral therapy (ART)-naive men living in Malawi with (n = 19) and without (n = 5) STI-associated urethritis; for a subset of samples, full-length env genes were generated for sequence analysis and to test entry phenotype. Cytokine concentrations in the blood and semen were also measured, and a reduction in the levels of proinflammatory cytokines was observed following STI treatment. We observed no difference in the prevalence of diverse compartmentalized semen-derived lineages in men with or without STI-associated urethritis, and these viral populations were largely stable during STI treatment. Clonal amplification of one or a few viral sequences accounted for nearly 50% of the viral population, indicating a recent bottleneck followed by limited viral replication. We conclude that the male genital tract is a site where virus can be brought in from the blood, where localized sustained replication can occur, and where specific genotypes can be amplified, perhaps initially by cellular proliferation but further by limited viral replication.IMPORTANCE HIV-1 infection is a sexually transmitted infection that coexists with other STI. Here, we examined the impact of a concurrent STI resulting in urethritis on the HIV-1 population within the male genital tract. We found that viral populations remain largely stable even with treatment of the STI. These results show that viral populations within the male genital tract are defined by factors beyond transient inflammation associated with a concurrent STI.", + "year": "2020", + "author": "Council, Olivia D and Zhou, Shuntai and McCann, Chase D and Hoffman, Irving and Tegha, Gerald and Kamwendo, Deborah and Matoga, Mitch and Pond, Sergei LK and Cohen, Myron S and Swanstrom, Ronald", + "journal": "J Virol" + }, + { + "id": "Wisotsky:2020ab", + "title": "Synonymous Site-to-Site Substitution Rate Variation Dramatically Inflates False Positive Rates of Selection Analyses: Ignore at Your Own Peril", + "abstract": "Most molecular evolutionary studies of natural selection maintain the decades-old assumption that synonymous substitution rate variation (SRV) across sites within genes occurs at levels that are either nonexistent or negligible. However, numerous studies challenge this assumption from a biological perspective and show that SRV is comparable in magnitude to that of nonsynonymous substitution rate variation. We evaluated the impact of this assumption on methods for inferring selection at the molecular level by incorporating SRV into an existing method (BUSTED) for detecting signatures of episodic diversifying selection in genes. Using simulated data we found that failing to account for even moderate levels of SRV in selection testing is likely to produce intolerably high false positive rates. To evaluate the effect of the SRV assumption on actual inferences we compared results of tests with and without the assumption in an empirical analysis of over 13,000 Euteleostomi (bony vertebrate) gene alignments from the Selectome database. This exercise reveals that close to 50% of positive results (i.e., evidence for selection) in empirical analyses disappear when SRV is modeled as part of the statistical analysis and are thus candidates for being false positives. The results from this work add to a growing literature establishing that tests of selection are much more sensitive to certain model assumptions than previously believed.", + "year": "2020", + "author": "Wisotsky, Sadie R and Pond, Sergei LK and Shank, Stephen D and Muse, Spencer V", + "journal": "Mol Biol Evol" + }, + { + "id": "Pollock:2020ab", + "title": "Viral CpG Deficiency Provides No Evidence That Dogs Were Intermediate Hosts for SARS-CoV-2", + "abstract": "Due to the scope and impact of the COVID-19 pandemic there exists a strong desire to understand where the SARS-CoV-2 virus came from and how it jumped species boundaries to humans. Molecular evolutionary analyses can trace viral origins by establishing relatedness and divergence times of viruses and identifying past selective pressures. However, we must uphold rigorous standards of inference and interpretation on this topic because of the ramifications of being wrong. Here, we dispute the conclusions of Xia (2020. Extreme genomic CpG deficiency in SARS-CoV-2 and evasion of host antiviral defense. Mol Biol Evol. doi:10.1093/molbev/masa095) that dogs are a likely intermediate host of a SARS-CoV-2 ancestor. We highlight major flaws in Xia's inference process and his analysis of CpG deficiencies, and conclude that there is no direct evidence for the role of dogs as intermediate hosts. Bats and pangolins currently have the greatest support as ancestral hosts of SARS-CoV-2, with the strong caveat that sampling of wildlife species for coronaviruses has been limited.", + "year": "2020", + "author": "Pollock, David D and Castoe, Todd A and Perry, Blair W and Lytras, Spyros and Wade, Kristen J and Robertson, David L and Holmes, Edward C and Boni, Maciej F and Pond, Sergei LK and Parry, Rhys and Carlton, Elizabeth J and Wood, James L N and Pennings, Pleuni S and Goldstein, Richard A", + "journal": "Mol Biol Evol" + }, + { + "id": "Kosakovsky-Pond:2020aa", + "title": "Contrast-FEL - a test for differences in selective pressures at individual sites among clades and sets of branches", + "abstract": "A number of evolutionary hypotheses can be tested by comparing selective pressures among sets of branches in a phylogenetic tree. When the question of interest is to identify specific sites within genes that may be evolving differently, a common approach is to perform separate analyses on subsets of sequences, and compare parameter estimates in a post hoc fashion. This approach is statistically suboptimal, and not always applicable. Here, we develop a simple extension of a popular fixed effects likelihood method in the context of codon-based evolutionary phylogenetic maximum likelihood testing, Contrast-FEL. It is suitable for identifying individual alignment sites where any among the K ≥ 2 sets of branches in a phylogenetic tree have detectably different ω ratios, indicative of different selective regimes. Using extensive simulations, we show that Contrast-FEL delivers good power, exceeding 90% for sufficiently large differences, while maintaining tight control over false positive rates, when the model is correctly specified. We conclude by applying Contrast-FEL to data from five previously published studies spanning a diverse range of organisms and focusing on different evolutionary questions.", + "year": "2020", + "author": "Pond, Sergei LK and Wisotsky, Sadie R and Escalante, Ananias and Magalis, Brittany Rife and Weaver, Steven", + "journal": "Mol Biol Evol" + }, + { + "id": "Mavian:2020ab", + "title": "Sampling bias and incorrect rooting make phylogenetic network tracing of SARS-COV-2 infections unreliable", + "year": "2020", + "author": "Mavian, Carla and Pond, Sergei Kosakovsky and Marini, Simone and Magalis, Brittany Rife and Vandamme, Anne-Mieke and Dellicour, Simon and Scarpino, Samuel V and Houldcroft, Charlotte and Villabona-Arenas, Julian and Paisie, Taylor K and Trov{\\~a}o, N{\\'\\i}dia S and Boucher, Christina and Zhang, Yun and Scheuermann, Richard H and Gascuel, Olivier and Lam, Tommy Tsan-Yuk and Suchard, Marc A and Abecasis, Ana and Wilkinson, Eduan and de Oliveira, Tulio and Bento, Ana I and Schmidt, Heiko A and Martin, Darren and Hadfield, James and Faria, Nuno and Grubaugh, Nathan D and Neher, Richard A and Baele, Guy and Lemey, Philippe and Stadler, Tanja and Albert, Jan and Crandall, Keith A and Leitner, Thomas and Stamatakis, Alexandros and Prosperi, Mattia and Salemi, Marco", + "journal": "Proc Natl Acad Sci U S A" + }, + { + "id": "Baker:2020aa", + "title": "No more business as usual: Agile and effective responses to emerging pathogen threats require open data and open analytics", + "abstract": "The current state of much of the Wuhan pneumonia virus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) research shows a regrettable lack of data sharing and considerable analytical obfuscation. This impedes global research cooperation, which is essential for tackling public health emergencies and requires unimpeded access to data, analysis tools, and computational infrastructure. Here, we show that community efforts in developing open analytical software tools over the past 10 years, combined with national investments into scientific computational infrastructure, can overcome these deficiencies and provide an accessible platform for tackling global health emergencies in an open and transparent manner. Specifically, we use all SARS-CoV-2 genomic data available in the public domain so far to (1) underscore the importance of access to raw data and (2) demonstrate that existing community efforts in curation and deployment of biomedical software can reliably support rapid, reproducible research during global health crises. All our analyses are fully documented at https://github.com/galaxyproject/SARS-CoV-2.", + "year": "2020", + "author": "Baker, Dannon and van den Beek, Marius and Blankenberg, Daniel and Bouvier, Dave and Chilton, John and Coraor, Nate and Coppens, Frederik and Eguinoa, Ignacio and Gladman, Simon and Gr{\\\"u}ning, Bj{\\\"o}rn and Keener, Nicholas and Larivi{\\`e}re, Delphine and Lonie, Andrew and Kosakovsky Pond, Sergei and Maier, Wolfgang and Nekrutenko, Anton and Taylor, James and Weaver, Steven", + "journal": "PLoS Pathog" + }, + { + "id": "RifeMagalis:2020aa", + "title": "Phyloanatomic characterization of the distinct T cell and monocyte contributions to the peripheral blood HIV population within the host", + "abstract": "Human immunodeficiency virus (HIV) is a rapidly evolving virus, allowing its genetic sequence to act as a fingerprint for epidemiological processes among, as well as within, individual infected hosts. Though primarily infecting the CD4+ T-cell population, HIV can also be found in monocytes, an immune cell population that differs in several aspects from the canonical T-cell viral target. Using single genome viral sequencing and statistical phylogenetic inference, we investigated the viral RNA diversity and relative contribution of each of these immune cell types to the viral population within the peripheral blood. Results provide evidence of an increased prevalence of circulating monocytes harboring virus in individuals with high viral load in the absence of suppressive antiretroviral therapy. Bayesian phyloanatomic analysis of three of these individuals demonstrated a measurable role for these cells, but not the circulating T-cell population, as a source of cell-free virus in the plasma, supporting the hypothesis that these cells can act as an additional conduit of virus spread.", + "year": "2020", + "author": "RifeMagalis, Brittany and Strickland, Samantha L and Shank, Stephen D and Autissier, Patrick and Schuetz, Alexandra and Sithinamsuwan, Pasiri and Lerdlum, Sukalaya and Fletcher, James L K and de Souza, Mark and Ananworanich, Jintanat and Valcour, Victor and {Search007 Study Group} and Williams, Kenneth C and Pond, Sergei L Kosakovsky and RattoKim, Silvia and Salemi, Marco", + "journal": "Virus Evol" + }, + { + "id": "Mannino:2020aa", + "title": "Equiprobable discrete models of site-specific substitution rates underestimate the extent of rate variability", + "abstract": "It is standard practice to model site-to-site variability of substitution rates by discretizing a continuous distribution into a small number, K, of equiprobable rate categories. We demonstrate that the variance of this discretized distribution has an upper bound determined solely by the choice of K and the mean of the distribution. This bound can introduce biases into statistical inference, especially when estimating parameters governing site-to-site variability of substitution rates. Applications to two large collections of sequence alignments demonstrate that this upper bound is often reached in analyses of real data. When parameter estimation is of primary interest, additional rate categories or more flexible modeling methods should be considered.", + "year": "2020", + "author": "Mannino, Frank and Wisotsky, Sadie and Pond, Sergei L Kosakovsky and Muse, Spencer V", + "journal": "PLoS One" + }, + { + "id": "Tzou:2020aa", + "title": "Analysis of unusual and signature APOBEC-mutations in HIV-1 pol next-generation sequences", + "abstract": "INTRODUCTION: At low mutation-detection thresholds, next generation sequencing (NGS) for HIV-1 genotypic resistance testing is susceptible to artifactual detection of mutations arising from PCR error and APOBEC-mediated G-to-A hypermutation.\nMETHODS: We analyzed published HIV-1 pol Illumina NGS data to characterize the distribution of mutations at eight NGS mutation detection thresholds: 20%, 10%, 5%, 2%, 1%, 0.5%, 0.2%, and 0.1%. At each threshold, we determined proportions of amino acid mutations that were unusual (defined as having a prevalence <0.01% in HIV-1 group M sequences) or signature APOBEC mutations.\nRESULTS: Eight studies, containing 855 samples, in the NCBI Sequence Read Archive were analyzed. As detection thresholds were lowered, there was a progressive increase in the proportion of positions with usual and unusual mutations and in the proportion of all mutations that were unusual. The median proportion of positions with an unusual mutation increased gradually from 0% at the 20% threshold to 0.3% at the 1% threshold and then exponentially to 1.3% (0.5% threshold), 6.9% (0.2% threshold), and 23.2% (0.1% threshold). In two of three studies with available plasma HIV-1 RNA levels, the proportion of positions with unusual mutations was negatively associated with virus levels. Although the complete set of signature APOBEC mutations was much smaller than that of unusual mutations, the former outnumbered the latter in one-sixth of samples at the 0.5%, 1%, and 2% thresholds.\nCONCLUSIONS: The marked increase in the proportion of positions with unusual mutations at thresholds below 1% and in samples with lower virus loads suggests that, at low thresholds, many unusual mutations are artifactual, reflecting PCR error or G-to-A hypermutation. Profiling the numbers of unusual and signature APOBEC pol mutations at different NGS mutation detection thresholds may be useful to avoid selecting a threshold that is too low and poses an unacceptable risk of identifying artifactual mutations.", + "year": "2020", + "author": "Tzou, Philip L and Pond, Sergei L Kosakovsky and Avila-Rios, Santiago and Holmes, Susan P and Kantor, Rami and Shafer, Robert W", + "journal": "PLoS One" + }, + { + "id": "Miura:2020aa", + "title": "A new method for inferring timetrees from temporally sampled molecular sequences", + "abstract": "Pathogen timetrees are phylogenies scaled to time. They reveal the temporal history of a pathogen spread through the populations as captured in the evolutionary history of strains. These timetrees are inferred by using molecular sequences of pathogenic strains sampled at different times. That is, temporally sampled sequences enable the inference of sequence divergence times. Here, we present a new approach (RelTime with Dated Tips [RTDT]) to estimating pathogen timetrees based on a relative rate framework underlying the RelTime approach that is algebraic in nature and distinct from all other current methods. RTDT does not require many of the priors demanded by Bayesian approaches, and it has light computing requirements. In analyses of an extensive collection of computer-simulated datasets, we found the accuracy of RTDT time estimates and the coverage probabilities of their confidence intervals (CIs) to be excellent. In analyses of empirical datasets, RTDT produced dates that were similar to those reported in the literature. In comparative benchmarking with Bayesian and non-Bayesian methods (LSD, TreeTime, and treedater), we found that no method performed the best in every scenario. So, we provide a brief guideline for users to select the most appropriate method in empirical data analysis. RTDT is implemented for use via a graphical user interface and in high-throughput settings in the newest release of cross-platform MEGA X software, freely available from http://www.megasoftware.net.", + "year": "2020", + "author": "Miura, Sayaka and Tamura, Koichiro and Tao, Qiqing and Huuki, Louise A and Pond, Sergei L Kosakovsky and Priest, Jessica and Deng, Jiamin and Kumar, Sudhir", + "journal": "PLoS Comput Biol" + }, + { + "id": "Wisotsky:2020aa", + "title": "Synonymous site-to-site substitution rate variation dramatically inflates false positive rates of selection analyses: ignore at your own peril", + "abstract": "Most molecular evolutionary studies of natural selection maintain the decades-old assumption that synonymous substitution rate variation across sites within genes occurs at levels that are either nonexistent or negligible. However, numerous studies challenge this assumption from a biological perspective and show that synonymous substitution rate variation (SRV) is comparable in magnitude to that of nonsynonymous substitution rate variation. We evaluated the impact of this assumption on methods for inferring selection at the molecular level by incorporating SRV into an existing method (BUSTED) for detecting signatures of episodic diversifying selection in genes. Using simulated data we found that failing to account for even moderate levels of SRV in selection testing is likely to produce intolerably high false positive rates. To evaluate the effect of the SRV assumption on actual inferences we compared results of tests with and without the assumption in an empirical analysis of over 13, 000 Euteleostomi (bony vertebrate) gene alignments from the Selectome database. This exercise reveals that close to 50% of positive results (i.e., evidence for selection) in empirical analyses disappear when SRV is modeled as part of the statistical analysis and are thus candidates for being false positives. The results from this work add to a growing literature establishing that tests of selection are much more sensitive to certain model assumptions than previously believed.", + "year": "2020", + "author": "Wisotsky, Sadie R and Pond, Sergei L Kosakovsky and Shank, Stephen D and Muse, Spencer V", + "journal": "Mol Biol Evol" + }, + { + "id": "Yan:2019aa", + "title": "Single-Cell Transcriptomics Reveal a Correlation between Genome Architecture and Gene Family Evolution in Ciliates", + "abstract": "Ciliates, a eukaryotic clade that is over 1 billion years old, are defined by division of genome function between transcriptionally inactive germline micronuclei and functional somatic macronuclei. To date, most analyses of gene family evolution have been limited to cultivable model lineages (e.g., Tetrahymena, Paramecium, Oxytricha, and Stylonychia). Here, we focus on the uncultivable Karyorelictea and its understudied sister class Heterotrichea, which represent two extremes in genome architecture. Somatic macronuclei within the Karyorelictea are described as nearly diploid, while the Heterotrichea have hyperpolyploid somatic genomes. Previous analyses indicate that genome architecture impacts ciliate gene family evolution as the most diverse and largest gene families are found in lineages with extensively processed somatic genomes (i.e., possessing thousands of gene-sized chromosomes). To further assess ciliate gene family evolution, we analyzed 43 single-cell transcriptomes from 33 ciliate species representing 10 classes. Focusing on conserved eukaryotic genes, we use estimates of transcript diversity as a proxy for the number of paralogs in gene families among four focal clades: Karyorelictea, Heterotrichea, extensive fragmenters (with gene-size somatic chromosomes), and non-extensive fragmenters (with more traditional somatic chromosomes), the latter two within the subphylum Intramacronucleata. Our results show that (i) the Karyorelictea have the lowest average transcript diversity, while Heterotrichea are highest among the four groups; (ii) proteins in Karyorelictea are under the highest functional constraints, and the patterns of selection in ciliates may reflect genome architecture; and (iii) stop codon reassignments vary among members of the Heterotrichea and Spirotrichea but are conserved in other classes.IMPORTANCE To further our understanding of genome evolution in eukaryotes, we assess the relationship between patterns of molecular evolution within gene families and variable genome structures found among ciliates. We combine single-cell transcriptomics with bioinformatic tools, focusing on understudied and uncultivable lineages selected from across the ciliate tree of life. Our analyses show that genome architecture correlates with patterns of protein evolution as lineages with more canonical somatic genomes, such as the class Karyorelictea, have more conserved patterns of molecular evolution compared to other classes. This study showcases the power of single-cell transcriptomics for investigating genome architecture and evolution in uncultivable microbial lineages and provides transcriptomic resources for further research on genome evolution.", + "year": "2019", + "author": "Yan, Ying and Maurer-Alcal{\\'a}, Xyrus X and Knight, Rob and Pond, Sergei L Kosakovsky and Katz, Laura A", + "journal": "mBio" + }, + { + "id": "Abrahams:2019aa", + "title": "The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation", + "abstract": "Although antiretroviral therapy (ART) is highly effective at suppressing HIV-1 replication, the virus persists as a latent reservoir in resting CD4+ T cells during therapy. This reservoir forms even when ART is initiated early after infection, but the dynamics of its formation are largely unknown. The viral reservoirs of individuals who initiate ART during chronic infection are generally larger and genetically more diverse than those of individuals who initiate therapy during acute infection, consistent with the hypothesis that the reservoir is formed continuously throughout untreated infection. To determine when viruses enter the latent reservoir, we compared sequences of replication-competent viruses from resting peripheral CD4+ T cells from nine HIV-positive women on therapy to viral sequences circulating in blood collected longitudinally before therapy. We found that, on average, 71% of the unique viruses induced from the post-therapy latent reservoir were most genetically similar to viruses replicating just before ART initiation. This proportion is far greater than would be expected if the reservoir formed continuously and was always long lived. We conclude that ART alters the host environment in a way that allows the formation or stabilization of most of the long-lived latent HIV-1 reservoir, which points to new strategies targeted at limiting the formation of the reservoir around the time of therapy initiation.", + "year": "2019", + "author": "Abrahams, Melissa-Rose and Joseph, Sarah B and Garrett, Nigel and Tyers, Lynn and Moeser, Matthew and Archin, Nancie and Council, Olivia D and Matten, David and Zhou, Shuntai and Doolabh, Deelan and Anthony, Colin and Goonetilleke, Nilu and Karim, Salim Abdool and Margolis, David M and Pond, Sergei Kosakovsky and Williamson, Carolyn and Swanstrom, Ronald", + "journal": "Sci Transl Med" + }, + { + "id": "Avanzato:2019aa", + "title": "A structural basis for antibody-mediated neutralization of Nipah virus reveals a site of vulnerability at the fusion glycoprotein apex", + "abstract": "Nipah virus (NiV) is a highly pathogenic paramyxovirus that causes frequent outbreaks of severe neurologic and respiratory disease in humans with high case fatality rates. The 2 glycoproteins displayed on the surface of the virus, NiV-G and NiV-F, mediate host-cell attachment and membrane fusion, respectively, and are targets of the host antibody response. Here, we provide a molecular basis for neutralization of NiV through antibody-mediated targeting of NiV-F. Structural characterization of a neutralizing antibody (nAb) in complex with trimeric prefusion NiV-F reveals an epitope at the membrane-distal domain III (DIII) of the molecule, a region that undergoes substantial refolding during host-cell entry. The epitope of this monoclonal antibody (mAb66) is primarily protein-specific and we observe that glycosylation at the periphery of the interface likely does not inhibit mAb66 binding to NiV-F. Further characterization reveals that a Hendra virus-F-specific nAb (mAb36) and many antibodies in an antihenipavirus-F polyclonal antibody mixture (pAb835) also target this region of the molecule. Integrated with previously reported paramyxovirus F-nAb structures, these data support a model whereby the membrane-distal region of the F protein is targeted by the antibody-mediated immune response across henipaviruses. Notably, our domain-specific sequence analysis reveals no evidence of selective pressure at this region of the molecule, suggestive that functional constraints prevent immune-driven sequence variation. Combined, our data reveal the membrane-distal region of NiV-F as a site of vulnerability on the NiV surface.", + "year": "2019", + "author": "Avanzato, Victoria A and Oguntuyo, Kasopefoluwa Y and Escalera-Zamudio, Marina and Gutierrez, Bernardo and Golden, Michael and Pond, Sergei L Kosakovsky and Pryce, Rhys and Walter, Thomas S and Seow, Jeffrey and Doores, Katie J and Pybus, Oliver G and Munster, Vincent J and Lee, Benhur and Bowden, Thomas A", + "journal": "Proc Natl Acad Sci U S A" + }, + { + "id": "Kosakovsky-Pond:2019aa", + "title": "HyPhy 2.5 - a customizable platform for evolutionary hypothesis testing using phylogenies", + "abstract": "hyphy (HYpothesis testing using PHYlogenies) is a scriptable, open-source package for fitting a broad range of evolutionary models to multiple sequence alignments, and for conducting subsequent parameter estimation and hypothesis testing, primarily in the maximum likelihood statistical framework. It has become a popular choice for characterizing various aspects of the evolutionary process: natural selection, evolutionary rates, recombination, and coevolution. The 2.5 release (available from www.hyphy.org) includes a completely re-engineered computational core and analysis library that introduces new classes of evolutionary models and statistical tests, delivers substantial performance and stability enhancements, improves usability, streamlines end-to-end analysis workflows, makes it easier to develop custom analyses, and is mostly backwards compatible with previous HyPhy releases.", + "year": "2019", + "author": "Pond, Sergei L Kosakovsky and Poon, Art F Y and Velazquez, Ryan and Weaver, Steven and Hepler, N Lance and Murrell, Ben and Shank, Stephen D and Magalis, Brittany Rife and Bouvier, Dave and Nekrutenko, Anton and Wisotsky, Sadie and Spielman, Stephanie J and Frost, Simon D W and Muse, Spencer V", + "journal": "Mol Biol Evol" + }, + { + "id": "Spielman:2019aa", + "title": "Evolution of Viral Genomes: Interplay Between Selection, Recombination, and Other Forces", + "abstract": "Natural selection is a fundamental force shaping organismal evolution, as it both maintains function and enables adaptation and innovation. Viruses, with their typically short and largely coding genomes, experience strong and diverse selective forces, sometimes acting on timescales that can be directly measured. These selection pressures emerge from an antagonistic interplay between rapidly changing fitness requirements (immune and antiviral responses from hosts, transmission between hosts, or colonization of new host species) and functional imperatives (the ability to infect hosts or host cells and replicate within hosts). Indeed, computational methods to quantify these evolutionary forces using molecular sequence data were initially, dating back to the 1980s, applied to the study of viral pathogens. This preference largely emerged because the strong selective forces are easiest to detect in viruses, and, of course, viruses have clear biomedical relevance. Recent commoditization of affordable high-throughput sequencing has made it possible to generate truly massive genomic data sets, on which powerful and accurate methods can yield a very detailed depiction of when, where, and (sometimes) how viral pathogens respond to various selective forces.Here, we present recent statistical developments and state-of-the-art methods to identify and characterize these selection pressures from protein-coding sequence alignments and phylogenies. Methods described here can reveal critical information about various evolutionary regimes, including whole-gene selection, lineage-specific selection, and site-specific selection acting upon viral genomes, while accounting for confounding biological processes, such as recombination and variation in mutation rates.", + "year": "2019", + "author": "Spielman, Stephanie J and Weaver, Steven and Shank, Stephen D and Magalis, Brittany Rife and Li, Michael and Pond, Sergei L Kosakovsky", + "journal": "Methods Mol Biol" + }, + { + "id": "Rhee:2019ab", + "title": "Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted Human Immunodeficiency Virus Type 1 Drug Resistance in a Large US Clinic Population", + "abstract": "Background: There are few large studies of transmitted drug resistance (TDR) prevalence and the drug resistance mutations (DRMs) responsible for TDR in the United States.\nMethods: Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and protease sequences were obtained from 4253 antiretroviral therapy (ART)-naive individuals in a California clinic population from 2003 to 2016. Phylogenetic analyses were performed to study linkages between TDR strains and selection pressure on TDR-associated DRMs.\nResults: From 2003 to 2016, there was a significant increase in overall (odds ratio [OR], 1.05 per year [95% confidence interval {CI}, 1.03-1.08]; P < .001) and nonnucleoside RT inhibitor (NNRTI)-associated TDR (OR, 1.11 per year [95% CI, 1.08-1.15]; P < .001). Between 2012 and 2016, TDR rates to any drug class ranged from 15.7% to 19.2%, and class-specific rates ranged from 10.0% to 12.8% for NNRTIs, 4.1% to 8.1% for nucleoside RT inhibitors (NRTIs), and 3.6% to 5.2% for protease inhibitors. The thymidine analogue mutations, M184V/I and the tenofovir-associated DRMs K65R and K70E/Q/G/N/T accounted for 82.9%, 7.3%, and 1.4% of NRTI-associated TDR, respectively. Thirty-seven percent of TDR strains clustered with other TDR strains sharing the same DRMs.\nConclusions: Although TDR has increased significantly in this large cohort, many TDR strains are unlikely to influence the activity of currently preferred first-line ART regimens. The high proportion of DRMs associated with infrequently used regimens combined with the clustering of TDR strains suggest that some TDR strains are being transmitted between ART-naive individuals.", + "year": "2019", + "author": "Rhee, Soo-Yon and Clutter, Dana and Fessel, W Jeffrey and Klein, Daniel and Slome, Sally and Pinsky, Benjamin A and Marcus, Julia L and Hurley, Leo and Silverberg, Michael J and Pond, Sergei L Kosakovsky and Shafer, Robert W", + "journal": "Clin Infect Dis" + }, + { + "id": "Eren:2018aa", + "title": "Full-Length Envelope Analyzer (FLEA): A tool for longitudinal analysis of viral amplicons", + "abstract": "Next generation sequencing of viral populations has advanced our understanding of viral population dynamics, the development of drug resistance, and escape from host immune responses. Many applications require complete gene sequences, which can be impossible to reconstruct from short reads. HIV env, the protein of interest for HIV vaccine studies, is exceptionally challenging for long-read sequencing and analysis due to its length, high substitution rate, and extensive indel variation. While long-read sequencing is attractive in this setting, the analysis of such data is not well handled by existing methods. To address this, we introduce FLEA (Full-Length Envelope Analyzer), which performs end-to-end analysis and visualization of long-read sequencing data. FLEA consists of both a pipeline (optionally run on a high-performance cluster), and a client-side web application that provides interactive results. The pipeline transforms FASTQ reads into high-quality consensus sequences (HQCSs) and uses them to build a codon-aware multiple sequence alignment. The resulting alignment is then used to infer phylogenies, selection pressure, and evolutionary dynamics. The web application provides publication-quality plots and interactive visualizations, including an annotated viral alignment browser, time series plots of evolutionary dynamics, visualizations of gene-wide selective pressures (such as dN/dS) across time and across protein structure, and a phylogenetic tree browser. We demonstrate how FLEA may be used to process Pacific Biosciences HIV env data and describe recent examples of its use. Simulations show how FLEA dramatically reduces the error rate of this sequencing platform, providing an accurate portrait of complex and variable HIV env populations. A public instance of FLEA is hosted at http://flea.datamonkey.org. The Python source code for the FLEA pipeline can be found at https://github.com/veg/flea-pipeline. The client-side application is available at https://github.com/veg/flea-web-app. A live demo of the P018 results can be found at http://flea.murrell.group/view/P018.", + "year": "2018", + "author": "Eren, Kemal and Weaver, Steven and Ketteringham, Robert and Valentyn, Morn{\\'e} and Laird Smith, Melissa and Kumar, Venkatesh and Mohan, Sanjay and Pond, Sergei L Kosakovsky and Murrell, Ben", + "journal": "PLoS Comput Biol" + }, + { + "id": "Dalai:2018aa", + "title": "Combining Phylogenetic and Network Approaches to Identify HIV-1 Transmission Links in San Mateo County, California", + "abstract": "The HIV epidemic in San Mateo County is sustained by multiple overlapping risk groups and is an important hub for HIV transmission in northern California. Limited access to care has led historically to delayed clinical presentation, higher rates of opportunistic infections, and an increased prevalence of antiretroviral drug resistance. The virologic and clinical consequences of treatment within these multiple ethnic and behavioral groups are poorly understood, highlighting the need for efficient surveillance strategies that are able to elucidate transmission networks and drug resistance patterns. We obtained sequence data from a group of 316 HIV-positive individuals in the San Mateo AIDS Program over a 14-year period and integrated epidemiologic, phylogenetic, and network approaches to characterize transmission clusters, risk factors and drug resistance. Drug resistance mutations were identified using the Stanford HIV Drug Resistance Database. A maximum likelihood tree was inferred in RAxML and subjected to clustering analysis in Cluster Picker. Network analysis using pairwise genetic distances was performed in HIV-TRACE. Participants were primarily male (60%), white Hispanics and non-Hispanics (32%) and African American (20.6%). The most frequent behavior risk factor was male-male sex (33.5%), followed by heterosexual (23.4%) and injection drug use (9.5%). Nearly all sequences were subtype B (96%) with subtypes A, C, and CRF01_AE also observed. Sequences from 65% of participants had at least one drug resistance mutation. Clustered transmissions included a higher number of women when compared to non-clustered individuals and were more likely to include heterosexual or people who inject drugs (PWID). Detailed analysis of the largest network (N = 47) suggested that PWID played a central role in overall transmission of HIV-1 as well as bridging men who have sex with men (MSM) transmission with heterosexual/PWID among primarily African American men. Combined phylogenetic and network analysis of HIV sequence data identified several overlapping risk factors in the epidemic, including MSM, heterosexual and PWID transmission with a disproportionate impact on African Americans and a high prevalence of drug resistance.", + "year": "2018", + "author": "Dalai, Sudeb C and Junqueira, Dennis Maletich and Wilkinson, Eduan and Mehra, Renee and Pond, Sergei L Kosakovsky and Levy, Vivian and Israelski, Dennis and de Oliveira, Tulio and Katzenstein, David", + "journal": "Front Microbiol" + }, + { + "id": "Rhee:2019aa", + "title": "National and International Dimensions of Human Immunodeficiency Virus-1 Sequence Clusters in a Northern California Clinical Cohort", + "abstract": "Background: Recent advances in high-throughput molecular epidemiology are transforming the analysis of viral infections.\nMethods: Human immunodeficiency virus (HIV)-1 pol sequences from a Northern Californian cohort (NCC) of 4553 antiretroviral-naive individuals sampled between 1998 and 2016 were analyzed together with 140 000 previously published global pol sequences. The HIV-TRAnsmission Cluster Engine (HIV-TRACE) was used to infer a transmission network comprising links between NCC and previously published sequences having a genetic distance ≤1.5%.\nResults: Twenty-five percent of NCC sequences were included in 264 clusters linked to a published sequence, and approximately one third of these (8.0% of the total) were linked to 1 or more non-US sequences. The largest cluster, containing 512 NCC sequences (11.2% of the total), comprised the subtype B lineage that traced its origin to the earliest North American sequences. Approximately 5 percent of NCC sequences belonged to a non-B subtype, and these were more likely to cluster with a non-US sequence. Twenty-two NCC sequences belonged to 1 of 4 large clusters containing sequences from rapidly growing regional epidemics: CRF07_BC (East Asia), subtype A6 (former Soviet Union), a Japanese subtype B lineage, and an East/Southeast Asian CRF01_AE lineage. Bayesian phylogenetics suggested that most non-B sequences resulted from separate introductions but that local spread within the largest CRF01_AE cluster occurred twice.\nConclusions: The NCC contains national and international links to previously published sequences including many to the subtype B strain that originated in North America and several to rapidly growing Asian epidemics. Despite their rapid regional growth, the Asian epidemic strains demonstrated limited NCC spread.", + "year": "2019", + "author": "Rhee, Soo-Yon and Magalis, Brittany R and Hurley, Leo and Silverberg, Michael J and Marcus, Julia L and Slome, Sally and Pond, Sergei L Kosakovsky and Shafer, Robert W", + "journal": "Open Forum Infect Dis" + }, + { + "id": "Wertheim:2018aa", + "title": "Growth of HIV-1 Molecular Transmission Clusters in New York City", + "abstract": "Background: HIV-1 genetic sequences can be used to infer viral transmission history and dynamics. Throughout the United States, HIV-1 sequences from drug resistance testing are reported to local public health departments.\nMethods: We investigated whether inferred HIV transmission network dynamics can identify individuals and clusters of individuals most likely to give rise to future HIV cases in a surveillance setting. We used HIV-TRACE, a genetic distance-based clustering tool, to infer molecular transmission clusters from HIV-1 pro/RT sequences from 65,736 people in the New York City surveillance registry. Logistic and LASSO regression analyses were used to identify correlates of clustering and cluster growth, respectively. We performed retrospective transmission network analyses to evaluate individual- and cluster-level prioritization schemes for identifying parts of the network most likely to give rise to new cases in the subsequent year.\nResults: Individual-level prioritization schemes predicted network growth better than random targeting. Across the 3,600 inferred molecular transmission clusters, previous growth dynamics were superior predictors of future transmission cluster growth compared to individual-level prediction schemes. Cluster-level prioritization schemes considering previous cluster growth relative to cluster size further improved network growth predictions.\nConclusions: Prevention efforts based on HIV molecular epidemiology may improve public health outcomes in a U.S. surveillance setting.", + "year": "2018", + "author": "Wertheim, Joel O and Murrell, Ben and Mehta, Sanjay R and Forgione, Lisa A and Pond, Sergei L Kosakovsky and Smith, Davey M and Torian, Lucia V", + "journal": "J Infect Dis" + }, + { + "id": "Shank:2018aa", + "title": "phylotree.js - a JavaScript library for application development and interactive data visualization in phylogenetics", + "abstract": "BACKGROUND: While several JavaScript packages for visualizing phylogenetic trees exist, most are best characterized as frameworks that are designed with a specific set of tasks in mind. Extending such packages to use cases that are not available as features often ends up being difficult. Moreover, existing packages tend to produce standalone widgets that are not designed to serve as middleware, as opposed to flexible tools that can integrate with other components of an application.\nRESULTS: phylotree.js is a library that extends the popular data visualization framework d3.js, and is suitable for building JavaScript applications where users can view and interact with phylogenetic trees. The effects of such interactions can be captured and communicated to other package components, making it possible to engineer complex and responsive applications that include phylogenetic trees. phylotree.js implements several abstractions in addition to features, and comes with a documented application programming interface, thus promoting interoperability and extensibility. Example applications include a tool to visualize and annotate phylogenetic trees, a web application for comparative sequence analysis, a structural viewer that interacts with a large phylogenetic tree, and an interactive tanglegram.\nCONCLUSIONS: phylotree.js is a useful tool and application module for a variety of computational biology software applications. The code is available on Github and is released under the MIT license.", + "year": "2018", + "author": "Shank, Stephen D and Weaver, Steven and Pond, Sergei L Kosakovsky", + "journal": "BMC Bioinformatics" + }, + { + "id": "Tzou:2018aa", + "title": "Selection analyses of paired HIV-1 gag and gp41 sequences obtained before and after antiretroviral therapy", + "abstract": "Most HIV-1-infected individuals with virological failure on a pharmacologically-boosted protease inhibitor (PI) regimen do not develop PI-resistance protease mutations. One proposed explanation is that HIV-1 gag or gp41 cytoplasmic domain mutations might also reduce PI susceptibility. In a recent study of paired gag and gp41 sequences from individuals with virological failure on a PI regimen, we did not identify PI-selected mutations and concluded that if such mutations existed, larger numbers of paired sequences from multiple studies would be needed for their identification. In this study, we generated site-specific amino acid profiles using gag and gp41 published sequences from 5,338 and 4,242 ART-na{\\\"\\i}ve individuals, respectively, to assist researchers identify unusual mutations arising during therapy and to provide scripts for performing established and novel maximal likelihood estimates of dN/dS substitution rates in paired sequences. The pipelines used to generate the curated sequences, amino acid profiles, and dN/dS analyses will facilitate the application of consistent methods to paired gag and gp41 sequence datasets and expedite the identification of potential sites under PI-selection pressure.", + "year": "2018", + "author": "Tzou, Philip L and Rhee, Soo-Yon and Pond, Sergei L Kosakovsky and Manasa, Justen and Shafer, Robert W", + "journal": "Sci Data" + }, + { + "id": "Pacheco:2018qf", + "title": "Mode and Rate of Evolution of Haemosporidian Mitochondrial Genomes: Timing the Radiation of Avian Parasites", + "abstract": "Haemosporidians are a diverse group of vector-borne parasitic protozoa that includes the agents of human malaria; however, most of the described species are found in birds and reptiles. Although our understanding of these parasites' diversity has expanded by analyses of their mitochondrial genes, there is limited information on these genes' evolutionary rates. Here, 114 mitochondrial genomes (mtDNA) were studied from species belonging to four genera: Leucocytozoon, Haemoproteus, Hepatocystis, and Plasmodium. Contrary to previous assertions, the mtDNA is phylogenetically informative. The inferred phylogeny showed that, like the genus Plasmodium, the Leucocytozoon and Haemoproteus genera are not monophyletic groups. Although sensitive to the assumptions of the molecular dating method used, the estimated times indicate that the diversification of the avian haemosporidian subgenera/genera took place after the Cretaceous-Paleogene boundary following the radiation of modern birds. Furthermore, parasite clade differences in mtDNA substitution rates and strength of negative selection were detected. These differences may affect the biological interpretation of mtDNA gene lineages used as a proxy to species in ecological and parasitological investigations. Given that the mitochondria are critically important in the parasite life cycle stages that take place in the vector and that the transmission of parasites belonging to particular clades has been linked to specific insect families/subfamilies, this study suggests that differences in vectors have affected the mode of evolution of haemosporidian mtDNA genes. The observed patterns also suggest that the radiation of haemosporidian parasites may be the result of community-level evolutionary processes between their vertebrate and invertebrate hosts.", + "year": "2018", + "author": "Pacheco, M Andre{\\'\\i}na and Matta, Nubia E and Valkiunas, Gediminas and Parker, Patricia G and Mello, Beatriz and Stanley, Jr, Craig E and Lentino, Miguel and Garcia-Amado, Maria Alexandra and Cranfield, Michael and Pond, Sergei L Kosakovsky and Escalante, Ananias A", + "journal": "Mol Biol Evol" + }, + { + "id": "Rife-Magalis:2018ys", + "title": "Evaluation of global HIV/SIV envelope gp120 RNA structure and evolution within and among infected hosts", + "abstract": "Lentiviral RNA genomes contain structural elements that play critical roles in viral replication. Although structural features of 5'-untranslated regions have been well characterized, attempts to identify important structures in other genomic regions by Selective 2'-Hydroxyl Acylation analyzed by Primer Extension (SHAPE) have led to conflicting structural and mechanistic conclusions. Previous approaches accounted neither for sequence heterogeneity that is ubiquitous in viral populations, nor for selective constraints operating at the protein level. We developed an approach that augments SHAPE with phylogenetic analyses and applied it to investigate structure in coding regions (cRNA) within the HIV and SIV envelope genes. Analysis of single-genome SHAPE data with phylogenetic information from diverse lentiviral sequences argues against the conservation of a putative global gp120 RNA structure but points to the existence of core RNA sub-structures. Our findings establish a framework for considering sequence heterogeneity and protein function in de novo RNA structure inference approaches.", + "year": "2018", + "author": "Rife Magalis, Brittany and Pond, Sergei L Kosakovsky and Summers, Michael F and Salemi, Marco", + "journal": "Virus Evol" + }, + { + "id": "Rhee:2018vn", + "title": "Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance in a Large U.S. Clinic Population", + "abstract": "Background: There are few large studies of transmitted drug resistance (TDR) prevalence and the drug resistance mutations (DRMs) responsible for TDR in the U.S.\nMethods: HIV-1 RT and protease sequences were obtained from 4,253 antiretroviral therapy (ART)-na{\\\"\\i}ve individuals in a California clinic population from 2003-2016. Phylogenetic analyses were performed to study linkages between TDR strains and selection pressure on TDR-associated DRMs.\nResults: From 2003-2016, there was a significant increase in overall (odds ratio [OR]=1.05 per year; 95% CI: 1.03 - 1.08; p<0.001) and nonnucleoside RT inhibitor (NNRTI)-associated TDR (OR=1.11 per year; 95% CI: 1.08 - 1.15; p<0.001). Between 2012 and 2016, TDR rates to any drug class ranged from 15.7%-19.2%, and class-specific rates ranged from 10.0%-12.8% for NNRTIs, 4.1%-8.1% for nucleoside RT inhibitors (NRTIs), and 3.6%-5.2% for protease inhibitors. K103N/S, Y181C, Y188L, and G190A mutations accounted for 88.5% of NNRTI-associated TDR. The thymidine analog mutations, M184V/I, and the tenofovir-associated DRMs K65R and K70E/Q/G/N/T accounted for 82.9%, 7.3%, and 1.4% of NRTI-associated TDR, respectively. The proportions of individuals with low-level resistance or higher to boosted atazanavir and darunavir were 2.2% and 0.3%, respectively. 37% of TDR strains clustered with other TDR strains sharing the same DRMs.\nConclusions: Although TDR has increased significantly in this large cohort, many TDR strains are unlikely to influence the activity of currently preferred first-line ART regimens. The high proportion of DRMs associated with infrequently used regimens combined with the clustering of TDR strains suggest that some TDR strains are being transmitted between ART-na{\\\"\\i}ve individuals.", + "year": "2018", + "author": "Rhee, Soo-Yon and Clutter, Dana and Fessel, W Jeffrey and Klein, Daniel and Slome, Sally and Pinsky, Benjamin A and Marcus, Julia L and Hurley, Leo and Silverberg, Michael J and Pond, Sergei L Kosakovsky and Shafer, Robert W", + "journal": "Clin Infect Dis" + }, + { + "id": "Frost:2018kx", + "title": "Neutral Theory and Rapidly Evolving Viral Pathogens", + "abstract": "The evolution of viral pathogens is shaped by strong selective forces that are exerted during jumps to new hosts, confrontations with host immune responses and antiviral drugs, and numerous other processes. However, while undeniably strong and frequent, adaptive evolution is largely confined to small parts of information-packed viral genomes, and the majority of observed variation is effectively neutral. The predictions and implications of the neutral theory have proven immensely useful in this context, with applications spanning understanding within-host population structure, tracing the origins and spread of viral pathogens, predicting evolutionary dynamics, and modeling the emergence of drug resistance. We highlight the multiple ways in which the neutral theory has had an impact, which has been accelerated in the age of high-throughput, high-resolution genomics.", + "year": "2018", + "author": "Frost, Simon D W and Magalis, Brittany Rife and Pond, Sergei L Kosakovsky", + "journal": "Mol Biol Evol" + }, + { + "id": "Spielman:2018uq", + "title": "Relative evolutionary rates in proteins are largely insensitive to the substitution model", + "abstract": "The relative evolutionary rates at individual sites in proteins are informative measures of conservation or adaptation. Often used as evolutionarily-aware conservation scores, relative rates reveal key functional or strongly-selected residues. Estimating rates in a phylogenetic context requires specifying a protein substitution model, which is typically a phenomenological model trained on a large empirical dataset. A strong emphasis has traditionally been placed on selecting the \"best-fit\" model, with the implicit understanding that suboptimal or otherwise ill-fitting models might bias inferences. However, the pervasiveness and degree of such bias has not been systematically examined. We investigated how model choice impacts site-wise relative rates in a large set of empirical protein alignments. We compared models designed for use on any general protein, models designed for specific domains of life, and the simple equal-rates Jukes Cantor-style model (JC). As expected, information theoretic measures showed overwhelming evidence that some models fit the data decidedly better than others. By contrast, estimates of site-specific evolutionary rates were impressively insensitive to the substitution model used, revealing an unexpected degree of robustness to potential model misspecification. A deeper examination of the fewer than 5% of sites for which model inferences differed in a meaningful way showed that the JC model could uniquely identify rapidly-evolving sites that models with empirically-derived exchangeabilities failed to detect. We conclude that relative protein rates appear robust to the applied substitution model, and any sensible model of protein evolution, regardless of its fit to the data, should produce broadly consistent evolutionary rates.", + "year": "2018", + "author": "Spielman, Stephanie J and Pond, Sergei L Kosakovsky", + "journal": "Mol Biol Evol" + }, + { + "id": "Kosakovsky-Pond:2018fk", + "title": "HIV-TRACE (TRAnsmission Cluster Engine): a Tool for Large Scale Molecular Epidemiology of HIV-1 and Other Rapidly Evolving Pathogens", + "abstract": "In modern applications of molecular epidemiology, genetic sequence data are routinely used to identify clusters of transmission in rapidly evolving pathogens, most notably HIV-1. Traditional 'shoe-leather' epidemiology infers transmission clusters by tracing chains of partners sharing epidemiological connections (e.g., sexual contact). Here, we present a computational tool for identifying a molecular transmission analog of such clusters: HIV-TRACE (TRAnsmission Cluster Engine). HIV-TRACE implements an approach inspired by traditional epidemiology, by identifying chains of partners whose viral genetic relatedness imply direct or indirect epidemiological connections. Molecular transmission clusters are constructed using codon-aware pairwise alignment to a reference sequence followed by pairwise genetic distance estimation among all sequences. This approach is computationally tractable and is capable of identifying HIV-1 transmission clusters in large surveillance databases comprising tens or hundreds of thousands of sequences in near real time, that is, on the order of minutes to hours. HIV-TRACE is available at www.hivtrace.org and from www.github.com/veg/hivtrace, along with the accompanying result visualization module from www.github.com/veg/hivtrace-viz. Importantly, the approach underlying HIV-TRACE is not limited to the study of HIV-1 and can be applied to study outbreaks and epidemics of other rapidly evolving pathogens.", + "year": "2018", + "author": "Pond, Sergei L Kosakovsky and Weaver, Steven and Leigh Brown, Andrew J and Wertheim, Joel O", + "journal": "Mol Biol Evol" + }, + { + "id": "Spielman:2018aa", + "title": "Relative evolutionary rate inference in HyPhy with LEISR", + "abstract": "We introduce LEISR (Likehood Estimation of Individual Site Rates, pronounced \"laser\"), a tool to infer relative evolutionary rates from protein and nucleotide data, implemented in HyPhy. LEISR is based on the popular Rate4Site (Pupko et al., 2002) approach for inferring relative site-wise evolutionary rates, primarily from protein data. We extend the original method for more general use in several key ways: (i) we increase the support for nucleotide data with additional models, (ii) we allow for datasets of arbitrary size, (iii) we support analysis of site-partitioned datasets to correct for the presence of recombination breakpoints, (iv) we produce rate estimates at all sites rather than at just a subset of sites, and (v) we implemented LEISR as MPI-enabled to support rapid, high-throughput analysis. LEISR is available in HyPhy starting with version 2.3.8, and it is accessible as an option in the HyPhy analysis menu (\"Relative evolutionary rate inference\"), which calls the HyPhy batchfile LEISR.bf.", + "year": "2018", + "author": "Spielman, Stephanie J and Pond, Sergei L Kosakovsky", + "journal": "PeerJ" + }, + { + "id": "Weaver:2018aa", + "title": "Datamonkey 2.0: a modern web application for characterizing selective and other evolutionary processes", + "abstract": "Inference of how evolutionary forces have shaped extant genetic diversity is a cornerstone of modern comparative sequence analysis. Advances in sequence generation and increased statistical sophistication of relevant methods now allow researchers to extract ever more evolutionary signal from the data, albeit at an increased computational cost. Here, we announce the release of Datamonkey 2.0, a completely re-engineered version of the Datamonkey web-server for analyzing evolutionary signatures in sequence data. For this endeavor, we leveraged recent developments in open-source libraries that facilitate interactive, robust, and scalable web application development. Datamonkey 2.0 provides a carefully curated collection of methods for interrogating coding-sequence alignments for imprints of natural selection, packaged as a responsive (i.e. can be viewed on tablet and mobile devices), fully interactive, and API-enabled web application. To complement Datamonkey 2.0, we additionally release HyPhy Vision, an accompanying JavaScript application for visualizing analysis results. HyPhy Vision can also be used separately from Datamonkey 2.0 to visualize locally-executed HyPhy analyses. Together, Datamonkey 2.0 and HyPhy Vision showcase how scientific software development can benefit from general-purpose open-source frameworks. Datamonkey 2.0 is freely and publicly available at http://www.datamonkey. org, and the underlying codebase is available from https://github.com/veg/datamonkey-js.", + "year": "2018", + "author": "Weaver, Steven and Shank, Stephen D and Spielman, Stephanie J and Li, Michael and Muse, Spencer V and Pond, Sergei L Kosakovsky", + "journal": "Mol Biol Evol" + }, + { + "id": "Landais:2017aa", + "title": "HIV Envelope Glycoform Heterogeneity and Localized Diversity Govern the Initiation and Maturation of a V2 Apex Broadly Neutralizing Antibody Lineage", + "abstract": "Understanding how broadly neutralizing antibodies (bnAbs) to HIV envelope (Env) develop during natural infection can help guide the rational design of an HIV vaccine. Here, we described a bnAb lineage targeting the Env V2 apex and the Ab-Env co-evolution that led to development of neutralization breadth. The lineage Abs bore an anionic heavy chain complementarity-determining region 3 (CDRH3) of 25 amino acids, among the shortest known for this class of Abs, and achieved breadth with only 10% nucleotide somatic hypermutation and no insertions or deletions. The data suggested a role for Env glycoform heterogeneity in the activation of the lineage germline B cell. Finally, we showed that localized diversity at key V2 epitope residues drove bnAb maturation toward breadth, mirroring the Env evolution pattern described for another donor who developed V2-apex targeting bnAbs. Overall, these findings suggest potential strategies for vaccine approaches based on germline-targeting and serial immunogen design.", + "year": "2017", + "author": "Landais, Elise and Murrell, Ben and Briney, Bryan and Murrell, Sasha and Rantalainen, Kimmo and Berndsen, Zachary T and Ramos, Alejandra and Wickramasinghe, Lalinda and Smith, Melissa Laird and Eren, Kemal and de Val, Natalia and Wu, Mengyu and Cappelletti, Audrey and Umotoy, Jeffrey and Lie, Yolanda and Wrin, Terri and Algate, Paul and Chan-Hui, Po-Ying and Karita, Etienne and {IAVI Protocol C Investigators} and {IAVI African HIV Research Network} and Ward, Andrew B and Wilson, Ian A and Burton, Dennis R and Smith, Davey and Pond, Sergei L Kosakovsky and Poignard, Pascal", + "journal": "Immunity" + }, + { + "id": "Lorenzo-Redondo:2017aa", + "title": "Lorenzo-Redondo et al. reply", + "year": "2017", + "author": "Lorenzo-Redondo, Ramon and Fryer, Helen R and Bedford, Trevor and Kim, Eun-Young and Archer, John and Pond, Sergei L Kosakovsky and Chung, Yoon-Seok and Penugonda, Sudhir and Chipman, Jeffrey G and Fletcher, Courtney V and Schacker, Timothy W and Malim, Michael H and Rambaut, Andrew and Haase, Ashley T and McLean, Angela R and Wolinsky, Steven M", + "journal": "Nature" + }, + { + "id": "Manasa:2017aa", + "title": "Evolution of gag and gp41 in Patients Receiving Ritonavir-Boosted Protease Inhibitors", + "abstract": "Several groups have proposed that genotypic determinants in gag and the gp41 cytoplasmic domain (gp41-CD) reduce protease inhibitor (PI) susceptibility without PI-resistance mutations in protease. However, no gag and gp41-CD mutations definitively responsible for reduced PI susceptibility have been identified in individuals with virological failure (VF) while receiving a boosted PI (PI/r)-containing regimen. To identify gag and gp41 mutations under selective PI pressure, we sequenced gag and/or gp41 in 61 individuals with VF on a PI/r (n = 40) or NNRTI (n = 20) containing regimen. We quantified nonsynonymous and synonymous changes in both genes and identified sites exhibiting signal for directional or diversifying selection. We also used published gag and gp41 polymorphism data to highlight mutations displaying a high selection index, defined as changing from a conserved to an uncommon amino acid. Many amino acid mutations developed in gag and in gp41-CD in both the PI- and NNRTI-treated groups. However, in neither gene, were there discernable differences between the two groups in overall numbers of mutations, mutations displaying evidence of diversifying or directional selection, or mutations with a high selection index. If gag and/or gp41 encode PI-resistance mutations, they may not be confined to consistent mutations at a few sites.", + "year": "2017", + "author": "Manasa, Justen and Varghese, Vici and Pond, Sergei L Kosakovsky and Rhee, Soo-Yon and Tzou, Philip L and Fessel, W Jeffrey and Jang, Karen S and White, Elizabeth and R{\\\"o}gnvaldsson, Thorsteinn and Katzenstein, David A and Shafer, Robert W", + "journal": "Sci Rep" + }, + { + "id": "Forrester:2017aa", + "title": "Evolution and spread of Venezuelan equine encephalitis complex alphavirus in the Americas", + "abstract": "Venezuelan equine encephalitis (VEE) complex alphaviruses are important re-emerging arboviruses that cause life-threatening disease in equids during epizootics as well as spillover human infections. We conducted a comprehensive analysis of VEE complex alphaviruses by sequencing the genomes of 94 strains and performing phylogenetic analyses of 130 isolates using complete open reading frames for the nonstructural and structural polyproteins. Our analyses confirmed purifying selection as a major mechanism influencing the evolution of these viruses as well as a confounding factor in molecular clock dating of ancestors. Times to most recent common ancestors (tMRCAs) could be robustly estimated only for the more recently diverged subtypes; the tMRCA of the ID/IAB/IC/II and IE clades of VEE virus (VEEV) were estimated at ca. 149-973 years ago. Evolution of the IE subtype has been characterized by a significant evolutionary shift from the rest of the VEEV complex, with an increase in structural protein substitutions that are unique to this group, possibly reflecting adaptation to its unique enzootic mosquito vector Culex (Melanoconion) taeniopus. Our inferred tree topologies suggest that VEEV is maintained primarily in situ, with only occasional spread to neighboring countries, probably reflecting the limited mobility of rodent hosts and mosquito vectors.", + "year": "2017", + "author": "Forrester, Naomi L and Wertheim, Joel O and Dugan, Vivian G and Auguste, Albert J and Lin, David and Adams, A Paige and Chen, Rubing and Gorchakov, Rodion and Leal, Grace and Estrada-Franco, Jose G and Pandya, Jyotsna and Halpin, Rebecca A and Hari, Kumar and Jain, Ravi and Stockwell, Timothy B and Das, Suman R and Wentworth, David E and Smith, Martin D and Pond, Sergei L Kosakovsky and Weaver, Scott C", + "journal": "PLoS Negl Trop Dis" + }, + { + "id": "Brayne:2017aa", + "title": "Genotype-Specific Evolution of Hepatitis E Virus", + "abstract": "Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis globally. HEV comprises four genotypes with different geographic distributions and host ranges. We utilize this natural case-control study for investigating the evolution of zoonotic viruses compared to single-host viruses, using 244 near-full-length HEV genomes. Genome-wide estimates of the ratio of nonsynonymous to synonymous evolutionary changes (dN/dS ratio) located a region of overlapping reading frames, which is subject to positive selection in genotypes 3 and 4. The open reading frames (ORFs) involved have functions related to host-pathogen interaction, so genotype-specific evolution of these regions may reflect their fitness. Bayesian inference of evolutionary rates shows that genotypes 3 and 4 have significantly higher rates than genotype 1 across all ORFs. Reconstruction of the phylogenies of zoonotic genotypes demonstrates significant intermingling of isolates between hosts. We speculate that the genotype-specific differences may result from cyclical adaptation to different hosts in genotypes 3 and 4.IMPORTANCE Hepatitis E virus (HEV) is increasingly recognized as a pathogen that affects both the developing and the developed world. While most often clinically mild, HEV can be severe or fatal in certain demographics, such as expectant mothers. Like many other viral pathogens, HEV has been classified into several distinct genotypes. We show that most of the HEV genome is evolutionarily constrained. One locus of positive selection is unusual in that it encodes two distinct protein products. We are the first to detect positive selection in this overlap region. Genotype 1, which infects humans only, appears to be evolving differently from genotypes 3 and 4, which infect multiple species, possibly because genotypes 3 and 4 are unable to achieve the same fitness due to repeated host jumps.", + "year": "2017", + "author": "Brayne, Adam B and Dearlove, Bethany L and Lester, James S and Pond, Sergei L Kosakovsky and Frost, Simon D W", + "journal": "J Virol" + }, + { + "id": "El-Bannoudi:2017aa", + "title": "Unbiased RACE-Based Massive Parallel Surveys of Human IgA Antibody Repertoires", + "abstract": "For investigations of human B-cell receptor (BCR) repertoires, we have developed a protocol for large-scale surveys of human antibody heavy chain (VH) rearrangements. Here we study IgA repertoires, as more IgA antibodies are synthesized in the human body on a daily level than all other isotypes combined. In fact, IgA is secreted at all mucosal surfaces, and it is also secreted in the perspiration that coats our cutaneous surfaces. In these studies we can characterize the IgA clonal diversity of B-cell populations obtained from any donor. To recover representative repertoire libraries, we make our libraries from antibody gene transcript templates (i.e., cDNA), as these are closer reflections of the immune repertoire expressed at the antibody protein level. To avoid biases potentially introduced by upstream oligonucleotide primers that hybridize to variable region framework regions, our approach also uses rapid amplification of cDNA ends (RACE) of antibody transcripts. For exploration of human IgA responses, we have designed a duplexing antisense constant region primer that efficiently amplifies, side-by-side, heavy chain transcripts of both the IgA1 and IgA2 subclasses. By these methods we have begun to define the molecular differences in the IgA1 and IgA2 responses occurring simultaneously in different donors. These methods will be used to investigate the effects of microbial virulence factors on host defenses, during autoimmune responses, and in B-cell malignancies.", + "year": "2017", + "author": "El Bannoudi, Hanane and Anquetil, C{\\'e}line and Braunstein, Marc J and Pond, Sergei L Kosakovsky and Silverman, Gregg J", + "journal": "Methods Mol Biol" + }, + { + "id": "Wagner:2017aa", + "title": "Intrasubtype B HIV-1 Superinfection Correlates with Delayed Neutralizing Antibody Response", + "abstract": "Understanding whether the neutralizing antibody (NAb) response impacts HIV-1 superinfection and how superinfection subsequently modulates the NAb response can help clarify correlates of protection from HIV exposures and better delineate pathways of NAb development. We examined associations between the development of NAb and the occurrence of superinfection in a well-characterized, antiretroviral therapy (ART)-naive, primary infection cohort of men who have sex with men. Deep sequencing was applied to blood plasma samples from the cohort to detect cases of superinfection. We compared the NAb activity against autologous and heterologous viruses between 10 participants with intrasubtype B superinfection and 19 monoinfected controls, matched to duration of infection and risk behavior. Three to 6 months after primary infection, individuals who would later become superinfected had significantly weaker NAb activity against tier 1 subtype B viruses (P = 0.003 for SF-162 and P = 0.017 for NL4-3) and marginally against autologous virus (P = 0.054). Lower presuperinfection NAb responses correlated with weaker gp120 binding and lower plasma total IgG titers. Soon after superinfection, the NAb response remained lower, but between 2 and 3 years after primary infection, NAb levels strengthened and reached those of controls. Superinfecting viruses were typically not susceptible to neutralization by presuperinfection plasma. These observations suggest that recently infected individuals with a delayed NAb response against primary infecting and tier 1 subtype B viruses are more susceptible to superinfection.IMPORTANCE Our findings suggest that within the first year after HIV infection, a relatively weak neutralizing antibody response against primary and subtype-specific neutralization-sensitive viruses increases susceptibility to superinfection in the face of repeated exposures. As natural infection progresses, the immune response strengthens significantly in some superinfected individuals. These findings will inform HIV vaccine design by providing testable correlates of protection from initial HIV infection.", + "year": "2017", + "author": "Wagner, Gabriel A and Landais, Elise and Caballero, Gemma and Phung, Pham and Pond, Sergei L Kosakovsky and Poignard, Pascal and Richman, Douglas D and Little, Susan J and Smith, Davey M", + "journal": "J Virol" + }, + { + "id": "Choi:2017aa", + "title": "Molecular Features of the V1-V4 Coding Region of Sexually Transmitted Human Immunodeficiency Virus Type 1", + "abstract": "Background.: Investigations into which human immunodeficiency virus type 1 (HIV-1) sequence features may be selected for transmission during sexual exposure have been hampered by the small number of characterized transmission pairs in individual studies.\nMethods.: To boost statistical power to detect differences in glycosylation, length, and electrical charge in the HIV-1 V1-V4 coding region, we reanalyzed all available 2485 env sequences derived from 114 subjects representing 58 transmission pairs from previous studies using mixed-effects linear regression and an approach to approximate the unobserved transmitted virus.\nResults.: The recipient partner had a shorter V1-V4 region and fewer potential N-linked glycosylation sites (PNGS) than sequences from the source partner. We also detected a trend toward more PNGS and lower isoelectric points in transmitted sequences with source partner and the evolutionary tendency to shorten V1-V4 sequences, reduce the number of PNGS, and lower isoelectric points in the recipient following transmission.\nConclusions.: By using all available well-characterized env sequences from transmission pairs via sexual exposure, we were able to identify several important virologic factors that may be important in the development of biomedical preventive interventions.", + "year": "2017", + "author": "Choi, Jun Yong and Pond, Sergei L Kosakovsky and Anderson, Christy M and Richman, Douglas D and Smith, Davey M", + "journal": "J Infect Dis" + }, + { + "id": "doi:10.1093/ve/vew018", + "title": "Rapid Sequencing of Complete env Genes from Primary HIV-1 Samples", + "year": "2016", + "author": "Laird Smith, Melissa and Murrell, Ben and Eren, Kemal and Ignacio, Caroline and Landais, Elise and Weaver, Steven and Phung, Pham and Ludka, Colleen and Hepler, Lance and Caballero, Gemma and Pollner, Tristan and Guo, Yan and Richman, Douglas and , and Poignard, Pascal and Paxinos, Ellen E. and Pond, Sergei L Kosakovsky. and Smith, Davey M.", + "journal": "Virus Evolution" + }, + { + "id": "Green:2017aa", + "title": "Partner services in adults with acute and early HIV infection", + "abstract": "BACKGROUND: To examine the yield of HIV partner services provided to persons newly diagnosed with acute and early HIV infection (AEH) in San Diego, United States.\nDESIGN: Observational cohort study.\nMETHODS: The study investigated the yield (i.e. number of new HIV and AEH diagnoses, genetically linked partnerships and high-risk uninfected partners) of partner services (confidential contact tracing) for individuals with AEH enrolled in the San Diego Primary Infection Resource Consortium 1996-2014.\nRESULTS: A total of 107 of 574 persons with AEH (19%; i.e. index cases) provided sufficient information to recruit 119 sex partners. Fifty-seven percent of the 119 recruited partners were HIV infected, and 33% of the 119 were newly HIV diagnosed. Among those newly HIV diagnosed, 36% were diagnosed during AEH. There were no significant demographic or behavioral risk differences between HIV-infected and HIV-uninfected recruited partners. Genetic sequences were available for both index cases and partners in 62 partnerships, of which 61% were genetically linked. Partnerships in which both index case and partner enrolled within 30 days were more likely to yield a new HIV diagnosis (P = 0.01) and to be genetically linked (P < 0.01).\nCONCLUSION: Partner services for persons with AEH within 30 days of diagnosis represents an effective tool to find HIV-unaware persons, including those with AEH who are at greatest risk of HIV transmission.", + "year": "2017", + "author": "Green, Nella and Hoenigl, Martin and Chaillon, Antoine and Anderson, Christy M and Pond, Sergei L Kosakovsky and Smith, Davey M and Little, Susan J", + "journal": "AIDS" + }, + { + "id": "Wertheim:2017aa", + "title": "Social and Genetic Networks of HIV-1 Transmission in New York City", + "abstract": "BACKGROUND: Sexually transmitted infections spread across contact networks. Partner elicitation and notification are commonly used public health tools to identify, notify, and offer testing to persons linked in these contact networks. For HIV-1, a rapidly evolving pathogen with low per-contact transmission rates, viral genetic sequences are an additional source of data that can be used to infer or refine transmission networks.\nMETHODS AND FINDINGS: The New York City Department of Health and Mental Hygiene interviews individuals newly diagnosed with HIV and elicits names of sexual and injection drug using partners. By law, the Department of Health also receives HIV sequences when these individuals enter healthcare and their physicians order resistance testing. Our study used both HIV sequence and partner naming data from 1342 HIV-infected persons in New York City between 2006 and 2012 to infer and compare sexual/drug-use named partner and genetic transmission networks. Using these networks, we determined a range of genetic distance thresholds suitable for identifying potential transmission partners. In 48% of cases, named partners were infected with genetically closely related viruses, compatible with but not necessarily representing or implying, direct transmission. Partner pairs linked through the genetic similarity of their HIV sequences were also linked by naming in 53% of cases. Persons who reported high-risk heterosexual contact were more likely to name at least one partner with a genetically similar virus than those reporting their risk as injection drug use or men who have sex with men.\nCONCLUSIONS: We analyzed an unprecedentedly large and detailed partner tracing and HIV sequence dataset and determined an empirically justified range of genetic distance thresholds for identifying potential transmission partners. We conclude that genetic linkage provides more reliable evidence for identifying potential transmission partners than partner naming, highlighting the importance and complementarity of both epidemiological and molecular genetic surveillance for characterizing regional HIV-1 epidemics.", + "year": "2017", + "author": "Wertheim, Joel O and Pond, Sergei L Kosakovsky and Forgione, Lisa A and Mehta, Sanjay R and Murrell, Ben and Shah, Sharmila and Smith, Davey M and Scheffler, Konrad and Torian, Lucia V", + "journal": "PLoS Pathog" + }, + { + "id": "Wagner:2016kq", + "title": "HIV-associated neurocognitive disorder is associated with HIV-1 dual infection", + "abstract": "OBJECTIVE: Compared to HIV monoinfection, HIV dual infection (DI) has been associated with decreased CD4 T-cell counts and increased viral loads. The same markers are also associated with the development of HIV-associated neurocognitive disorder (HAND), which continues to be a prevalent problem in the era of combination antiretroviral therapy (ART). We sought to determine the relationship between DI and HAND.\nMETHODS: Participants on ART (N = 38) underwent deep sequencingoffour PCR-amplified HIVcoding regions derived from peripheral blood mononuclear cell (PBMC) DNA samples. Phylogenetic analyses were performedto evaluate whether two distinct viral lineages, i.e. DI, were present in the same individual. All study participants underwent neurocognitive, substance use, and neuromedical assessments at each study visit.\nRESULTS: Of 38 participants, 9 (23.7%) had evidence of DI. Using clinical ratings, global neurocognitive impairment was identified in 21 (55%) participants, and multivariate analysis demonstrated a significant association between DI and impairment;OR (95%CI) = 18.3 (1.9,414.2), p = 0.028. Neurocognitive impairment was also associated with lower current (p = 0.028) and nadir (p = 0.043) CD4 T-cell counts.\nCONCLUSIONS: Deep sequencing of HIV DNA populations in PBMC identified DI in nearly a quarter ofHIV-infected adultsreceiving ART, and DI was associated with HAND. Dual infection may contribute to the development of HAND, perhaps due to increased viral diversity. Further investigation is needed to determine how DI results in worse neurocognitive performance.", + "year": "2016", + "author": "Wagner, Gabriel A and Chaillon, Antoine and Liu, Siqi and Franklin, Jr, Donald R and Caballero, Gemma and Pond, Sergei L Kosakovsky and Vaida, Florin and Heaton, Robert K and Letendre, Scott L and Grant, Igor and Richman, Douglas D and Smith, Davey M", + "journal": "AIDS" + }, + { + "id": "Gianellavew020", + "title": "Compartmentalized HIV rebound in the central nervous system after interruption of antiretroviral therapy", + "abstract": "To design effective eradication strategies, it may be necessary to target HIV reservoirs in anatomic compartments other than blood. This study examined HIV RNA rebound following interruption of antiretroviral therapy (ART) in blood and cerebrospinal fluid (CSF) to determine whether the central nervous system (CNS) might serve as an independent source of resurgent viral replication.Paired blood and CSF samples were collected longitudinally from 14 chronically HIV-infected individuals undergoing ART interruption. HIV env (C2-V3), gag (p24) and pol (reverse transcriptase) were sequenced from cell-free HIV RNA and cell-associated HIV DNA in blood and CSF using the Roche 454 FLX Titanium platform. Comprehensive sequence and phylogenetic analyses were performed to search for evidence of unique or differentially represented viral subpopulations emerging in CSF supernatant as compared with blood plasma.Using a conservative definition of compartmentalization based on four distinct statistical tests, nine participants presented a compartmentalized HIV RNA rebound within the CSF after interruption of ART, even when sampled within 2 weeks from viral rebound. The degree and duration of viral compartmentalization varied considerably between subjects and between time-points within a subject. In 10 cases, we identified viral populations within the CSF supernatant at the first sampled time-point after ART interruption, which were phylogenetically distinct from those present in the paired blood plasma and mostly persisted over time (when longitudinal time-points were available). Our data suggest that an independent source of HIV RNA contributes to viral rebound within the CSF after treatment interruption. The most likely source of compartmentalized HIV RNA is a CNS reservoir that would need to be targeted to achieve complete HIV eradication.", + "year": "2016", + "author": "Gianella, Sara and Pond, Sergei L. Kosakovsky and Oliveira, Michelli F. and Scheffler, Konrad and Strain, Matt C. and De la Torre, Antonio and Letendre, Scott and Smith, Davey M. and Ellis, Ronald J.", + "journal": "Virus Evolution" + }, + { + "id": "Garcia-Knight:2016aa", + "title": "Viral Evolution and Cytotoxic T Cell Restricted Selection in Acute Infant HIV-1 Infection", + "abstract": "Antiretroviral therapy-naive HIV-1 infected infants experience poor viral containment and rapid disease progression compared to adults. Viral factors (e.g. transmitted cytotoxic T- lymphocyte (CTL) escape mutations) or infant factors (e.g. reduced CTL functional capacity) may explain this observation. We assessed CTL functionality by analysing selection in CTL-targeted HIV-1 epitopes following perinatal infection. HIV-1 gag, pol and nef sequences were generated from a historical repository of longitudinal specimens from 19 vertically infected infants. Evolutionary rate and selection were estimated for each gene and in CTL-restricted and non-restricted epitopes. Evolutionary rate was higher in nef and gag vs. pol, and lower in infants with non-severe immunosuppression vs. severe immunosuppression across gag and nef. Selection pressure was stronger in infants with non-severe immunosuppression vs. severe immunosuppression across gag. The analysis also showed that infants with non-severe immunosuppression had stronger selection in CTL-restricted vs. non-restricted epitopes in gag and nef. Evidence of stronger CTL selection was absent in infants with severe immunosuppression. These data indicate that infant CTLs can exert selection pressure on gag and nef epitopes in early infection and that stronger selection across CTL epitopes is associated with favourable clinical outcomes. These results have implications for the development of paediatric HIV-1 vaccines.", + "year": "2016", + "author": "Garcia-Knight, Miguel A and Slyker, Jennifer and Payne, Barbara Lohman and Pond, Sergei L Kosakovsky and de Silva, Thushan I and Chohan, Bhavna and Khasimwa, Brian and Mbori-Ngacha, Dorothy and John-Stewart, Grace and Rowland-Jones, Sarah L and Esbj{\\\"o}rnsson, Joakim", + "journal": "Sci Rep" + }, + { + "id": "Landais:2016fv", + "title": "Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort", + "abstract": "Broadly neutralizing antibodies (bnAbs) are thought to be a critical component of a protective HIV vaccine. However, designing vaccines immunogens able to elicit bnAbs has proven unsuccessful to date. Understanding the correlates and immunological mechanisms leading to the development of bnAb responses during natural HIV infection is thus critical to the design of a protective vaccine. The IAVI Protocol C program investigates a large longitudinal cohort of primary HIV-1 infection in Eastern and South Africa. Development of neutralization was evaluated in 439 donors using a 6 cross-clade pseudo-virus panel predictive of neutralization breadth on larger panels. About 15% of individuals developed bnAb responses, essentially between year 2 and year 4 of infection. Statistical analyses revealed no influence of gender, age or geographical origin on the development of neutralization breadth. However, cross-clade neutralization strongly correlated with high viral load as well as with low CD4 T cell counts, subtype-C infection and HLA-A*03(-) genotype. A correlation with high overall plasma IgG levels and anti-Env IgG binding titers was also found. The latter appeared not associated with higher affinity, suggesting a greater diversity of the anti-Env responses in broad neutralizers. Broadly neutralizing activity targeting glycan-dependent epitopes, largely the N332-glycan epitope region, was detected in nearly half of the broad neutralizers while CD4bs and gp41-MPER bnAb responses were only detected in very few individuals. Together the findings suggest that both viral and host factors are critical for the development of bnAbs and that the HIV Env N332-glycan supersite may be a favorable target for vaccine design.", + "year": "2016", + "author": "Landais, Elise and Huang, Xiayu and Havenar-Daughton, Colin and Murrell, Ben and Price, Matt A and Wickramasinghe, Lalinda and Ramos, Alejandra and Bian, Charoan B and Simek, Melissa and Allen, Susan and Karita, Etienne and Kilembe, William and Lakhi, Shabir and Inambao, Mubiana and Kamali, Anatoli and Sanders, Eduard J and Anzala, Omu and Edward, Vinodh and Bekker, Linda-Gail and Tang, Jianming and Gilmour, Jill and Pond, Sergei L Kosakovsky and Phung, Pham and Wrin, Terri and Crotty, Shane and Godzik, Adam and Poignard, Pascal", + "journal": "PLoS Pathog" + }, + { + "id": "Lorenzo-Redondo:2016zl", + "title": "Persistent HIV-1 replication maintains the tissue reservoir during therapy", + "abstract": "Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy.", + "year": "2016", + "author": "Lorenzo-Redondo, Ramon and Fryer, Helen R and Bedford, Trevor and Kim, Eun-Young and Archer, John and Pond, Sergei L Kosakovsky and Chung, Yoon-Seok and Penugonda, Sudhir and Chipman, Jeffrey G and Fletcher, Courtney V and Schacker, Timothy W and Malim, Michael H and Rambaut, Andrew and Haase, Ashley T and McLean, Angela R and Wolinsky, Steven M", + "journal": "Nature" + }, + { + "id": "Tully:2016rz", + "title": "Differences in the Selection Bottleneck between Modes of Sexual Transmission Influence the Genetic Composition of the HIV-1 Founder Virus", + "abstract": "Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome. Analysis of 74 acute and early HIV-1 infected subjects revealed that 83% of men who have sex with men (MSM) exhibit a single founder virus, levels similar to those previously observed in heterosexual (HSX) transmission. In a metadata analysis of a total of 354 subjects, including HSX, MSM and injecting drug users (IDU), we also observed no significant differences in the frequency of single founder virus infections between HSX and MSM transmissions. However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants. Moreover, specific genetic \"signatures\" within MSM and HSX founder viruses were identified, with single polymorphisms within gp41 enriched among HSX viruses while more complex patterns, including clustered polymorphisms surrounding the CD4 binding site, were enriched in MSM viruses. While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition. This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission.", + "year": "2016", + "author": "Tully, Damien C and Ogilvie, Colin B and Batorsky, Rebecca E and Bean, David J and Power, Karen A and Ghebremichael, Musie and Bedard, Hunter E and Gladden, Adrianne D and Seese, Aaron M and Amero, Molly A and Lane, Kimberly and McGrath, Graham and Bazner, Suzane B and Tinsley, Jake and Lennon, Niall J and Henn, Matthew R and Brumme, Zabrina L and Norris, Philip J and Rosenberg, Eric S and Mayer, Kenneth H and Jessen, Heiko and Pond, Sergei L Kosakovsky and Walker, Bruce D and Altfeld, Marcus and Carlson, Jonathan M and Allen, Todd M", + "journal": "PLoS Pathog" + }, + { + "id": "Mehta:2016ty", + "title": "Using HIV Sequence and Epidemiologic Data to Assess the Effect of Self-referral Testing for Acute HIV Infection on Incident Diagnoses in San Diego, California", + "abstract": "BACKGROUND:  Because recently infected individuals disproportionately contribute to the spread of human immunodeficiency virus (HIV), we evaluated the impact of a primary HIV screening program (the Early Test) implemented in San Diego.\nMETHODS:  The Early Test program used combined nucleic acid and serology testing to screen for primary infection targeting local high-risk individuals. Epidemiologic, HIV sequence, and geographic data were obtained from the San Diego County Department of Public Health and the Early Test program. Poisson regression analysis was performed to determine whether the Early Test program was temporally and geographically associated with changes in incident HIV diagnoses. Transmission chains were inferred by phylogenetic analysis of sequence data.\nRESULTS:  Over time, a decrease in incident HIV diagnoses was observed proportional to the number primary HIV infections diagnosed in each San Diego region (P < .001). Molecular network analyses also showed that transmission chains were more likely to terminate in regions where the program was marketed (P = .002). Although, individuals in these zip codes had infection diagnosed earlier (P = .08), they were not treated earlier (P = .83).\nCONCLUSIONS:  These findings suggests that early HIV diagnoses by this primary infection screening program probably contributed to the observed decrease in new HIV diagnoses in San Diego, and they support the expansion and evaluation of similar programs.", + "year": "2016", + "author": "Mehta, Sanjay R and Murrell, Ben and Anderson, Christy M and Pond, Sergei L Kosakovsky and Wertheim, Joel O and Young, Jason A and Freitas, Lorri and Richman, Douglas D and Mathews, W Chris and Scheffler, Konrad and Little, Susan J and Smith, Davey M", + "journal": "Clin Infect Dis" + }, + { + "id": "MacLeod:2016qv", + "title": "Early Antibody Lineage Diversification and Independent Limb Maturation Lead to Broad HIV-1 Neutralization Targeting the Env High-Mannose Patch", + "abstract": "The high-mannose patch on HIV Env is a preferred target for broadly neutralizing antibodies (bnAbs), but to date, no vaccination regimen has elicited bnAbs against this region. Here, we present the development of a bnAb lineage targeting the high-mannose patch in an HIV-1 subtype-C-infected donor from sub-Saharan Africa. The Abs first acquired autologous neutralization, then gradually matured to achieve breadth. One Ab neutralized >47% of HIV-1 strains with only ∼11% somatic hypermutation and no insertions or deletions. By sequencing autologous env, we determined key residues that triggered the lineage and participated in Ab-Env coevolution. Next-generation sequencing of the Ab repertoire showed an early expansive diversification of the lineage followed by independent maturation of individual limbs, several of them developing notable breadth and potency. Overall, the findings are encouraging from a vaccine standpoint and suggest immunization strategies mimicking the evolution of the entire high-mannose patch and promoting maturation of multiple diverse Ab pathways.", + "year": "2016", + "author": "MacLeod, Daniel T and Choi, Nancy M and Briney, Bryan and Garces, Fernando and Ver, Lorena S and Landais, Elise and Murrell, Ben and Wrin, Terri and Kilembe, William and Liang, Chi-Hui and Ramos, Alejandra and Bian, Chaoran B and Wickramasinghe, Lalinda and Kong, Leopold and Eren, Kemal and Wu, Chung-Yi and Wong, Chi-Huey and {IAVI Protocol C Investigators \\& The IAVI African HIV Research Network} and Pond, Sergei L Kosakovsky and Wilson, Ian A and Burton, Dennis R and Poignard, Pascal", + "journal": "Immunity" + }, + { + "id": "Oliveira:2015aa", + "title": "Comparative Analysis of Cell-Associated HIV DNA Levels in Cerebrospinal Fluid and Peripheral Blood by Droplet Digital PCR", + "abstract": "BACKGROUND: Measurement of HIV DNA-bearing cells in cerebrospinal fluid (CSF) is challenging because few cells are present. We present a novel application of the sensitive droplet digital (dd)PCR in this context.\nMETHODS: We analyzed CSF cell pellets and paired peripheral blood mononuclear cells (PBMC) from 28 subjects, 19 of whom had undetectable HIV RNA (<48 copies/mL) in both compartments. We extracted DNA from PBMC using silica-based columns and used direct lysis on CSF cells. HIV DNA and the host housekeeping gene (RPP30) were measured in CSF and PBMC by (dd)PCR. We compared HIV DNA levels in virally-suppressed and-unsuppressed subgroups and calculated correlations between HIV DNA and RNA levels in both compartments using non-parametric tests.\nRESULTS: HIV DNA was detected in 18/28 (64%) CSF cell pellets, including 10/19 (53%) samples with undetectable HIV RNA. HIV DNA levels in CSF cell pellets were not correlated with RPP30 (p = 0.3), but correlated positively with HIV RNA in CSF (p = 0.04) and HIV DNA in PBMC (p = 0.03). Cellular HIV DNA in CSF was detected in comparable levels in HIV RNA-suppressed and unsuppressed subjects (p = 0.14). In contrast, HIV DNA levels in PBMC were significantly lower in HIV RNA-suppressed than in unsuppressed subjects (p = 0.014). Among subjects with detectable HIV DNA in both compartments, HIV DNA levels in CSF were significantly higher than in PBMC (p<0.001).\nCONCLUSIONS: Despite low mononuclear cell numbers in CSF, HIV DNA was detected in most virally suppressed individuals. In contrast to PBMC, suppressive ART was not associated with lower HIV DNA levels in CSF cells, compared to no ART, perhaps due to poorer ART penetration, slower decay of HIV DNA, or enrichment of HIV DNA-bearing mononuclear cells into the CSF, compared to blood. Future studies should determine what fraction of HIV DNA is replication-competent in CSF leukocytes, compared to PBMC.", + "year": "2015", + "author": "de Oliveira, Michelli Faria and Gianella, Sara and Letendre, Scott and Scheffler, Konrad and Pond, Sergei L Kosakovsky and Smith, Davey M and Strain, Matt and Ellis, Ronald J", + "journal": "PLoS One" + }, + { + "id": "lapp20072006", + "title": "The 2006 NESCent phyloinformatics hackathon: a field report", + "year": "2007", + "author": "Lapp, Hilmar and Bala, Sendu and Balhoff, James P and Bouck, Amy and Goto, Naohisa and Holder, Mark and Holland, Richard and Holloway, Alisha and Katayama, Toshiaki and Lewis, Paul O and others", + "journal": "Evolutionary Bioinformatics Online" + }, + { + "id": "landais2014development", + "title": "Development of a V1/V2-targeting Quaternary-specific Broadly Neutralizing Lineage", + "year": "2014", + "author": "Landais, Elise and Briney, Bryan S and Pond, Sergei L Kosakovsky and MacLeod, Daniel T and Lie, Yolanda and Algate, Paul and Burton, Dennis R and Wrin, Terri and Chan-Hui, Po-Ying and Poignard, Pascal", + "journal": "AIDS Res Hum Retroviruses" + }, + { + "id": "Volz:2014wj", + "title": "Phylodynamic analysis of ebola virus in the 2014 Sierra Leone epidemic", + "abstract": "BACKGROUND: The Ebola virus (EBOV) epidemic in Western Africa is the largest in recorded history and control efforts have so far failed to stem the rapid growth in the number of infections. Mathematical models serve a key role in estimating epidemic growth rates and the reproduction number (R0) from surveillance data and, recently, molecular sequence data. Phylodynamic analysis of existing EBOV time-stamped sequence data may provide independent estimates of the unobserved number of infections, reveal recent epidemiological history, and provide insight into selective pressures acting upon viral genes.\nMETHODS: We fit a series mathematical models of infectious disease dynamics to phylogenies estimated from 78 whole EBOV genomes collected from distinct patients in May and June of 2014 in Sierra Leone, and perform evolutionary analysis on these genomes combined with closely related EBOV genomes from previous outbreaks. Two analyses are conducted with values of the latent period that have been used in recent modelling efforts. We also examined the EBOV sequences for evidence of possible episodic adaptive molecular evolution during the 2014 outbreak.\nRESULTS: We find evidence for adaptive evolution affecting L and GP protein coding regions of the EBOV genome, which is unlikely to bias molecular clock and phylodynamic analyses. We estimate R0=2.40 (95% HPD:1.54-3.87 ) if the mean latent period is 5.3 days, and R0=3.81, (95% HPD:2.47-6.3) if the mean latent period is 12.7 days. The estimated coefficient of variation (CV) of the number of transmissions per infected host is very high, and a large proportion of infections yield no transmissions.\nCONCLUSIONS: Estimates of R0 are sensitive to the unknown latent infectious period which can not be reliably estimated from genetic data alone. EBOV phylogenies show significant evidence for superspreading and extreme variance in the number of transmissions per infected individual during the early epidemic in Sierra Leone.", + "year": "2014", + "author": "Volz, Erik and Pond, Sergei L Kosakovsky", + "journal": "PLoS Curr" + }, + { + "id": "Frost:2015wb", + "title": "Assigning and visualizing germline genes in antibody repertoires", + "abstract": "Identifying the germline genes involved in immunoglobulin rearrangements is an essential first step in the analysis of antibody repertoires. Based on our prior work in analysing diverse recombinant viruses, we present IgSCUEAL (Immunoglobulin Subtype Classification Using Evolutionary ALgorithms), a phylogenetic approach to assign V and J regions of immunoglobulin sequences to their corresponding germline alleles, with D regions assigned using a simple pairwise alignment algorithm. We also develop an interactive web application for viewing the results, allowing the user to explore the frequency distribution of sequence assignments and CDR3 region length statistics, which is useful for summarizing repertoires, as well as a detailed viewer of rearrangements and region alignments for individual query sequences. We demonstrate the accuracy and utility of our method compared with sequence similarity-based approaches and other non-phylogenetic model-based approaches, using both simulated data and a set of evaluation datasets of human immunoglobulin heavy chain sequences. IgSCUEAL demonstrates the highest accuracy of V and J assignment amongst existing approaches, even when the reassorted sequence is highly mutated, and can successfully cluster sequences on the basis of shared V/J germline alleles.", + "year": "2015", + "author": "Frost, Simon D W and Murrell, Ben and Hossain, A S Md Mukarram and Silverman, Gregg J and Pond, Sergei L Kosakovsky", + "journal": "Philos Trans R Soc Lond B Biol Sci" + }, + { + "id": "Murrell:2015ct", + "title": "Gene-wide identification of episodic selection", + "abstract": "We present BUSTED, a new approach to identifying gene-wide evidence of episodic positive selection, where the non-synonymous substitution rate is transiently greater than the synonymous rate. BUSTED can be used either on an entire phylogeny (without requiring an a priori hypothesis regarding which branches are under positive selection) or on a pre-specified subset of foreground lineages (if a suitable a priori hypothesis is available). Selection is modeled as varying stochastically over branches and sites, and we propose a computationally inexpensive evidence metric for identifying sites subject to episodic positive selection on any foreground branches. We compare BUSTED with existing models on simulated and empirical data. An implementation is available on www.datamonkey.org/busted, with a widget allowing the interactive specification of foreground branches.", + "year": "2015", + "author": "Murrell, Ben and Weaver, Steven and Smith, Martin D and Wertheim, Joel O and Murrell, Sasha and Aylward, Anthony and Eren, Kemal and Pollner, Tristan and Martin, Darren P and Smith, Davey M and Scheffler, Konrad and Pond, Sergei L Kosakovsky", + "journal": "Mol Biol Evol" + }, + { + "id": "Smith:2015oa", + "title": "Less is more: an adaptive branch-site random effects model for efficient detection of episodic diversifying selection", + "abstract": "Over the past two decades, comparative sequence analysis using codon-substitution models has been honed into a powerful and popular approach for detecting signatures of natural selection from molecular data. A substantial body of work has focused on developing a class of \"branch-site\" models which permit selective pressures on sequences, quantified by the ω ratio, to vary among both codon sites and individual branches in the phylogeny. We develop and present a method in this class, adaptive branch-site random effects likelihood (aBSREL), whose key innovation is variable parametric complexity chosen with an information theoretic criterion. By applying models of different complexity to different branches in the phylogeny, aBSREL delivers statistical performance matching or exceeding best-in-class existing approaches, while running an order of magnitude faster. Based on simulated data analysis, we offer guidelines for what extent and strength of diversifying positive selection can be detected reliably and suggest that there is a natural limit on the optimal parametric complexity for \"branch-site\" models. An aBSREL analysis of 8,893 Euteleostomes gene alignments demonstrates that over 80% of branches in typical gene phylogenies can be adequately modeled with a single ω ratio model, that is, current models are unnecessarily complicated. However, there are a relatively small number of key branches, whose identities are derived from the data using a model selection procedure, for which it is essential to accurately model evolutionary complexity.", + "year": "2015", + "author": "Smith, Martin D and Wertheim, Joel O and Weaver, Steven and Murrell, Ben and Scheffler, Konrad and Pond, Sergei L Kosakovsky", + "journal": "Mol Biol Evol" + }, + { + "id": "Edlefsen:2015ya", + "title": "Comprehensive sieve analysis of breakthrough HIV-1 sequences in the RV144 vaccine efficacy trial", + "abstract": "The RV144 clinical trial showed the partial efficacy of a vaccine regimen with an estimated vaccine efficacy (VE) of 31% for protecting low-risk Thai volunteers against acquisition of HIV-1. The impact of vaccine-induced immune responses can be investigated through sieve analysis of HIV-1 breakthrough infections (infected vaccine and placebo recipients). A V1/V2-targeted comparison of the genomes of HIV-1 breakthrough viruses identified two V2 amino acid sites that differed between the vaccine and placebo groups. Here we extended the V1/V2 analysis to the entire HIV-1 genome using an array of methods based on individual sites, k-mers and genes/proteins. We identified 56 amino acid sites or \"signatures\" and 119 k-mers that differed between the vaccine and placebo groups. Of those, 19 sites and 38 k-mers were located in the regions comprising the RV144 vaccine (Env-gp120, Gag, and Pro). The nine signature sites in Env-gp120 were significantly enriched for known antibody-associated sites (p = 0.0021). In particular, site 317 in the third variable loop (V3) overlapped with a hotspot of antibody recognition, and sites 369 and 424 were linked to CD4 binding site neutralization. The identified signature sites significantly covaried with other sites across the genome (mean = 32.1) more than did non-signature sites (mean = 0.9) (p < 0.0001), suggesting functional and/or structural relevance of the signature sites. Since signature sites were not preferentially restricted to the vaccine immunogens and because most of the associations were insignificant following correction for multiple testing, we predict that few of the genetic differences are strongly linked to the RV144 vaccine-induced immune pressure. In addition to presenting results of the first complete-genome analysis of the breakthrough infections in the RV144 trial, this work describes a set of statistical methods and tools applicable to analysis of breakthrough infection genomes in general vaccine efficacy trials for diverse pathogens.", + "year": "2015", + "author": "Edlefsen, Paul T and Rolland, Morgane and Hertz, Tomer and Tovanabutra, Sodsai and Gartland, Andrew J and deCamp, Allan C and Magaret, Craig A and Ahmed, Hasan and Gottardo, Raphael and Juraska, Michal and McCoy, Connor and Larsen, Brendan B and Sanders-Buell, Eric and Carrico, Chris and Menis, Sergey and Bose, Meera and {RV144 Sequencing Team} and Arroyo, Miguel A and O'Connell, Robert J and Nitayaphan, Sorachai and Pitisuttithum, Punnee and Kaewkungwal, Jaranit and Rerks-Ngarm, Supachai and Robb, Merlin L and Kirys, Tatsiana and Georgiev, Ivelin S and Kwong, Peter D and Scheffler, Konrad and Pond, Sergei L Kosakovsky and Carlson, Jonathan M and Michael, Nelson L and Schief, William R and Mullins, James I and Kim, Jerome H and Gilbert, Peter B", + "journal": "PLoS Comput Biol" + }, + { + "id": "Fisher:2015xz", + "title": "Next generation sequencing improves detection of drug resistance mutations in infants after PMTCT failure", + "abstract": "BACKGROUND: Next generation sequencing (NGS) allows the detection of minor variant HIV drug resistance mutations (DRMs). However data from new NGS platforms after Prevention-of-Mother-to-Child-Transmission (PMTCT) regimen failure are limited.\nOBJECTIVE: To compare major and minor variant HIV DRMs with Illumina MiSeq and Life Technologies Ion Personal Genome Machine (PGM) in infants infected despite a PMTCT regimen.\nSTUDY DESIGN: We conducted a cross-sectional study of NGS for detecting DRMs in infants infected despite a zidovudine (AZT) and Nevirapine (NVP) regimen, before initiation of combination antiretroviral therapy. Sequencing was performed on PCR products from plasma samples on PGM and MiSeq platforms. Bioinformatic analyses were undertaken using a codon-aware version of the Smith-Waterman mapping algorithm and a mixture multinomial error filtering statistical model.\nRESULTS: Of 15 infants, tested at a median age of 3.4 months after birth, 2 (13%) had non-nucleoside reverse transcriptase inhibitor (NNRTI) DRMs (K103N and Y181C) by bulk sequencing, whereas PGM detected 4 (26%) and MiSeq 5 (30%). NGS enabled the detection of additional minor variant DRMs in the infant with K103N. Coverage and instrument quality scores were higher with MiSeq, increasing the confidence of minor variant calls.\nCONCLUSIONS: NGS followed by bioinformatic analyses detected multiple minor variant DRMs in HIV-1 RT among infants where PMTCT failed. The high coverage of MiSeq and high read quality improved the confidence of identified DRMs and may make this platform ideal for minor variant detection.", + "year": "2015", + "author": "Fisher, Randall G and Smith, Davey M and Murrell, Ben and Slabbert, Ruhan and Kirby, Bronwyn M and Edson, Clair and Cotton, Mark F and Haubrich, Richard H and Pond, Sergei L Kosakovsky and Van Zyl, Gert U", + "journal": "J Clin Virol" + }, + { + "id": "Wertheim:2015fb", + "title": "RELAX: detecting relaxed selection in a phylogenetic framework", + "abstract": "Relaxation of selective strength, manifested as a reduction in the efficiency or intensity of natural selection, can drive evolutionary innovation and presage lineage extinction or loss of function. Mechanisms through which selection can be relaxed range from the removal of an existing selective constraint to a reduction in effective population size. Standard methods for estimating the strength and extent of purifying or positive selection from molecular sequence data are not suitable for detecting relaxed selection, because they lack power and can mistake an increase in the intensity of positive selection for relaxation of both purifying and positive selection. Here, we present a general hypothesis testing framework (RELAX) for detecting relaxed selection in a codon-based phylogenetic framework. Given two subsets of branches in a phylogeny, RELAX can determine whether selective strength was relaxed or intensified in one of these subsets relative to the other. We establish the validity of our test via simulations and show that it can distinguish between increased positive selection and a relaxation of selective strength. We also demonstrate the power of RELAX in a variety of biological scenarios where relaxation of selection has been hypothesized or demonstrated previously. We find that obligate and facultative γ-proteobacteria endosymbionts of insects are under relaxed selection compared with their free-living relatives and obligate endosymbionts are under relaxed selection compared with facultative endosymbionts. Selective strength is also relaxed in asexual Daphnia pulex lineages, compared with sexual lineages. Endogenous, nonfunctional, bornavirus-like elements are found to be under relaxed selection compared with exogenous Borna viruses. Finally, selection on the short-wavelength sensitive, SWS1, opsin genes in echolocating and nonecholocating bats is relaxed only in lineages in which this gene underwent pseudogenization; however, selection on the functional medium/long-wavelength sensitive opsin, M/LWS1, is found to be relaxed in all echolocating bats compared with nonecholocating bats.", + "year": "2015", + "author": "Wertheim, Joel O and Murrell, Ben and Smith, Martin D and Pond, Sergei L Kosakovsky and Scheffler, Konrad", + "journal": "Mol Biol Evol" + }, + { + "id": "Carter:2015jb", + "title": "HIV-1 neutralizing antibody response and viral genetic diversity characterized with next generation sequencing", + "abstract": "To better understand the dynamics of HIV-specific neutralizing antibody (NAb), we examined associations between viral genetic diversity and the NAb response against a multi-subtype panel of heterologous viruses in a well-characterized, therapy-na{\\\"\\i}ve primary infection cohort. Using next generation sequencing (NGS), we computed sequence-based measures of diversity within HIV-1 env, gag and pol, and compared them to NAb breadth and potency as calculated by a neutralization score. Contemporaneous env diversity and the neutralization score were positively correlated (p=0.0033), as were the neutralization score and estimated duration of infection (EDI) (p=0.0038), and env diversity and EDI (p=0.0005). Neither early env diversity nor baseline viral load correlated with future NAb breadth and potency (p>0.05). Taken together, it is unlikely that neutralizing capability in our cohort was conditioned on viral diversity, but rather that env evolution was driven by the level of NAb selective pressure.", + "year": "2015", + "author": "Carter, Christoph C and Wagner, Gabriel A and Hightower, George K and Caballero, Gemma and Phung, Pham and Richman, Douglas D and Pond, Sergei L Kosakovsky and Smith, Davey M", + "journal": "Virology" + }, + { + "id": "Minoarivelo:2014kr", + "title": "Detecting phylogenetic signal in mutualistic interaction networks using a Markov process model", + "abstract": "Ecological interaction networks, such as those describing the mutualistic interactions between plants and their pollinators or between plants and their frugivores, exhibit non-random structural properties that cannot be explained by simple models of network formation. One factor affecting the formation and eventual structure of such a network is its evolutionary history. We argue that this, in many cases, is closely linked to the evolutionary histories of the species involved in the interactions. Indeed, empirical studies of interaction networks along with the phylogenies of the interacting species have demonstrated significant associations between phylogeny and network structure. To date, however, no generative model explaining the way in which the evolution of individual species affects the evolution of interaction networks has been proposed. We present a model describing the evolution of pairwise interactions as a branching Markov process, drawing on phylogenetic models of molecular evolution. Using knowledge of the phylogenies of the interacting species, our model yielded a significantly better fit to 21% of a set of plant - pollinator and plant - frugivore mutualistic networks. This highlights the importance, in a substantial minority of cases, of inheritance of interaction patterns without excluding the potential role of ecological novelties in forming the current network architecture. We suggest that our model can be used as a null model for controlling evolutionary signals when evaluating the role of other factors in shaping the emergence of ecological networks.", + "year": "2014", + "author": "Minoarivelo, H O and Hui, C and Terblanche, J S and Pond, S L Kosakovsky and Scheffler, K", + "journal": "Oikos" + }, + { + "id": "Hepler:2014xi", + "title": "IDEPI: rapid prediction of HIV-1 antibody epitopes and other phenotypic features from sequence data using a flexible machine learning platform", + "abstract": "Since its identification in 1983, HIV-1 has been the focus of a research effort unprecedented in scope and difficulty, whose ultimate goals--a cure and a vaccine--remain elusive. One of the fundamental challenges in accomplishing these goals is the tremendous genetic variability of the virus, with some genes differing at as many as 40% of nucleotide positions among circulating strains. Because of this, the genetic bases of many viral phenotypes, most notably the susceptibility to neutralization by a particular antibody, are difficult to identify computationally. Drawing upon open-source general-purpose machine learning algorithms and libraries, we have developed a software package IDEPI (IDentify EPItopes) for learning genotype-to-phenotype predictive models from sequences with known phenotypes. IDEPI can apply learned models to classify sequences of unknown phenotypes, and also identify specific sequence features which contribute to a particular phenotype. We demonstrate that IDEPI achieves performance similar to or better than that of previously published approaches on four well-studied problems: finding the epitopes of broadly neutralizing antibodies (bNab), determining coreceptor tropism of the virus, identifying compartment-specific genetic signatures of the virus, and deducing drug-resistance associated mutations. The cross-platform Python source code (released under the GPL 3.0 license), documentation, issue tracking, and a pre-configured virtual machine for IDEPI can be found at https://github.com/veg/idepi.", + "year": "2014", + "author": "Hepler, N Lance and Scheffler, Konrad and Weaver, Steven and Murrell, Ben and Richman, Douglas D and Burton, Dennis R and Poignard, Pascal and Smith, Davey M and Pond, Sergei L Kosakovsky", + "journal": "PLoS Comput Biol" + }, + { + "id": "Nayak:2015ri", + "title": "Structure-function analysis of hepatitis C virus envelope glycoproteins E1 and E2", + "abstract": "Hepatitis C virus (HCV) is the leading cause of chronic liver disease in humans. The envelope proteins of HCV are potential candidates for vaccine development. The absence of three-dimensional (3D) structures for the functional domain of HCV envelope proteins [E1.E2] monomer complex has hindered overall understanding of the virus infection, and also structure-based drug design initiatives. In this study, we report a 3D model containing both E1 and E2 proteins of HCV using the recently published structure of the core domain of HCV E2 and the functional part of E1, and investigate immunogenic implications of the model. HCV [E1.E2] molecule is modeled by using aa205-319 of E1 to aa421-716 of E2. Published experimental data were used to further refine the [E1.E2] model. Based on the model, we predict 77 exposed residues and several antigenic sites within the [E1.E2] that could serve as vaccine epitopes. This study identifies eight peptides which have antigenic propensity and have two or more sequentially exposed amino acids and 12 singular sites are under negative selection pressure that can serve as vaccine or therapeutic targets. Our special interest is 285FLVGQLFTFSPRRHW299 which has five negatively selected sites (L286, V287, G288, T292, and G303) with three of them sequential and four amino acids exposed (F285, L286, T292, and R296). This peptide in the E1 protein maps to dengue envelope vaccine target identified previously by our group. Our model provides for the first time an overall view of both the HCV envelope proteins thereby allowing researchers explore structure-based drug design approaches.", + "year": "2015", + "author": "Nayak, Aparajita and Pattabiraman, Nagarajan and Fadra, Numrah and Goldman, Radoslav and Pond, Sergei L Kosakovsky and Mazumder, Raja", + "journal": "J Biomol Struct Dyn" + }, + { + "id": "Wertheim:2014mq", + "title": "Evolutionary origins of human herpes simplex viruses 1 and 2", + "abstract": "Herpesviruses have been infecting and codiverging with their vertebrate hosts for hundreds of millions of years. The primate simplex viruses exemplify this pattern of virus-host codivergence, at a minimum, as far back as the most recent common ancestor of New World monkeys, Old World monkeys, and apes. Humans are the only primate species known to be infected with two distinct herpes simplex viruses: HSV-1 and HSV-2. Human herpes simplex viruses are ubiquitous, with over two-thirds of the human population infected by at least one virus. Here, we investigated whether the additional human simplex virus is the result of ancient viral lineage duplication or cross-species transmission. We found that standard phylogenetic models of nucleotide substitution are inadequate for distinguishing among these competing hypotheses; the extent of synonymous substitutions causes a substantial underestimation of the lengths of some of the branches in the phylogeny, consistent with observations in other viruses (e.g., avian influenza, Ebola, and coronaviruses). To more accurately estimate ancient viral divergence times, we applied a branch-site random effects likelihood model of molecular evolution that allows the strength of natural selection to vary across both the viral phylogeny and the gene alignment. This selection-informed model favored a scenario in which HSV-1 is the result of ancient codivergence and HSV-2 arose from a cross-species transmission event from the ancestor of modern chimpanzees to an extinct Homo precursor of modern humans, around 1.6 Ma. These results provide a new framework for understanding human herpes simplex virus evolution and demonstrate the importance of using selection-informed models of sequence evolution when investigating viral origin hypotheses.", + "year": "2014", + "author": "Wertheim, Joel O and Smith, Martin D and Smith, Davey M and Scheffler, Konrad and Pond, Sergei L Kosakovsky", + "journal": "Mol Biol Evol" + }, + { + "id": "Little:2014pz", + "title": "Using HIV networks to inform real time prevention interventions", + "abstract": "OBJECTIVE: To reconstruct the local HIV-1 transmission network from 1996 to 2011 and use network data to evaluate and guide efforts to interrupt transmission.\nDESIGN: HIV-1 pol sequence data were analyzed to infer the local transmission network.\nMETHODS: We analyzed HIV-1 pol sequence data to infer a partial local transmission network among 478 recently HIV-1 infected persons and 170 of their sexual and social contacts in San Diego, California. A transmission network score (TNS) was developed to estimate the risk of HIV transmission from a newly diagnosed individual to a new partner and target prevention interventions.\nRESULTS: HIV-1 pol sequences from 339 individuals (52.3%) were highly similar to sequences from at least one other participant (i.e., clustered). A high TNS (top 25%) was significantly correlated with baseline risk behaviors (number of unique sexual partners and insertive unprotected anal intercourse (p = 0.014 and p = 0.0455, respectively) and predicted risk of transmission (p<0.0001). Retrospective analysis of antiretroviral therapy (ART) use, and simulations of ART targeted to individuals with the highest TNS, showed significantly reduced network level HIV transmission (p<0.05).\nCONCLUSIONS: Sequence data from an HIV-1 screening program focused on recently infected persons and their social and sexual contacts enabled the characterization of a highly connected transmission network. The network-based risk score (TNS) was highly correlated with transmission risk behaviors and outcomes, and can be used identify and target effective prevention interventions, like ART, to those at a greater risk for HIV-1 transmission.", + "year": "2014", + "author": "Little, Susan J and Pond, Sergei L Kosakovsky and Anderson, Christy M and Young, Jason A and Wertheim, Joel O and Mehta, Sanjay R and May, Susanne and Smith, Davey M", + "journal": "PLoS One" + }, + { + "id": "Scheffler:2014wm", + "title": "On the validity of evolutionary models with site-specific parameters", + "abstract": "Evolutionary models that make use of site-specific parameters have recently been criticized on the grounds that parameter estimates obtained under such models can be unreliable and lack theoretical guarantees of convergence. We present a simulation study providing empirical evidence that a simple version of the models in question does exhibit sensible convergence behavior and that additional taxa, despite not being independent of each other, lead to improved parameter estimates. Although it would be desirable to have theoretical guarantees of this, we argue that such guarantees would not be sufficient to justify the use of these models in practice. Instead, we emphasize the importance of taking the variance of parameter estimates into account rather than blindly trusting point estimates - this is standardly done by using the models to construct statistical hypothesis tests, which are then validated empirically via simulation studies.", + "year": "2014", + "author": "Scheffler, Konrad and Murrell, Ben and Pond, Sergei L Kosakovsky", + "journal": "PLoS One" + }, + { + "id": "Benndorf:2014sh", + "title": "Neuropathy- and myopathy-associated mutations in human small heat shock proteins: Characteristics and evolutionary history of the mutation sites", + "abstract": "Mutations in four of the ten human small heat shock proteins (sHSP) are associated with various forms of motor neuropathies and myopathies. In HspB1, HspB3, and HspB8 all known mutations cause motor neuropathies, whereas in HspB5 they cause myopathies. Several features are common to the majority of these mutations: (i) they are missense mutations, (ii) most associated disease phenotypes exhibit a dominant inheritance pattern and late disease onset, (iii) in the primary protein sequences, the sites of most mutations are located in the conserved α-crystallin domain and the variable C-terminal extensions, and (iv) most human mutation sites are highly conserved among the vertebrate orthologs and have been historically exposed to significant purifying selection. In contrast, a minor fraction of these mutations deviate from these rules: they are (i) frame shifting, nonsense, or elongation mutations, (ii) associated with recessive or early onset disease phenotypes, (iii) positioned in the N-terminal domain of the proteins, and (iv) less conserved among the vertebrates and were historically not subject to a strong selective pressure. In several vertebrate sHSPs (including primate sHSPs), homologous sites differ from the human sequence and occasionally even encode the same amino acid residues that cause the disease in humans. Apparently, a number of these mutations sites are not crucial for the protein function in single species or entire taxa, and single species even seem to have adopted mechanisms that compensate for potentially adverse effects of 'mutant-like' sHSPs. The disease-associated dominant sHSP missense mutations have a number of cellular consequences that are consistent with gain-of-function mechanisms of genetic dominance: dominant-negative effects, the formation of cytotoxic amyloid protein oligomers and precipitates, disruption of cytoskeletal networks, and increased downstream enzymatic activities. Future therapeutic concepts should aim for reducing these adverse effects of mutant sHSPs in patients. Indeed, initial experimental results are encouraging.", + "year": "2014", + "author": "Benndorf, Rainer and Martin, Jody L and Pond, Sergei L Kosakovsky and Wertheim, Joel O", + "journal": "Mutat Res Rev Mutat Res" + }, + { + "id": "Wagner:2014lp", + "title": "Incidence and prevalence of intrasubtype HIV-1 dual infection in at-risk men in the United States", + "abstract": "BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) dual infection (DI) has been associated with decreased CD4 T-cell counts and increased viral loads; however, the frequency of intrasubtype DI is poorly understood. We used ultradeep sequencing (UDS) to estimate the frequency of DI in a primary infection cohort of predominantly men who have sex with men (MSM).\nMETHODS:  HIV-1 genomes from longitudinal blood samples of recently infected, therapy-naive participants were interrogated with UDS. DI was confirmed when maximum sequence divergence was excessive and supported by phylogenetic analysis. Coinfection was defined as DI at baseline; superinfection was monoinfection at baseline and DI at a later time point.\nRESULTS:  Of 118 participants, 7 were coinfected and 10 acquired superinfection. Superinfection incidence rate was 4.96 per 100 person-years (95% confidence interval [CI], 2.67-9.22); 6 occurred in the first year and 4 in the second. Overall cumulative prevalence of intrasubtype B DI was 14.4% (95% CI, 8.6%-22.1%). Primary HIV-1 incidence was 4.37 per 100 person-years (95% CI, 3.56-5.36).\nCONCLUSIONS:  Intrasubtype DI was frequent and comparable to primary infection rates among MSM in San Diego; however, superinfection rates declined over time. DI is likely an important component of the HIV epidemic dynamics, and development of stronger immune responses to the initial infection may protect from superinfection.", + "year": "2014", + "author": "Wagner, Gabriel A and Pacold, Mary E and Pond, Sergei L Kosakovsky and Caballero, Gemma and Chaillon, Antoine and Rudolph, Abby E and Morris, Sheldon R and Little, Susan J and Richman, Douglas D and Smith, Davey M", + "journal": "J Infect Dis" + }, + { + "id": "Wertheim:2014jh", + "title": "The global transmission network of HIV-1", + "abstract": "Human immunodeficiency virus type 1 (HIV-1) is pandemic, but its contemporary global transmission network has not been characterized. A better understanding of the properties and dynamics of this network is essential for surveillance, prevention, and eventual eradication of HIV. Here, we apply a simple and computationally efficient network-based approach to all publicly available HIV polymerase sequences in the global database, revealing a contemporary picture of the spread of HIV-1 within and between countries. This approach automatically recovered well-characterized transmission clusters and extended other clusters thought to be contained within a single country across international borders. In addition, previously undescribed transmission clusters were discovered. Together, these clusters represent all known modes of HIV transmission. The extent of international linkage revealed by our comprehensive approach demonstrates the need to consider the global diversity of HIV, even when describing local epidemics. Finally, the speed of this method allows for near-real-time surveillance of the pandemic's progression.", + "year": "2014", + "author": "Wertheim, Joel O and Leigh Brown, Andrew J and Hepler, N Lance and Mehta, Sanjay R and Richman, Douglas D and Smith, Davey M and Pond, Sergei L Kosakovsky", + "journal": "J Infect Dis" + }, + { + "id": "Chaillon:2013ta", + "title": "Dynamics of viral evolution and neutralizing antibody response after HIV-1 superinfection", + "abstract": "Investigating the incidence and prevalence of HIV-1 superinfection is challenging due to the complex dynamics of two infecting strains. The superinfecting strain can replace the initial strain, be transiently expressed, or persist along with the initial strain in distinct or in recombined forms. Various selective pressures influence these alternative scenarios in different HIV-1 coding regions. We hypothesized that the potency of the neutralizing antibody (NAb) response to autologous viruses would modulate viral dynamics in env following superinfection in a limited set of superinfection cases. HIV-1 env pyrosequencing data were generated from blood plasma collected from 7 individuals with evidence of superinfection. Viral variants within each patient were screened for recombination, and viral dynamics were evaluated using nucleotide diversity. NAb responses to autologous viruses were evaluated before and after superinfection. In 4 individuals, the superinfecting strain replaced the original strain. In 2 individuals, both initial and superinfecting strains continued to cocirculate. In the final individual, the surviving lineage was the product of interstrain recombination. NAb responses to autologous viruses that were detected within the first 2 years of HIV-1 infection were weak or absent for 6 of the 7 recently infected individuals at the time of and shortly following superinfection. These 6 individuals had detectable on-going viral replication of distinct superinfecting virus in the env coding region. In the remaining case, there was an early and strong autologous NAb response, which was associated with extensive recombination in env between initial and superinfecting strains. This extensive recombination made superinfection more difficult to identify and may explain why the detection of superinfection has typically been associated with low autologous NAb titers.", + "year": "2013", + "author": "Chaillon, Antoine and Wagner, Gabriel A and Hepler, N Lance and Little, Susan J and Pond, Sergei L Kosakovsky and Caballero, Gemma and Pacold, Mary E and Phung, Pham and Wrin, Terri and Richman, Douglas D and Wertheim, Joel O and Smith, Davey M", + "journal": "J Virol" + }, + { + "id": "Hightower:2013zh", + "title": "HIV-1 clade B pol evolution following primary infection", + "abstract": "OBJECTIVE: Characterize intra-individual HIV-1 subtype B pol evolution in antiretroviral naive individuals.\nDESIGN: Longitudinal cohort study of individuals enrolled during primary infection.\nMETHODS: Eligible individuals were antiretroviral na{\\\"\\i}ve participants enrolled in the cohort from December 1997-December 2005 and having at least two blood samples available with the first one collected within a year of their estimated date of infection. Population-based pol sequences were generated from collected blood samples and analyzed for genetic divergence over time in respect to dual infection status, HLA, CD4 count and viral load.\nRESULTS: 93 participants were observed for a median of 1.8 years (Mean = 2.2 years, SD =1.9 years). All participants classified as mono-infected had less than 0.7% divergence between any two of their pol sequences using the Tamura-Nei model (TN93), while individuals with dual infection had up to 7.0% divergence. The global substitution rates (substitutions/nucleotide/year) for mono and dually infected individuals were significantly different (p<0.001); however, substitution rates were not associated with HLA haplotype, CD4 or viral load.\nCONCLUSIONS: Even after a maximum of almost 9 years of follow-up, all mono-infected participants had less than 1% divergence between baseline and longitudinal sequences, while participants with dual infection had 10 times greater divergence. These data support the use of HIV-1 pol sequence data to evaluate transmission events, networks and HIV-1 dual infection.", + "year": "2013", + "author": "Hightower, George K and May, Susanne J and Perez-Santiago, Josue and Pacold, Mary E and Wagner, Gabriel A and Little, Susan J and Richman, Douglas D and Mehta, Sanjay R and Smith, Davey M and Pond, Sergei L Kosakovsky", + "journal": "PLoS One" + }, + { + "id": "Murray:2013bu", + "title": "Suppressors of RNAi from plant viruses are subject to episodic positive selection", + "abstract": "Viral suppressors of RNAi (VSRs) are proteins that actively inhibit the antiviral RNA interference (RNAi) immune response, providing an immune evasion route for viruses. It has been hypothesized that VSRs are engaged in a molecular 'arms race' with RNAi pathway genes. Two lines of evidence support this. First, VSRs from plant viruses display high sequence diversity, and are frequently gained and lost over evolutionary time scales. Second, Drosophila antiviral RNAi genes show high rates of adaptive evolution. Here, we investigate whether VSRs diversify faster than other genes and, if so, whether this is a result of positive selection, as might be expected in an arms race. By analysis of 12 plant RNA viruses, we show that the relative rate of protein evolution is higher for VSRs than for other genes, but that this is not attributable to pervasive positive selection. We argue that, because evolutionary time scales are extremely different for viruses and eukaryotes, it is improbable that viral adaptation (as measured by the ratio of non-synonymous to synonymous change) will be dominated by one-to-one coevolution with eukaryotes. Instead, for plant virus VSRs, we find strong evidence of episodic selection--diversifying selection that acts on a subset of lineages--which might be attributable to frequent shifts between different host genotypes or species.", + "year": "2013", + "author": "Murray, Gemma G R and Pond, Sergei L Kosakovsky and Obbard, Darren J", + "journal": "Proc Biol Sci" + }, + { + "id": "Wagner:2013xh", + "title": "Using ultradeep pyrosequencing to study HIV-1 coreceptor usage in primary and dual infection", + "abstract": "HIV-1 dual infection (DI) and CXCR4 (X4) coreceptor usage are associated with accelerated disease progression but frequency and dynamics of coreceptor usage during DI is unknown. Ultradeep sequencing was used to interrogate for DI and infer coreceptor usage in longitudinal blood samples of 102 subjects. At baseline, X4 usage was high (23 subjects harbored X4 variants) and was not associated with infection duration or DI. Coreceptor usage changed over time in 12 of 47 participants, and X4 usage emerged in 4 of 41 monoinfections vs 2 of 5 superinfections (P = .12), suggesting a weak statistical trend toward occurrence of superinfection and acquiring X4 usage.", + "year": "2013", + "author": "Wagner, Gabriel A and Pacold, Mary E and Vigil, Edgar and Caballero, Gemma and Morris, Sheldon R and Pond, Sergei L Kosakovsky and Little, Susan J and Richman, Douglas D and Gianella, Sara and Smith, Davey M", + "journal": "J Infect Dis" + }, + { + "id": "Wertheim:2013wa", + "title": "A case for the ancient origin of coronaviruses", + "abstract": "Coronaviruses are found in a diverse array of bat and bird species, which are believed to act as natural hosts. Molecular clock dating analyses of coronaviruses suggest that the most recent common ancestor of these viruses existed around 10,000 years ago. This relatively young age is in sharp contrast to the ancient evolutionary history of their putative natural hosts, which began diversifying tens of millions of years ago. Here, we attempted to resolve this discrepancy by applying more realistic evolutionary models that have previously revealed the ancient evolutionary history of other RNA viruses. By explicitly modeling variation in the strength of natural selection over time and thereby improving the modeling of substitution saturation, we found that the time to the most recent ancestor common for all coronaviruses is likely far greater (millions of years) than the previously inferred range.", + "year": "2013", + "author": "Wertheim, Joel O and Chu, Daniel K W and Peiris, Joseph S M and Pond, Sergei L Kosakovsky and Poon, Leo L M", + "journal": "J Virol" + }, + { + "id": "Hoffenberg:2013dl", + "title": "Identification of an HIV-1 clade A envelope that exhibits broad antigenicity and neutralization sensitivity and elicits antibodies targeting three distinct epitopes", + "abstract": "Broadly neutralizing antibodies (bNAbs) PG9 and PG16 were isolated from an International AIDS Vaccine Initiative (IAVI) Protocol G subject infected with human immunodeficiency virus type 1 (HIV-1) clade A. Both antibodies are highly potent and neutralize greater than 70% of viruses tested. We sought to begin immunogen design based on viral sequences from this patient; however, pseudoviruses prepared with 19 envelope sequences from this subject were resistant to neutralization by PG9 and PG16. Therefore, we used a bioinformatics approach to identify closely related viruses that were potentially sensitive to PG9 and PG16. A most-recent common ancestor (MRCA) sequence for the viral envelope (Env) was determined and aligned with 99 subtype A gp160 sequences from the Los Alamos HIV database. Virus BG505.W6M.ENV.C2 (BG505) was found to have the highest degree of homology (73%) to the MRCA sequence. Pseudoviruses prepared with this Env were sensitive to neutralization with a broad panel of bNAbs, including PG9 and PG16. When expressed by 293T cells as soluble gp120, the BG505 monomer bound well to both PG9 and PG16. We further showed that a point mutation (L111A) enabled more efficient production of a stable gp120 monomer that preserves the major neutralization epitopes. Finally, we showed that an adjuvanted formulation of this gp120 protein elicited neutralizing antibodies in rabbits (following a gp120 DNA vaccine prime) and that the antisera competed with bNAbs from 3 classes of nonoverlapping epitopes. Thus, the BG505 Env protein warrants further investigation as an HIV vaccine candidate, as a stand-alone protein, or as a component of a vaccine vector.", + "year": "2013", + "author": "Hoffenberg, Simon and Powell, Rebecca and Carpov, Alexei and Wagner, Denise and Wilson, Aaron and Pond, Sergei L Kosakovsky and Lindsay, Ross and Arendt, Heather and Destefano, Joanne and Phogat, Sanjay and Poignard, Pascal and Fling, Steven P and Simek, Melissa and Labranche, Celia and Montefiori, David and Wrin, Terri and Phung, Pham and Burton, Dennis and Koff, Wayne and King, C Richter and Parks, Christopher L and Caulfield, Michael J", + "journal": "J Virol" + }, + { + "id": "Murrell:2013pt", + "title": "FUBAR: a fast, unconstrained bayesian approximation for inferring selection", + "abstract": "Model-based analyses of natural selection often categorize sites into a relatively small number of site classes. Forcing each site to belong to one of these classes places unrealistic constraints on the distribution of selection parameters, which can result in misleading inference due to model misspecification. We present an approximate hierarchical Bayesian method using a Markov chain Monte Carlo (MCMC) routine that ensures robustness against model misspecification by averaging over a large number of predefined site classes. This leaves the distribution of selection parameters essentially unconstrained, and also allows sites experiencing positive and purifying selection to be identified orders of magnitude faster than by existing methods. We demonstrate that popular random effects likelihood methods can produce misleading results when sites assigned to the same site class experience different levels of positive or purifying selection--an unavoidable scenario when using a small number of site classes. Our Fast Unconstrained Bayesian AppRoximation (FUBAR) is unaffected by this problem, while achieving higher power than existing unconstrained (fixed effects likelihood) methods. The speed advantage of FUBAR allows us to analyze larger data sets than other methods: We illustrate this on a large influenza hemagglutinin data set (3,142 sequences). FUBAR is available as a batch file within the latest HyPhy distribution (http://www.hyphy.org), as well as on the Datamonkey web server (http://www.datamonkey.org/).", + "year": "2013", + "author": "Murrell, Ben and Moola, Sasha and Mabona, Amandla and Weighill, Thomas and Sheward, Daniel and Pond, Sergei L Kosakovsky and Scheffler, Konrad", + "journal": "Mol Biol Evol" + }, + { + "id": "Wertheim:2013oy", + "title": "Phylogenetic relatedness of HIV-1 donor and recipient populations", + "year": "2013", + "author": "Wertheim, Joel O and Scheffler, Konrad and Choi, Jun Yong and Smith, Davey M and Pond, Sergei L Kosakovsky", + "journal": "J Infect Dis" + }, + { + "id": "Lemey:2012ez", + "title": "A counting renaissance: combining stochastic mapping and empirical Bayes to quickly detect amino acid sites under positive selection", + "abstract": "MOTIVATION: Statistical methods for comparing relative rates of synonymous and non-synonymous substitutions maintain a central role in detecting positive selection. To identify selection, researchers often estimate the ratio of these relative rates (dN/dS) at individual alignment sites. Fitting a codon substitution model that captures heterogeneity in dN/dS across sites provides a reliable way to perform such estimation, but it remains computationally prohibitive for massive datasets. By using crude estimates of the numbers of synonymous and non-synonymous substitutions at each site, counting approaches scale well to large datasets, but they fail to account for ancestral state reconstruction uncertainty and to provide site-specific dN/dS estimates.\nRESULTS: We propose a hybrid solution that borrows the computational strength of counting methods, but augments these methods with empirical Bayes modeling to produce a relatively fast and reliable method capable of estimating site-specific dN/dS values in large datasets. Importantly, our hybrid approach, set in a Bayesian framework, integrates over the posterior distribution of phylogenies and ancestral reconstructions to quantify uncertainty about site-specific dN/dS estimates. Simulations demonstrate that this method competes well with more-principled statistical procedures and, in some cases, even outperforms them. We illustrate the utility of our method using human immunodeficiency virus, feline panleukopenia and canine parvovirus evolution examples.", + "year": "2012", + "author": "Lemey, Philippe and Minin, Vladimir N and Bielejec, Filip and Pond, Sergei L Kosakovsky and Suchard, Marc A", + "journal": "Bioinformatics" + }, + { + "id": "Gianella:2012iw", + "title": "Sexual transmission of predicted CXCR4-tropic HIV-1 likely originating from the source partner's seminal cells", + "abstract": "We present a case of sexual transmission of HIV-1 predicted to have CXCR4-tropism during male-to-male sexual exposure. Phylogenetic analyses exclude cell-free virus in the seminal plasma of the source partner and possibly point to the seminal cells as the origin of the transmission event.", + "year": "2012", + "author": "Gianella, Sara and Mehta, Sanjay R and Young, Jason A and Vargas, Milenka V and Little, Susan J and Richman, Douglas D and Pond, Sergei L Kosakovsky and Smith, Davey M", + "journal": "Virology" + }, + { + "id": "Hightower:2012km", + "title": "Higher HIV-1 genetic diversity is associated with AIDS and neuropsychological impairment", + "abstract": "Standard methods used to estimate HIV-1 population diversity are often resource intensive (e.g., single genome amplification, clonal amplification and pyrosequencing) and not well suited for large study cohorts. Additional approaches are needed to address the relationships between intraindividual HIV-1 genetic diversity and 2 disease. With a small cohort of individuals, we validated three methods for measuring diversity: Shannon entropy and average pairwise distance (APD) using single genome sequences, and counts of mixed bases (i.e. ambiguous nucleotides) from population based sequences. In a large cohort, we then used the mixed base approach to determine associations between measure HIV-1 diversity and HIV associated disease. Normalized counts of mixed bases correlated with Shannon Entropy at both the nucleotide (rho=0.72, p=0.002) and amino acid level (rho=0.59, p=0.015), and APD (rho=0.75, p=0.001). Among participants who underwent neuropsychological and clinical assessments (n=187), increased HIV-1 population diversity was associated with both a diagnosis of AIDS and neuropsychological impairment.", + "year": "2012", + "author": "Hightower, George K and Wong, Joseph K and Letendre, Scott L and Umlauf, Anya A and Ellis, Ronald J and Ignacio, Caroline C and Heaton, Robert K and Collier, Ann C and Marra, Christina M and Clifford, David B and Gelman, Benjamin B and McArthur, Justin C and Morgello, Susan and Simpson, David M and McCutchan, J A and Grant, Igor and Little, Susan J and Richman, Douglas D and Pond, Sergei L Kosakovsky and Smith, Davey M and {CHARTER Study Group}", + "journal": "Virology" + }, + { + "id": "Gianella:2012gs", + "title": "Impact of seminal cytomegalovirus replication on HIV-1 dynamics between blood and semen", + "abstract": "The genital tract of individuals infected with human immunodeficiency virus type 1 (HIV-1) is an anatomic compartment that supports local HIV-1 and cytomegalovirus (CMV) replication. This study investigated the association of seminal CMV replication with changes in HIV-1 clonal expansion, evolution and phylogenetic compartmentalization between blood and semen. Fourteen paired blood and semen samples were analyzed from four untreated subjects. Clonal sequences (n = 607) were generated from extracted HIV-1 RNA (env C2-V3 region), and HIV-1 and CMV levels were measured in the seminal plasma by real-time PCR. Sequence alignments were evaluated for: (i) viral compartmentalization between semen and blood samples using Slatkin-Maddison and F(ST) methods, (ii) different nucleotide substitution rates in semen and blood, and (iii) association between proportions of clonal HIV-1 sequences in each compartment and seminal CMV levels. Half of the semen samples had detectable CMV DNA, with at least one CMV positive sample for each patient. Seminal CMV DNA levels correlated positively with seminal HIV-1 RNA levels (Spearman P = 0.05). A trend towards an association between compartmentalization of HIV-1 sequences sampled from blood and semen and presence of seminal CMV was observed (Cochran Q test P = 0.12). Evolutionary rates between semen and blood HIV-1 populations did not differ significantly, and there was no significant association between seminal CMV DNA levels and the frequency of non-unique clonal HIV-1 sequences in the semen. In conclusion, the effects of CMV replication on HIV-1 viral and immunologic dynamics within the male genital tract are not significant enough to perturb evolution or disrupt compartmentalization in the genital tract.", + "year": "2012", + "author": "Gianella, Sara and Mehta, Sanjay R and Strain, Matthew C and Young, Jason A and Vargas, Milenka V and Little, Susan J and Richman, Douglas D and Pond, Sergei L Kosakovsky and Smith, Davey M", + "journal": "J Med Virol" + }, + { + "id": "Murrell:2012ov", + "title": "Detecting individual sites subject to episodic diversifying selection", + "abstract": "The imprint of natural selection on protein coding genes is often difficult to identify because selection is frequently transient or episodic, i.e. it affects only a subset of lineages. Existing computational techniques, which are designed to identify sites subject to pervasive selection, may fail to recognize sites where selection is episodic: a large proportion of positively selected sites. We present a mixed effects model of evolution (MEME) that is capable of identifying instances of both episodic and pervasive positive selection at the level of an individual site. Using empirical and simulated data, we demonstrate the superior performance of MEME over older models under a broad range of scenarios. We find that episodic selection is widespread and conclude that the number of sites experiencing positive selection may have been vastly underestimated.", + "year": "2012", + "author": "Murrell, Ben and Wertheim, Joel O and Moola, Sasha and Weighill, Thomas and Scheffler, Konrad and Pond, Sergei L Kosakovsky", + "journal": "PLoS Genet" + }, + { + "id": "Aldous:2012qz", + "title": "Characterizing HIV transmission networks across the United States", + "abstract": "BACKGROUND: Clinically, human immunodeficiency virus type 1 (HIV-1) pol sequences are used to evaluate for drug resistance. These data can also be used to evaluate transmission networks and help describe factors associated with transmission risk.\nMETHODS: HIV-1 pol sequences from participants at 5 sites in the CFAR Network of Integrated Clinical Systems (CNICS) cohort from 2000-2009 were analyzed for genetic relatedness. Only the first available sequence per participant was included. Inferred transmission networks (\"clusters\") were defined as ≥2 sequences with ≤1.5% genetic distance. Clusters including ≥3 patients (\"networks\") were evaluated for clinical and demographic associations.\nRESULTS: Of 3697 sequences, 24% fell into inferred clusters: 155 clusters of 2 individuals (\"dyads\"), 54 clusters that included 3-14 individuals (\"networks\"), and 1 large cluster that included 336 individuals across all study sites. In multivariable analyses, factors associated with being in a cluster included not using antiretroviral (ARV) drugs at time of sampling (P < .001), sequence collected after 2004 (P < .001), CD4 cell count >350 cells/mL (P < .01), and viral load 10,000-100,000 copies/mL (P < .001) or >100,000 copies/mL (P < .001). In networks, women were more likely to cluster with other women (P < .001), and African Americans with other African Americans (P < .001).\nCONCLUSIONS: Molecular epidemiology can be applied to study HIV transmission networks in geographically and demographically diverse cohorts. Clustering was associated with lack of ARV use and higher viral load, implying transmission may be interrupted by earlier diagnosis and treatment. Observed female and African American networks reinforce the importance of diagnosis and prevention efforts targeted by sex and race.", + "year": "2012", + "author": "Aldous, Jeannette L and Pond, Sergei L Kosakovsky and Poon, Art and Jain, Sonia and Qin, Huifang and Kahn, James S and Kitahata, Mari and Rodriguez, Benigno and Dennis, Ann M and Boswell, Stephen L and Haubrich, Richard and Smith, Davey M", + "journal": "Clin Infect Dis" + }, + { + "id": "Gronwall:2012gd", + "title": "In vivo VL-targeted microbial superantigen induced global shifts in the B cell repertoire", + "abstract": "To subvert host defenses, some microbial pathogens produce proteins that interact with conserved motifs in V regions of B cell Ag receptor shared by large sets of lymphocytes, which define the properties of a superantigen. Because the clonal composition of the lymphocyte pool is a major determinant of immune responsiveness, this study was undertaken to examine the in vivo effect on the host immune system of exposure to a B cell superantigen, protein L (PpL), a product of the common commensal bacterial species, Finegoldia magna, which is one of the most common pathogenic species among Gram-positive anaerobic cocci. Libraries of Vκ L chain transcripts were generated from the spleens of control and PpL-exposed mice, and the expressed Vκ rearrangements were characterized by high-throughput sequencing. A total of 120,855 sequencing reads could be assigned to a germline Vκ gene, with all 20 known Vκ subgroups represented. In control mice, we found a recurrent and consistent hierarchy of Vκ gene usage, as well as patterns of preferential Vκ-Jκ pairing. PpL exposure induced significant targeted global shifts in repertoire with reduction of Vκ that contain the superantigen binding motif in all exposed mice. We found significant targeted reductions in the expression of clonotypes encoded by 14 specific Vκ genes with the predicted PpL binding motif. These rigorous surveys document the capacity of a microbial protein to modulate the composition of the expressed lymphocyte repertoire, which also has broad potential implications for host-microbiome and host-pathogen relationships.", + "year": "2012", + "author": "Gronwall, Caroline and Pond, Sergei L Kosakovsky and Young, Jason A and Silverman, Gregg J", + "journal": "J Immunol" + }, + { + "id": "Murrell:2012ix", + "title": "Modeling HIV-1 drug resistance as episodic directional selection", + "abstract": "The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS) which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.", + "year": "2012", + "author": "Murrell, Ben and de Oliveira, Tulio and Seebregts, Chris and Pond, Sergei L Kosakovsky and Scheffler, Konrad and {Southern African Treatment and Resistance Network-SATuRN Consortium}", + "journal": "PLoS Comput Biol" + }, + { + "id": "Fisher:2012rp", + "title": "Deep sequencing reveals minor protease resistance mutations in patients failing a protease inhibitor regimen", + "abstract": "Standard genotypic antiretroviral resistance testing, performed by bulk sequencing, does not readily detect variants that comprise <20% of the circulating HIV-1 RNA population. Nevertheless, it is valuable in selecting an antiretroviral regimen after antiretroviral failure. In patients with poor adherence, resistant variants may not reach this threshold. Therefore, deep sequencing would be potentially valuable for detecting minority resistant variants. We compared bulk sequencing and deep sequencing to detect HIV-1 drug resistance at the time of a second-line protease inhibitor (PI)-based antiretroviral regimen failure. Eligibility criteria were virologic failure (HIV-1 RNA load of >500 copies/ml) of a first-line nonnucleoside reverse transcriptase inhibitor-based regimen, with at least the M184V mutation (lamivudine resistance), and second-line failure of a lopinavir/ritonavir (LPV/r)-based regimen. An amplicon-sequencing approach on the Roche 454 system was used. Six patients with viral loads of >90,000 copies/ml and one patient with a viral load of 520 copies/ml were included. Mutations not detectable by bulk sequencing during first- and second-line failure were detected by deep sequencing during second-line failure. Low-frequency variants (>0.5% of the sequence population) harboring major protease inhibitor resistance mutations were found in 5 of 7 patients despite poor adherence to the LPV/r-based regimen. In patients with intermittent adherence to a boosted PI regimen, deep sequencing may detect minority PI-resistant variants, which likely represent early events in resistance selection. In patients with poor or intermittent adherence, there may be low evolutionary impetus for such variants to reach fixation, explaining the low prevalence of PI resistance.", + "year": "2012", + "author": "Fisher, Randall and van Zyl, Gert U and Travers, Simon A A and Pond, Sergei L Kosakovsky and Engelbrech, Susan and Murrell, Ben and Scheffler, Konrad and Smith, Davey", + "journal": "J Virol" + }, + { + "id": "Mehta:2012dd", + "title": "Associations between phylogenetic clustering and HLA profile among HIV-infected individuals in San Diego, California", + "abstract": "BACKGROUND: Specific sequence changes of human immunodeficiency virus type 1 (HIV-1) in the presence of specific HLA molecules may alter the composition and processing of viral peptides, leading to immune escape. Persistence of these mutations after transmission may leave the genetic fingerprint of the transmitter's HLA profile. Here, we evaluated the associations between HLA profiles and the phylogenetic relationships of HIV sequences sampled from a cohort of recently infected individuals in San Diego, California.\nMETHODS: We identified transmission clusters within the study cohort, using phylogenetic analysis of sampled HIV pol genotypes at a genetic distance of <1.5%. We then evaluated the association of specific HLA alleles, HLA homozygosity, HLA concordance, race and ethnicity, and mutational patterns within the clustering and nonclustering groups.\nRESULTS: From 350 cohort participants, we identified 162 clustering individuals and 188 nonclustering individuals. We identified trends for enrichment of particular alleles within individual clusters and evidence of viral escape within those clusters. We also found that discordance of HLA alleles was significantly associated with clustering individuals.\nCONCLUSIONS: Some transmission clusters demonstrate HLA enrichment, and viruses in these HLA-associated clusters often show evidence of escape to enriched alleles. Interestingly, HLA discordance was associated with clustering in our predominantly MSM population.", + "year": "2012", + "author": "Mehta, Sanjay R and Pond, Sergei L Kosakovsky and Young, Jason A and Richman, Douglas and Little, Susan and Smith, Davey M", + "journal": "J Infect Dis" + }, + { + "id": "Pond:2012zp", + "title": "Evolution of viral genomes: interplay between selection, recombination, and other forces", + "abstract": "RNA viruses evolve very rapidly, often recombine, and are subject to strong host (immune response) and anthropogenic (antiretroviral drugs) selective forces. Given their compact and extensively sequenced genomes, comparative analysis of RNA viral data can provide important insights into the molecular mechanisms of adaptation, pathogenicity, immune evasion, and drug resistance. In this chapter, we present an example-based overview of recent advances in evolutionary models and statistical approaches that enable screening viral alignments for evidence of adaptive change in the presence of recombination, detecting bursts of directional adaptive evolution associated with the phenotypic changes, and detecting of coevolving sites in viral genes.", + "year": "2012", + "author": "Pond, Sergei L Kosakovsky and Murrell, Ben and Poon, Art F Y", + "journal": "Methods Mol Biol" + }, + { + "id": "Wertheim:2011lc", + "title": "Using HIV transmission networks to investigate community effects in HIV prevention trials", + "abstract": "Effective population screening of HIV and prevention of HIV transmission are only part of the global fight against AIDS. Community-level effects, for example those aimed at thwarting future transmission, are potential outcomes of treatment and may be important in stemming the epidemic. However, current clinical trial designs are incapable of detecting a reduction in future transmission due to treatment. We took advantage of the fact that HIV is an evolving pathogen whose transmission network can be reconstructed using genetic sequence information to address this shortcoming. Here, we use an HIV transmission network inferred from recently infected men who have sex with men (MSM) in San Diego, California. We developed and tested a network-based statistic for measuring treatment effects using simulated clinical trials on our inferred transmission network. We explored the statistical power of this network-based statistic against conventional efficacy measures and find that when future transmission is reduced, the potential for increased statistical power can be realized. Furthermore, our simulations demonstrate that the network statistic is able to detect community-level effects (e.g., reduction in onward transmission) of HIV treatment in a clinical trial setting. This study demonstrates the potential utility of a network-based statistical metric when investigating HIV treatment options as a method to reduce onward transmission in a clinical trial setting.", + "year": "2011", + "author": "Wertheim, Joel O and Pond, Sergei L Kosakovsky and Little, Susan J and De Gruttola, Victor", + "journal": "PLoS One" + }, + { + "id": "Farrer:2011rw", + "title": "Multiple emergences of genetically diverse amphibian-infecting chytrids include a globalized hypervirulent recombinant lineage", + "abstract": "Batrachochytrium dendrobatidis (Bd) is a globally ubiquitous fungal infection that has emerged to become a primary driver of amphibian biodiversity loss. Despite widespread effort to understand the emergence of this panzootic, the origins of the infection, its patterns of global spread, and principle mode of evolution remain largely unknown. Using comparative population genomics, we discovered three deeply diverged lineages of Bd associated with amphibians. Two of these lineages were found in multiple continents and are associated with known introductions by the amphibian trade. We found that isolates belonging to one clade, the global panzootic lineage (BdGPL) have emerged across at least five continents during the 20th century and are associated with the onset of epizootics in North America, Central America, the Caribbean, Australia, and Europe. The two newly identified divergent lineages, Cape lineage (BdCAPE) and Swiss lineage (BdCH), were found to differ in morphological traits when compared against one another and BdGPL, and we show that BdGPL is hypervirulent. BdGPL uniquely bears the hallmarks of genomic recombination, manifested as extensive intergenomic phylogenetic conflict and patchily distributed heterozygosity. We postulate that contact between previously genetically isolated allopatric populations of Bd may have allowed recombination to occur, resulting in the generation, spread, and invasion of the hypervirulent BdGPL leading to contemporary disease-driven losses in amphibian biodiversity.", + "year": "2011", + "author": "Farrer, Rhys A and Weinert, Lucy A and Bielby, Jon and Garner, Trenton W J and Balloux, Francois and Clare, Frances and Bosch, Jaime and Cunningham, Andrew A and Weldon, Che and du Preez, Louis H and Anderson, Lucy and Pond, Sergei L Kosakovsky and Shahar-Golan, Revital and Henk, Daniel A and Fisher, Matthew C", + "journal": "Proc Natl Acad Sci U S A" + }, + { + "id": "Wertheim:2012nq", + "title": "Inconsistencies in estimating the age of HIV-1 subtypes due to heterotachy", + "abstract": "Rate heterogeneity among lineages is a common feature of molecular evolution, and it has long impeded our ability to accurately estimate the age of evolutionary divergence events. The development of relaxed molecular clocks, which model variable substitution rates among lineages, was intended to rectify this problem. Major subtypes of pandemic HIV-1 group M are thought to exemplify closely related lineages with different substitution rates. Here, we report that inferring the time of most recent common ancestor of all these subtypes in a single phylogeny under a single (relaxed) molecular clock produces significantly different dates for many of the subtypes than does analysis of each subtype on its own. We explore various methods to ameliorate this problem. We conclude that current molecular dating methods are inadequate for dealing with this type of substitution rate variation in HIV-1. Through simulation, we show that heterotachy causes root ages to be overestimated.", + "year": "2012", + "author": "Wertheim, Joel O and Fourment, Mathieu and Pond, Sergei L Kosakovsky", + "journal": "Mol Biol Evol" + }, + { + "id": "Pacold:2012wq", + "title": "Clinical, virologic, and immunologic correlates of HIV-1 intraclade B dual infection among men who have sex with men", + "abstract": "OBJECTIVE: To investigate the susceptibilities to and consequences of HIV-1 dual infection.\nDESIGN: We compared clinical, virologic, and immunologic factors between participants who were dually infected with HIV-1 subtype B and monoinfected controls who were matched by ongoing HIV risk factor.\nMETHODS: The viral load and CD4 progressions of dually and singly infected participant groups were compared with linear mixed-effects models, and individual dynamics before and after superinfection were assessed with a structural change test (Chow test). Recombination breakpoint analysis (GARD), HLA frequency analysis, and cytotoxic T-lymphocyte (CTL) epitope mapping were also performed (HIV LANL Database).\nRESULTS: The viral loads of dually infected participants increased more over 3 years of follow-up than the viral loads of monoinfected controls, whereas CD4 progressions of the two groups did not differ. Viral escape from CTL responses following superinfection was observed in two participants whose superinfecting strain completely replaced the initial strain. This pattern was not seen among participants whose superinfecting virus persisted in a recombinant form with the initial virus or was only detected transiently. Several HLA types were over-represented in dually infected participants as compared to monoinfected controls.\nCONCLUSIONS: These results identify potential factors for dual infection susceptibility and further define its clinical consequences.", + "year": "2012", + "author": "Pacold, Mary E and Pond, Sergei L Kosakovsky and Wagner, Gabriel A and Delport, Wayne and Bourque, Daniel L and Richman, Douglas D and Little, Susan J and Smith, Davey M", + "journal": "AIDS" + }, + { + "id": "Kumar:2012ec", + "title": "Statistics and truth in phylogenomics", + "abstract": "Phylogenomics refers to the inference of historical relationships among species using genome-scale sequence data and to the use of phylogenetic analysis to infer protein function in multigene families. With rapidly decreasing sequencing costs, phylogenomics is becoming synonymous with evolutionary analysis of genome-scale and taxonomically densely sampled data sets. In phylogenetic inference applications, this translates into very large data sets that yield evolutionary and functional inferences with extremely small variances and high statistical confidence (P value). However, reports of highly significant P values are increasing even for contrasting phylogenetic hypotheses depending on the evolutionary model and inference method used, making it difficult to establish true relationships. We argue that the assessment of the robustness of results to biological factors, that may systematically mislead (bias) the outcomes of statistical estimation, will be a key to avoiding incorrect phylogenomic inferences. In fact, there is a need for increased emphasis on the magnitude of differences (effect sizes) in addition to the P values of the statistical test of the null hypothesis. On the other hand, the amount of sequence data available will likely always remain inadequate for some phylogenomic applications, for example, those involving episodic positive selection at individual codon positions and in specific lineages. Again, a focus on effect size and biological relevance, rather than the P value, may be warranted. Here, we present a theoretical overview and discuss practical aspects of the interplay between effect sizes, bias, and P values as it relates to the statistical inference of evolutionary truth in phylogenomics.", + "year": "2012", + "author": "Kumar, Sudhir and Filipski, Alan J and Battistuzzi, Fabia U and Pond, Sergei L Kosakovsky and Tamura, Koichiro", + "journal": "Mol Biol Evol" + }, + { + "id": "Goto:2011yj", + "title": "A massively parallel sequencing approach uncovers ancient origins and high genetic variability of endangered Przewalski's horses", + "abstract": "The endangered Przewalski's horse is the closest relative of the domestic horse and is the only true wild horse species surviving today. The question of whether Przewalski's horse is the direct progenitor of domestic horse has been hotly debated. Studies of DNA diversity within Przewalski's horses have been sparse but are urgently needed to ensure their successful reintroduction to the wild. In an attempt to resolve the controversy surrounding the phylogenetic position and genetic diversity of Przewalski's horses, we used massively parallel sequencing technology to decipher the complete mitochondrial and partial nuclear genomes for all four surviving maternal lineages of Przewalski's horses. Unlike single-nucleotide polymorphism (SNP) typing usually affected by ascertainment bias, the present method is expected to be largely unbiased. Three mitochondrial haplotypes were discovered-two similar ones, haplotypes I/II, and one substantially divergent from the other two, haplotype III. Haplotypes I/II versus III did not cluster together on a phylogenetic tree, rejecting the monophyly of Przewalski's horse maternal lineages, and were estimated to split 0.117-0.186 Ma, significantly preceding horse domestication. In the phylogeny based on autosomal sequences, Przewalski's horses formed a monophyletic clade, separate from the Thoroughbred domestic horse lineage. Our results suggest that Przewalski's horses have ancient origins and are not the direct progenitors of domestic horses. The analysis of the vast amount of sequence data presented here suggests that Przewalski's and domestic horse lineages diverged at least 0.117 Ma but since then have retained ancestral genetic polymorphism and/or experienced gene flow.", + "year": "2011", + "author": "Goto, Hiroki and Ryder, Oliver A and Fisher, Allison R and Schultz, Bryant and Pond, Sergei L Kosakovsky and Nekrutenko, Anton and Makova, Kateryna D", + "journal": "Genome Biol Evol" + }, + { + "id": "Wertheim:2011yi", + "title": "Purifying selection can obscure the ancient age of viral lineages", + "abstract": "Statistical methods for molecular dating of viral origins have been used extensively to infer the time of most common recent ancestor for many rapidly evolving pathogens. However, there are a number of cases, in which epidemiological, historical, or genomic evidence suggests much older viral origins than those obtained via molecular dating. We demonstrate how pervasive purifying selection can mask the ancient origins of recently sampled pathogens, in part due to the inability of nucleotide-based substitution models to properly account for complex patterns of spatial and temporal variability in selective pressures. We use codon-based substitution models to infer the length of branches in viral phylogenies; these models produce estimates that are often considerably longer than those obtained with traditional nucleotide-based substitution models. Correcting the apparent underestimation of branch lengths suggests substantially older origins for measles, Ebola, and avian influenza viruses. This work helps to reconcile some of the inconsistencies between molecular dating and other types of evidence concerning the age of viral lineages.", + "year": "2011", + "author": "Wertheim, Joel O and Pond, Sergei L Kosakovsky", + "journal": "Mol Biol Evol" + }, + { + "id": "Kosakovsky-Pond:2011bf", + "title": "A random effects branch-site model for detecting episodic diversifying selection", + "abstract": "Adaptive evolution frequently occurs in episodic bursts, localized to a few sites in a gene, and to a small number of lineages in a phylogenetic tree. A popular class of \"branch-site\" evolutionary models provides a statistical framework to search for evidence of such episodic selection. For computational tractability, current branch-site models unrealistically assume that all branches in the tree can be partitioned a priori into two rigid classes--\"foreground\" branches that are allowed to undergo diversifying selective bursts and \"background\" branches that are negatively selected or neutral. We demonstrate that this assumption leads to unacceptably high rates of false positives or false negatives when the evolutionary process along background branches strongly deviates from modeling assumptions. To address this problem, we extend Felsenstein's pruning algorithm to allow efficient likelihood computations for models in which variation over branches (and not just sites) is described in the random effects likelihood framework. This enables us to model the process at every branch-site combination as a mixture of three Markov substitution models--our model treats the selective class of every branch at a particular site as an unobserved state that is chosen independently of that at any other branch. When benchmarked on a previously published set of simulated sequences, our method consistently matched or outperformed existing branch-site tests in terms of power and error rates. Using three empirical data sets, previously analyzed for episodic selection, we discuss how modeling assumptions can influence inference in practical situations.", + "year": "2011", + "author": "Pond, Sergei L Kosakovsky and Murrell, Ben and Fourment, Mathieu and Frost, Simon D W and Delport, Wayne and Scheffler, Konrad", + "journal": "Mol Biol Evol" + }, + { + "id": "Gianella:2011jy", + "title": "Detection of minority resistance during early HIV-1 infection: natural variation and spurious detection rather than transmission and evolution of multiple viral variants", + "abstract": "Reports of a high frequency of the transmission of minority viral populations with drug-resistant mutations (DRM) are inconsistent with evidence that HIV-1 infections usually arise from mono- or oligoclonal transmission. We performed ultradeep sequencing (UDS) of partial HIV-1 gag, pol, and env genes from 32 recently infected individuals. We then evaluated overall and per-site diversity levels, selective pressure, sequence reproducibility, and presence of DRM and accessory mutations (AM). To differentiate biologically meaningful mutations from those caused by methodological errors, we obtained multinomial confidence intervals (CI) for the proportion of DRM at each site and fitted a binomial mixture model to determine background error rates for each sample. We then examined the association between detected minority DRM and the virologic failure of first-line antiretroviral therapy (ART). Similar to other studies, we observed increased detection of DRM at low frequencies (average, 0.56%; 95% CI, 0.43 to 0.69; expected UDS error, 0.21 $\\pm$ 0.08% mutations/site). For 8 duplicate runs, there was variability in the proportions of minority DRM. There was no indication of increased diversity or selection at DRM sites compared to other sites and no association between minority DRM and AM. There was no correlation between detected minority DRM and clinical failure of first-line ART. It is unlikely that minority viral variants harboring DRM are transmitted and maintained in the recipient host. The majority of low-frequency DRM detected using UDS are likely errors inherent to UDS methodology or a consequence of error-prone HIV-1 replication.", + "year": "2011", + "author": "Gianella, Sara and Delport, Wayne and Pacold, Mary E and Young, Jason A and Choi, Jun Yong and Little, Susan J and Richman, Douglas D and Pond, Sergei L Kosakovsky and Smith, Davey M", + "journal": "J Virol" + }, + { + "id": "Smith:2010km", + "title": "Response to Comment on \"The Origins of Sexually Transmitted HIV Among Men Who Have Sex with Men\"", + "abstract": "In this investigation, we evaluated explanations for the unusual degree of genetic diversity in HIV populations within the sampled seminal cell and plasma compartments observed in our previous study. These analyses included clonal sequencing of HIV DNA in peripheral blood mononuclear cells, ultradeep sequencing of HIV RNA in blood plasma, human leukocyte antigen (HLA) haplotyping of previously used samples, and a BLAST screen against both a local and public repository of HIV-1 sequences, and the investigations to determine whether these observations were secondary to contamination or artifact were unsuccessful. As there are very few HIV sequences from seminal cell tissues and transmission pairs described in the literature, future studies that evaluate more transmission pairs with sampling from multiple anatomic compartments and at multiple time points will most likely be required to resolve this controversy.", + "year": "2010", + "author": "Smith, Davey and Delport, Wayne and Butler, David and Little, Susan and Richman, Douglas and Pond, Sergei L Kosakovsky", + "journal": "Sci Transl Med" + }, + { + "id": "Mehta:2011jf", + "title": "Using phylogeography to characterize the origins of the HIV-1 subtype F epidemic in Romania", + "abstract": "BACKGROUND: During the late 1980s and early 1990s, an estimated 10,000 Romanian children were infected with HIV-1 subtype F nosocomially through contaminated needles and blood transfusions. However, the geographic source and origins of this epidemic remain unclear.\nMETHODS: Here we used phylogenetic inference and \"relaxed\" molecular clock dating analysis to further characterize the Romanian HIV-1 subtype F epidemic.\nRESULTS: These analyses revealed a major lineage of Romanian HIV sequences consisting nearly entirely of virus sampled from adolescents and children and a distinct cluster that included a much higher ratio of adult sequences. Divergence time estimates inferred the time of most recent common ancestor of subtype F1 sequences to be 1973 (1966-1980) and for all Angolan sequences to 1975 (1968-1980). The most common ancestor of the Romanian sequences was dated to 1978 (1972-1983) with pediatric and adolescent sequences interspersed throughout the lineage. The phylogenetic structure of the entire subtype F epidemic suggests that multiple introductions of subtype F into Romania occurred either from the Angolan epidemic or from more distant ancestors. Since the historical records note that the Romanian pediatric epidemic did not begin until the late 1980s, the inferred time of most recent common ancestor of the Romanian lineage of 1978 suggests that there were multiple introductions of subtype F occurred into the pediatric population from HIV already circulating in Romania.\nCONCLUSIONS: Analysis of the subtype F HIV-1 epidemic in an historical context allows for a deeper appreciation of how the HIV pandemic has been influenced by socio-political events.", + "year": "2011", + "author": "Mehta, Sanjay R and Wertheim, Joel O and Delport, Wayne and Ene, Luminita and Tardei, Gratiela and Duiculescu, Dan and Pond, Sergei L Kosakovsky and Smith, Davey M", + "journal": "Infect Genet Evol" + }, + { + "id": "Price:2011qw", + "title": "Transmitted HIV type 1 drug resistance among individuals with recent HIV infection in East and Southern Africa", + "abstract": "To characterize WHO-defined transmitted HIV drug resistance mutation (TDRM) data from recently HIV-infected African volunteers, we sequenced HIV (pol) and evaluated for TDRM the earliest available specimens from ARV-naive volunteers diagnosed within 1 year of their estimated date of infection at eight research centers in sub-Saharan Africa. TDRMs were detected in 19/408 (5%) volunteers. The prevalence of TDRMs varied by research center, from 5/26 (19%) in Entebbe, 6/78 (8%) in Kigali, 2/49 (4%) in Kilifi, to 3/106 (3%) in Lusaka. One of five volunteers from Cape Town (20%) had TDRMs. Despite small numbers, our data suggest an increase in DRMs by year of infection in Zambia (p = 0.004). The prevalence observed in Entebbe was high across the entire study. ARV history data from 12 (63%) HIV-infected sexual partners were available; 3 reported ARV use prior to transmission. Among four partners with sequence data available, transmission linkage was confirmed and two had the same TDRMs as the newly infected volunteer (both K103N). As ARV therapy continues to increase in availability throughout Africa, monitoring incident virus strains for the presence of TDRMs should be a priority. Early HIV infection cohorts provide an excellent and important platform to monitor the development of TDRMs to inform treatment guidelines, drug choices, and strategies for secondary prevention of TDRM transmission.", + "year": "2011", + "author": "Price, Matt A and Wallis, Carole L and Lakhi, Shabir and Karita, Etienne and Kamali, Anatoli and Anzala, Omu and Sanders, Eduard J and Bekker, Linda-Gail and Twesigye, Rogers and Hunter, Eric and Kaleebu, Pontiano and Kayitenkore, Kayitesi and Allen, Susan and Ruzagira, Eugene and Mwangome, Mary and Mutua, Gaudensia and Amornkul, Pauli N and Stevens, Gwynn and Pond, Sergei L K and Schaefer, Malinda and Papathanasopoulos, Mary A and Stevens, Wendy and Gilmour, Jill and {IAVI Early Infection Cohort Study Group}", + "journal": "AIDS Res Hum Retroviruses" + }, + { + "id": "Mehta:2010lt", + "title": "The relatedness of HIV epidemics in the United States-Mexico border region", + "abstract": "Phylogeography can improve the understanding of local and worldwide HIV epidemics, including the migration of subepidemics across national borders. We analyzed HIV-1 sequences sampled from Mexico and San Diego, California to determine the relatedness of these epidemics. We sampled the HIV epidemics in (1) Mexico by downloading all publicly available HIV-1 pol sequences from antiretroviral-naive individuals in GenBank (n = 100) and generating similar sequences from cohorts of injection drug users and female sex workers in Tijuana, Mexico (n = 27) and (2) in San Diego, California by pol sequencing well-characterized primary (n = 395) and chronic (n = 267) HIV infection cohorts. Estimates of population structure (F(ST)), genetic distance cluster analysis, and a cladistic measure of migration events (Slatkin-Maddison test) were used to assess the relatedness of the epidemics. Both a test of population differentiation (F(ST) = 0.06; p < 0.01) and a cladistic estimate of migration events (84 migrations, p < 0.01) indicated that the Tijuana and San Diego epidemics were not freely mixing. A conservative cluster analysis identified 72 clusters (two or more sequences), with two clusters containing both Mexican and San Diego sequences (permutation p < 0.01). Analysis of this very large dataset of HIV-1 sequences suggested that the HIV-1 epidemics in San Diego, California and Tijuana, Mexico are distinct. Larger epidemiological studies are needed to quantify the magnitude and associations of cross-border mixing.", + "year": "2010", + "author": "Mehta, Sanjay R and Delport, Wayne and Brouwer, Kimberly C and Espitia, Stephen and Patterson, Thomas and Pond, Sergei L Kosakovsky and Strathdee, Steffanie A and Smith, Davey M", + "journal": "AIDS Res Hum Retroviruses" + }, + { + "id": "Pacold:2010vz", + "title": "Comparison of methods to detect HIV dual infection", + "abstract": "Current methods to detect intraclade HIV dual infection are poorly suited for determining its prevalence in large cohorts. To investigate the potential of ultra-deep sequencing to screen for dual infection, we compared it to bulk sequence-based synonymous mixture index and the current standard of single genome sequencing. The synonymous mixture index identified samples likely to harbor dual infection, while ultra-deep sequencing captured more intra-host viral diversity than single genome sequencing at approximately 40% of the cost and 20% of the laboratory and analysis time. The synonymous mixture index and ultra-deep sequencing are promising methods for rapid and cost-effective systematic identification of HIV dual infection.", + "year": "2010", + "author": "Pacold, Mary and Smith, Davey and Little, Susan and Cheng, Pok Man and Jordan, Parris and Ignacio, Caroline and Richman, Douglas and Pond, Sergei L Kosakovsky", + "journal": "AIDS Res Hum Retroviruses" + }, + { + "id": "Delport:2010kq", + "title": "CodonTest: modeling amino acid substitution preferences in coding sequences", + "abstract": "Codon models of evolution have facilitated the interpretation of selective forces operating on genomes. These models, however, assume a single rate of non-synonymous substitution irrespective of the nature of amino acids being exchanged. Recent developments have shown that models which allow for amino acid pairs to have independent rates of substitution offer improved fit over single rate models. However, these approaches have been limited by the necessity for large alignments in their estimation. An alternative approach is to assume that substitution rates between amino acid pairs can be subdivided into rate classes, dependent on the information content of the alignment. However, given the combinatorially large number of such models, an efficient model search strategy is needed. Here we develop a Genetic Algorithm (GA) method for the estimation of such models. A GA is used to assign amino acid substitution pairs to a series of rate classes, where is estimated from the alignment. Other parameters of the phylogenetic Markov model, including substitution rates, character frequencies and branch lengths are estimated using standard maximum likelihood optimization procedures. We apply the GA to empirical alignments and show improved model fit over existing models of codon evolution. Our results suggest that current models are poor approximations of protein evolution and thus gene and organism specific multi-rate models that incorporate amino acid substitution biases are preferred. We further anticipate that the clustering of amino acid substitution rates into classes will be biologically informative, such that genes with similar functions exhibit similar clustering, and hence this clustering will be useful for the evolutionary fingerprinting of genes.", + "year": "2010", + "author": "Delport, Wayne and Scheffler, Konrad and Botha, Gordon and Gravenor, Mike B and Muse, Spencer V and Pond, Sergei L Kosakovsky", + "journal": "PLoS Comput Biol" + }, + { + "id": "Kosakovsky-Pond:2010tp", + "title": "Correcting the bias of empirical frequency parameter estimators in codon models", + "abstract": "Markov models of codon substitution are powerful inferential tools for studying biological processes such as natural selection and preferences in amino acid substitution. The equilibrium character distributions of these models are almost always estimated using nucleotide frequencies observed in a sequence alignment, primarily as a matter of historical convention. In this note, we demonstrate that a popular class of such estimators are biased, and that this bias has an adverse effect on goodness of fit and estimates of substitution rates. We propose a \"corrected\" empirical estimator that begins with observed nucleotide counts, but accounts for the nucleotide composition of stop codons. We show via simulation that the corrected estimates outperform the de facto standard estimates not just by providing better estimates of the frequencies themselves, but also by leading to improved estimation of other parameters in the evolutionary models. On a curated collection of sequence alignments, our estimators show a significant improvement in goodness of fit compared to the approach. Maximum likelihood estimation of the frequency parameters appears to be warranted in many cases, albeit at a greater computational cost. Our results demonstrate that there is little justification, either statistical or computational, for continued use of the -style estimators.", + "year": "2010", + "author": "Pond, Sergei L Kosakovsky and Delport, Wayne and Muse, Spencer V and Scheffler, Konrad", + "journal": "PLoS One" + }, + { + "id": "Delport:2010vo", + "title": "Datamonkey 2010: a suite of phylogenetic analysis tools for evolutionary biology", + "abstract": "Datamonkey is a popular web-based suite of phylogenetic analysis tools for use in evolutionary biology. Since the original release in 2005, we have expanded the analysis options to include recently developed algorithmic methods for recombination detection, evolutionary fingerprinting of genes, codon model selection, co-evolution between sites, identification of sites, which rapidly escape host-immune pressure and HIV-1 subtype assignment. The traditional selection tools have also been augmented to include recent developments in the field. Here, we summarize the analyses options currently available on Datamonkey, and provide guidelines for their use in evolutionary biology. Availability and documentation: http://www.datamonkey.org.", + "year": "2010", + "author": "Delport, Wayne and Poon, Art F Y and Frost, Simon D W and Pond, Sergei L Kosakovsky", + "journal": "Bioinformatics" + }, + { + "id": "Delport:2010lp", + "title": "Benchmarking multi-rate codon models", + "abstract": "The single rate codon model of non-synonymous substitution is ubiquitous in phylogenetic modeling. Indeed, the use of a non-synonymous to synonymous substitution rate ratio parameter has facilitated the interpretation of selection pressure on genomes. Although the single rate model has achieved wide acceptance, we argue that the assumption of a single rate of non-synonymous substitution is biologically unreasonable, given observed differences in substitution rates evident from empirical amino acid models. Some have attempted to incorporate amino acid substitution biases into models of codon evolution and have shown improved model performance versus the single rate model. Here, we show that the single rate model of non-synonymous substitution is easily outperformed by a model with multiple non-synonymous rate classes, yet in which amino acid substitution pairs are assigned randomly to these classes. We argue that, since the single rate model is so easy to improve upon, new codon models should not be validated entirely on the basis of improved model fit over this model. Rather, we should strive to both improve on the single rate model and to approximate the general time-reversible model of codon substitution, with as few parameters as possible, so as to reduce model over-fitting. We hint at how this can be achieved with a Genetic Algorithm approach in which rate classes are assigned on the basis of sequence information content.", + "year": "2010", + "author": "Delport, Wayne and Scheffler, Konrad and Gravenor, Mike B and Muse, Spencer V and Pond, Sergei L Kosakovsky", + "journal": "PLoS One" + }, + { + "id": "Deng:2010hc", + "title": "DIVEIN: a web server to analyze phylogenies, sequence divergence, diversity, and informative sites", + "abstract": "DIVEIN is a web interface that performs automated phylogenetic and other analyses of nucleotide and amino acid sequences. Starting with a set of aligned sequences, DIVEIN estimates evolutionary parameters and phylogenetic trees while allowing the user to choose from a variety of evolutionary models; it then reconstructs the consensus (CON), most recent common ancestor (MRCA), and center of tree (COT) sequences. DIVEIN also provides tools for further analyses, including condensing sequence alignments to show only informative sites or private mutations; computing phylogenetic or pairwise divergence from any user-specified sequence (CON, MRCA, COT, or existing sequence from the alignment); computing and outputting all genetic distances in column format; calculating summary statistics of diversity and divergence from pairwise distances; and graphically representing the inferred tree and plots of divergence, diversity, and distance distribution histograms. DIVEIN is available at http://indra.mullins.microbiol.washington.edu/DIVEIN.", + "year": "2010", + "author": "Deng, Wenjie and Maust, Brandon S and Nickle, David C and Learn, Gerald H and Liu, Yi and Heath, Laura and Pond, Sergei L Kosakovsky and Mullins, James I", + "journal": "Biotechniques" + }, + { + "id": "Siebenga:2010kc", + "title": "Phylodynamic reconstruction reveals norovirus GII.4 epidemic expansions and their molecular determinants", + "abstract": "Noroviruses are the most common cause of viral gastroenteritis. An increase in the number of globally reported norovirus outbreaks was seen the past decade, especially for outbreaks caused by successive genogroup II genotype 4 (GII.4) variants. Whether this observed increase was due to an upswing in the number of infections, or to a surveillance artifact caused by heightened awareness and concomitant improved reporting, remained unclear. Therefore, we set out to study the population structure and changes thereof of GII.4 strains detected through systematic outbreak surveillance since the early 1990s. We collected 1383 partial polymerase and 194 full capsid GII.4 sequences. A Bayesian MCMC coalescent analysis revealed an increase in the number of GII.4 infections during the last decade. The GII.4 strains included in our analyses evolved at a rate of 4.3-9.0x10(-3) mutations per site per year, and share a most recent common ancestor in the early 1980s. Determinants of adaptation in the capsid protein were studied using different maximum likelihood approaches to identify sites subject to diversifying or directional selection and sites that co-evolved. While a number of the computationally determined adaptively evolving sites were on the surface of the capsid and possible subject to immune selection, we also detected sites that were subject to constrained or compensatory evolution due to secondary RNA structures, relevant in virus-replication. We highlight codons that may prove useful in identifying emerging novel variants, and, using these, indicate that the novel 2008 variant is more likely to cause a future epidemic than the 2007 variant. While norovirus infections are generally mild and self-limiting, more severe outcomes of infection frequently occur in elderly and immunocompromized people, and no treatment is available. The observed pattern of continually emerging novel variants of GII.4, causing elevated numbers of infections, is therefore a cause for concern.", + "year": "2010", + "author": "Siebenga, J Joukje and Lemey, Philippe and Pond, Sergei L Kosakovsky and Rambaut, Andrew and Vennema, Harry and Koopmans, Marion", + "journal": "PLoS Pathog" + }, + { + "id": "Butler:2010yu", + "title": "The origins of sexually transmitted HIV among men who have sex with men", + "abstract": "Although it is known that most HIV-1 infections worldwide result from exposure to virus in semen, it has not yet been established whether transmitted strains originate as RNA virions in seminal plasma or as integrated proviral DNA in infected seminal leukocytes. We present phylogenetic evidence that among six transmitting pairs of men who have sex with men, blood plasma virus in the recipient is consistently more closely related to the seminal plasma virus in the source. All sequences were subtype B, and the env C2V3 of transmitted variants tended to have higher mean isoelectric points, contain potential N-linked glycosylation sites, and favor CCR5 co-receptor usage. A statistically robust phylogenetically corrected analysis did not detect genetic signatures reliably associated with transmission, but further investigation of larger samples of transmitting pairs holds promise for determining which structural and genetic features of viral genomes are associated with transmission.", + "year": "2010", + "author": "Butler, David M and Delport, Wayne and Pond, Sergei L Kosakovsky and Lakdawala, Malcolm K and Cheng, Pok Man and Little, Susan J and Richman, Douglas D and Smith, Davey M", + "journal": "Sci Transl Med" + }, + { + "id": "Manosuthi:2010fd", + "title": "Protease polymorphisms in HIV-1 subtype CRF01_AE represent selection by antiretroviral therapy and host immune pressure", + "abstract": "BACKGROUND: Most of our knowledge about how antiretrovirals and host immune responses influence the HIV-1 protease gene is derived from studies of subtype B virus. We investigated the effect of protease resistance-associated mutations (PRAMs) and population-based HLA haplotype frequencies on polymorphisms found in CRF01_AE pro.\nMETHODS: We used all CRF01_AE protease sequences retrieved from the LANL database and obtained regional HLA frequencies from the dbMHC database. Polymorphisms and major PRAMs in the sequences were identified using the Stanford Resistance Database, and we performed phylogenetic and selection analyses using HyPhy. HLA binding affinities were estimated using the Immune Epitope Database and Analysis.\nRESULTS: Overall, 99% of CRF01_AE sequences had at least 1 polymorphism and 10% had at least 1 major PRAM. Three polymorphisms (L10 V, K20RMI and I62 V) were associated with the presence of a major PRAM (P < 0.05). Compared to the subtype B consensus, six additional polymorphisms (I13 V, E35D, M36I, R41K, H69K, L89M) were identified in the CRF01_AE consensus; all but L89M were located within epitopes recognized by HLA class I alleles. Of the predominant HLA haplotypes in the Asian regions of CRF01_AE origin, 80% were positively associated with the observed polymorphisms, and estimated HLA binding affinity was estimated to decrease 19-40 fold with the observed polymorphisms at positions 35, 36 and 41.\nCONCLUSION: Polymorphisms in CRF01_AE protease gene were common, and polymorphisms at residues 10, 20 and 62 most likely represent selection by use of protease inhibitors, whereas R41K and H69K were more likely attributable to recognition of epitopes by the HLA haplotypes of the host population.", + "year": "2010", + "author": "Manosuthi, Weerawat and Butler, David M and Perez-Santiago, Josue and Poon, Art Fy and Pillai, Satish K and Mehta, Sanjay R and Pacold, Mary E and Richman, Douglas D and Pond, Sergei L Kosakovsky and Smith, Davey M", + "journal": "AIDS" + }, + { + "id": "Kosakovsky-Pond:2009qm", + "title": "An evolutionary model-based algorithm for accurate phylogenetic breakpoint mapping and subtype prediction in HIV-1", + "abstract": "Genetically diverse pathogens (such as Human Immunodeficiency virus type 1, HIV-1) are frequently stratified into phylogenetically or immunologically defined subtypes for classification purposes. Computational identification of such subtypes is helpful in surveillance, epidemiological analysis and detection of novel variants, e.g., circulating recombinant forms in HIV-1. A number of conceptually and technically different techniques have been proposed for determining the subtype of a query sequence, but there is not a universally optimal approach. We present a model-based phylogenetic method for automatically subtyping an HIV-1 (or other viral or bacterial) sequence, mapping the location of breakpoints and assigning parental sequences in recombinant strains as well as computing confidence levels for the inferred quantities. Our Subtype Classification Using Evolutionary ALgorithms (SCUEAL) procedure is shown to perform very well in a variety of simulation scenarios, runs in parallel when multiple sequences are being screened, and matches or exceeds the performance of existing approaches on typical empirical cases. We applied SCUEAL to all available polymerase (pol) sequences from two large databases, the Stanford Drug Resistance database and the UK HIV Drug Resistance Database. Comparing with subtypes which had previously been assigned revealed that a minor but substantial (approximately 5%) fraction of pure subtype sequences may in fact be within- or inter-subtype recombinants. A free implementation of SCUEAL is provided as a module for the HyPhy package and the Datamonkey web server. Our method is especially useful when an accurate automatic classification of an unknown strain is desired, and is positioned to complement and extend faster but less accurate methods. Given the increasingly frequent use of HIV subtype information in studies focusing on the effect of subtype on treatment, clinical outcome, pathogenicity and vaccine design, the importance of accurate, robust and extensible subtyping procedures is clear.", + "year": "2009", + "author": "Pond, Sergei L Kosakovsky and Posada, David and Stawiski, Eric and Chappey, Colombe and Poon, Art F Y and Hughes, Gareth and Fearnhill, Esther and Gravenor, Mike B and Leigh Brown, Andrew J and Frost, Simon D W", + "journal": "PLoS Comput Biol" + }, + { + "id": "Poon:2010lg", + "title": "Phylogenetic analysis of population-based and deep sequencing data to identify coevolving sites in the nef gene of HIV-1", + "abstract": "Rapidly evolving viruses such as HIV-1 display extensive sequence variation in response to host-specific selection, while simultaneously maintaining functions that are critical to replication and infectivity. This apparent conflict between diversifying and purifying selection may be resolved by an abundance of epistatic interactions such that the same functional requirements can be met by highly divergent sequences. We investigate this hypothesis by conducting an extensive characterization of sequence variation in the HIV-1 nef gene that encodes a highly variable multifunctional protein. Population-based sequences were obtained from 686 patients enrolled in the HOMER cohort in British Columbia, Canada, from which the distribution of nonsynonymous substitutions in the phylogeny was reconstructed by maximum likelihood. We used a phylogenetic comparative method on these data to identify putative epistatic interactions between residues. Two interactions (Y120/Q125 and N157/S169) were chosen to further investigate within-host evolution using HIV-1 RNA extractions from plasma samples from eight patients. Clonal sequencing confirmed strong linkage between polymorphisms at these sites in every case. We used massively parallel pyrosequencing (MPP) to reconstruct within-host evolution in these patients. Experimental error associated with MPP was quantified by performing replicates at two different stages of the protocol, which were pooled prior to analysis to reduce this source of variation. Phylogenetic reconstruction from these data revealed correlated substitutions at Y120/Q125 or N157/S169 repeated across multiple lineages in every host, indicating convergent within-host evolution shaped by epistatic interactions.", + "year": "2010", + "author": "Poon, Art F Y and Swenson, Luke C and Dong, Winnie W Y and Deng, Wenjie and Pond, Sergei L Kosakovsky and Brumme, Zabrina L and Mullins, James I and Richman, Douglas D and Harrigan, P Richard and Frost, Simon D W", + "journal": "Mol Biol Evol" + }, + { + "id": "Pond:2010li", + "title": "Evolutionary fingerprinting of genes", + "abstract": "Over time, natural selection molds every gene into a unique mosaic of sites evolving rapidly or resisting change-an \"evolutionary fingerprint\" of the gene. Aspects of this evolutionary fingerprint, such as the site-specific ratio of nonsynonymous to synonymous substitution rates (dN/dS), are commonly used to identify genetic features of potential biological interest; however, no framework exists for comparing evolutionary fingerprints between genes. We hypothesize that protein-coding genes with similar protein structure and/or function tend to have similar evolutionary fingerprints and that comparing evolutionary fingerprints can be useful for discovering similarities between genes in a way that is analogous to, but independent of, discovery of similarity via sequence-based comparison tools such as Blast. To test this hypothesis, we develop a novel model of coding sequence evolution that uses a general bivariate discrete parameterization of the evolutionary rates. We show that this approach provides a better fit to the data using a smaller number of parameters than existing models. Next, we use the model to represent evolutionary fingerprints as probability distributions and present a methodology for comparing these distributions in a way that is robust against variations in data set size and divergence. Finally, using sequences of three rapidly evolving RNA viruses (HIV-1, hepatitis C virus, and influenza A virus), we demonstrate that genes within the same functional group tend to have similar evolutionary fingerprints. Our framework provides a sound statistical foundation for efficient inference and comparison of evolutionary rate patterns in arbitrary collections of gene alignments, clustering homologous and nonhomologous genes, and investigation of biological and functional correlates of evolutionary rates.", + "year": "2010", + "author": "Pond, Sergei L Kosakovsky and Scheffler, Konrad and Gravenor, Michael B and Poon, Art F Y and Frost, Simon D W", + "journal": "Mol Biol Evol" + }, + { + "id": "Kosakovsky-Pond:2009mk", + "title": "Windshield splatter analysis with the Galaxy metagenomic pipeline", + "abstract": "How many species inhabit our immediate surroundings? A straightforward collection technique suitable for answering this question is known to anyone who has ever driven a car at highway speeds. The windshield of a moving vehicle is subjected to numerous insect strikes and can be used as a collection device for representative sampling. Unfortunately the analysis of biological material collected in that manner, as with most metagenomic studies, proves to be rather demanding due to the large number of required tools and considerable computational infrastructure. In this study, we use organic matter collected by a moving vehicle to design and test a comprehensive pipeline for phylogenetic profiling of metagenomic samples that includes all steps from processing and quality control of data generated by next-generation sequencing technologies to statistical analyses and data visualization. To the best of our knowledge, this is also the first publication that features a live online supplement providing access to exact analyses and workflows used in the article.", + "year": "2009", + "author": "Pond, Sergei L Kosakovsky and Wadhawan, Samir and Chiaromonte, Francesca and Ananda, Guruprasad and Chung, Wen-Yu and Taylor, James and Nekrutenko, Anton and {Galaxy Team}", + "journal": "Genome Res" + }, + { + "id": "Volz:2009lf", + "title": "Phylodynamics of infectious disease epidemics", + "abstract": "We present a formalism for unifying the inference of population size from genetic sequences and mathematical models of infectious disease in populations. Virus phylogenies have been used in many recent studies to infer properties of epidemics. These approaches rely on coalescent models that may not be appropriate for infectious diseases. We account for phylogenetic patterns of viruses in susceptible-infected (SI), susceptible-infected-susceptible (SIS), and susceptible-infected-recovered (SIR) models of infectious disease, and our approach may be a viable alternative to demographic models used to reconstruct epidemic dynamics. The method allows epidemiological parameters, such as the reproductive number, to be estimated directly from viral sequence data. We also describe patterns of phylogenetic clustering that are often construed as arising from a short chain of transmissions. Our model reproduces the moments of the distribution of phylogenetic cluster sizes and may therefore serve as a null hypothesis for cluster sizes under simple epidemiological models. We examine a small cross-sectional sample of human immunodeficiency (HIV)-1 sequences collected in the United States and compare our results to standard estimates of effective population size. Estimated prevalence is consistent with estimates of effective population size and the known history of the HIV epidemic. While our model accurately estimates prevalence during exponential growth, we find that periods of decline are harder to identify.", + "year": "2009", + "author": "Volz, Erik M and Pond, Sergei L Kosakovsky and Ward, Melissa J and Leigh Brown, Andrew J and Frost, Simon D W", + "journal": "Genetics" + }, + { + "id": "Poon:2009zk", + "title": "Parsing social network survey data from hidden populations using stochastic context-free grammars", + "abstract": "BACKGROUND: Human populations are structured by social networks, in which individuals tend to form relationships based on shared attributes. Certain attributes that are ambiguous, stigmatized or illegal can create a OhiddenO population, so-called because its members are difficult to identify. Many hidden populations are also at an elevated risk of exposure to infectious diseases. Consequently, public health agencies are presently adopting modern survey techniques that traverse social networks in hidden populations by soliciting individuals to recruit their peers, e.g., respondent-driven sampling (RDS). The concomitant accumulation of network-based epidemiological data, however, is rapidly outpacing the development of computational methods for analysis. Moreover, current analytical models rely on unrealistic assumptions, e.g., that the traversal of social networks can be modeled by a Markov chain rather than a branching process.\nMETHODOLOGY/PRINCIPAL FINDINGS: Here, we develop a new methodology based on stochastic context-free grammars (SCFGs), which are well-suited to modeling tree-like structure of the RDS recruitment process. We apply this methodology to an RDS case study of injection drug users (IDUs) in Tijuana, Mexico, a hidden population at high risk of blood-borne and sexually-transmitted infections (i.e., HIV, hepatitis C virus, syphilis). Survey data were encoded as text strings that were parsed using our custom implementation of the inside-outside algorithm in a publicly-available software package (HyPhy), which uses either expectation maximization or direct optimization methods and permits constraints on model parameters for hypothesis testing. We identified significant latent variability in the recruitment process that violates assumptions of Markov chain-based methods for RDS analysis: firstly, IDUs tended to emulate the recruitment behavior of their own recruiter; and secondly, the recruitment of like peers (homophily) was dependent on the number of recruits.\nCONCLUSIONS: SCFGs provide a rich probabilistic language that can articulate complex latent structure in survey data derived from the traversal of social networks. Such structure that has no representation in Markov chain-based models can interfere with the estimation of the composition of hidden populations if left unaccounted for, raising critical implications for the prevention and control of infectious disease epidemics.", + "year": "2009", + "author": "Poon, Art F Y and Brouwer, Kimberly C and Strathdee, Steffanie A and Firestone-Cruz, Michelle and Lozada, Remedios M and Pond, Sergei L Kosakovsky and Heckathorn, Douglas D and Frost, Simon D W", + "journal": "PLoS One" + }, + { + "id": "Lycett:2009tg", + "title": "Detection of mammalian virulence determinants in highly pathogenic avian influenza H5N1 viruses: multivariate analysis of published data", + "abstract": "Highly pathogenic avian influenza (HPAI) virus H5N1 infects water and land fowl and can infect and cause mortality in mammals, including humans. However, HPAI H5N1 strains are not equally virulent in mammals, and some strains have been shown to cause only mild symptoms in experimental infections. Since most experimental studies of the basis of virulence in mammals have been small in scale, we undertook a meta-analysis of available experimental studies and used Bayesian graphical models (BGM) to increase the power of inference. We applied text-mining techniques to identify 27 individual studies that experimentally determined pathogenicity in HPAI H5N1 strains comprising 69 complete genome sequences. Amino acid sequence data in all 11 genes were coded as binary data for the presence or absence of mutations related to virulence in mammals or nonconsensus residues. Sites previously implicated as virulence determinants were examined for association with virulence in mammals in this data set, and the sites with the most significant association were selected for further BGM analysis. The analyses show that virulence in mammals is a complex genetic trait directly influenced by mutations in polymerase basic 1 (PB1) and PB2, nonstructural 1 (NS1), and hemagglutinin (HA) genes. Several intra- and intersegment correlations were also found, and we postulate that there may be two separate virulence mechanisms involving particular combinations of polymerase and NS1 mutations or of NS1 and HA mutations.", + "year": "2009", + "author": "Lycett, S J and Ward, M J and Lewis, F I and Poon, A F Y and Kosakovsky Pond, S L and Brown, A J Leigh", + "journal": "J Virol" + }, + { + "id": "Lu:2009yg", + "title": "Detection in 2009 of the swine origin influenza A (H1N1) virus by a subtyping microarray", + "year": "2009", + "author": "Lu, Qing and Zhang, Xing-Quan and Pond, Sergei L Kosakovsky and Reed, Sharon and Schooley, Robert T and Liu, Yu-Tsueng", + "journal": "J Clin Microbiol" + }, + { + "id": "Poon:2009dt", + "title": "Detecting signatures of selection from DNA sequences using Datamonkey", + "abstract": "Natural selection is a fundamental process affecting all evolving populations. In the simplest case, positive selection increases the frequency of alleles that confer a fitness advantage relative to the rest of the population, or increases its genetic diversity, and negative selection removes those alleles that are deleterious. Codon-based models of molecular evolution are able to infer signatures of selection from alignments of homologous sequences by estimating the relative rates of synonymous (dS) and non-synonymous substitutions (dN). Datamonkey (http://www.datamonkey.org) provides a user-friendly web interface to a wide collection of state-of-the-art statistical techniques for estimating dS and dN and identifying codons and lineages under selection, even in the presence of recombinant sequences.", + "year": "2009", + "author": "Poon, Art F Y and Frost, Simon D W and Pond, Sergei L Kosakovsky", + "journal": "Methods Mol Biol" + }, + { + "id": "Kosakovsky-Pond:2009tn", + "title": "Are all subtypes created equal? The effectiveness of antiretroviral therapy against non-subtype B HIV-1", + "year": "2009", + "author": "Pond, Sergei L Kosakovsky and Smith, Davey M", + "journal": "Clin Infect Dis" + }, + { + "id": "Smith:2009hc", + "title": "A public health model for the molecular surveillance of HIV transmission in San Diego, California", + "abstract": "BACKGROUND: Current public health efforts often use molecular technologies to identify and contain communicable disease networks, but not for HIV. Here, we investigate how molecular epidemiology can be used to identify highly related HIV networks within a population and how voluntary contact tracing of sexual partners can be used to selectively target these networks.\nMETHODS: We evaluated the use of HIV-1 pol sequences obtained from participants of a community-recruited cohort (n = 268) and a primary infection research cohort (n = 369) to define highly related transmission clusters and the use of contact tracing to link other individuals (n = 36) within these clusters. The presence of transmitted drug resistance was interpreted from the pol sequences (Calibrated Population Resistance v3.0).\nRESULTS: Phylogenetic clustering was conservatively defined when the genetic distance between any two pol sequences was less than 1%, which identified 34 distinct transmission clusters within the combined community-recruited and primary infection research cohorts containing 160 individuals. Although sequences from the epidemiologically linked partners represented approximately 5% of the total sequences, they clustered with 60% of the sequences that clustered from the combined cohorts (odds ratio 21.7; P < or = 0.01). Major resistance to at least one class of antiretroviral medication was found in 19% of clustering sequences.\nCONCLUSION: Phylogenetic methods can be used to identify individuals who are within highly related transmission groups, and contact tracing of epidemiologically linked partners of recently infected individuals can be used to link into previously defined transmission groups. These methods could be used to implement selectively targeted prevention interventions.", + "year": "2009", + "author": "Smith, Davey M and May, Susanne J and Tweeten, Samantha and Drumright, Lydia and Pacold, Mary E and Pond, Sergei L Kosakovsky and Pesano, Rick L and Lie, Yolanda S and Richman, Douglas D and Frost, Simon D W and Woelk, Christopher H and Little, Susan J", + "journal": "AIDS" + }, + { + "id": "Cachay:2007vp", + "title": "Active methamphetamine use is associated with transmitted drug resistance to non-nucleoside reverse transcriptase inhibitors in individuals with HIV infection of unknown duration", + "abstract": "BACKGROUND: Frequent methamphetamine use among recently HIV infected individuals is associated with transmitted drug resistance (TDR) to non-nucleoside reverse transcriptase inhibitors (NNRTI); however, the reversion time of TDR to drug susceptible HIV may exceed 3 years. We assessed whether recreational substance use is associated with detectable TDR among individuals newly diagnosed with HIV infection of unknown duration.\nDESIGN: Cross-sectional analysis.\nMETHODS: Subjects were enrolled at the University California, San Diego Early Intervention Program. Demographic, clinical and substance use data were collected using structured interviews. Genotypic resistance testing was performed using GeneSeq, Monogram Biosciences. We analyzed the association between substance use and TDR using bivariate analyses and the corresponding transmission networks using phylogenetic models.\nRESULTS: Between April 2004 and July 2006, 115 individuals with genotype data were enrolled. The prevalence of alcohol, marijuana and methamphetamine use were 98%, 71% and 64% respectively. Only active methamphetamine use in the 30 days prior to HIV diagnosis was independently associated with TDR to NNRTI (OR: 6.6; p=0.002).\nCONCLUSION: Despite not knowing the duration of their HIV infection, individuals reporting active methamphetamine use in the 30 days prior to HIV diagnosis are at an increased risk of having HIV strains that are resistant to NNRTI.", + "year": "2007", + "author": "Cachay, Edward R and Moini, Niousha and Pond, Sergei L Kosakovsky and Pesano, Rick and Lie, Yolanda S and Aiem, Heidi and Butler, David M and Letendre, Scott and Mathews, Wm Christopher and Smith, Davey M", + "journal": "Open AIDS J" + }, + { + "id": "Lam:2008fd", + "title": "Evolutionary and transmission dynamics of reassortant H5N1 influenza virus in Indonesia", + "abstract": "H5N1 highly pathogenic avian influenza (HPAI) viruses have seriously affected the Asian poultry industry since their recurrence in 2003. The viruses pose a threat of emergence of a global pandemic influenza through point mutation or reassortment leading to a strain that can effectively transmit among humans. In this study, we present phylogenetic evidences for the interlineage reassortment among H5N1 HPAI viruses isolated from humans, cats, and birds in Indonesia, and identify the potential genetic parents of the reassorted genome segments. Parsimony analyses of viral phylogeography suggest that the reassortant viruses may have originated from greater Jakarta and surroundings, and subsequently spread to other regions in the West Java province. In addition, Bayesian methods were used to elucidate the genetic diversity dynamics of the reassortant strain and one of its genetic parents, which revealed a more rapid initial growth of genetic diversity in the reassortant viruses relative to their genetic parent. These results demonstrate that interlineage exchange of genetic information may play a pivotal role in determining viral genetic diversity in a focal population. Moreover, our study also revealed significantly stronger diversifying selection on the M1 and PB2 genes in the lineages preceding and subsequent to the emergence of the reassortant viruses, respectively. We discuss how the corresponding mutations might drive the adaptation and onward transmission of the newly formed reassortant viruses.", + "year": "2008", + "author": "Lam, Tommy Tsan-Yuk and Hon, Chung-Chau and Pybus, Oliver G and Pond, Sergei L Kosakovsky and Wong, Raymond Tze-Yeung and Yip, Chi-Wai and Zeng, Fanya and Leung, Frederick Chi-Ching", + "journal": "PLoS Pathog" + }, + { + "id": "Poon:2008fb", + "title": "Spidermonkey: rapid detection of co-evolving sites using Bayesian graphical models", + "abstract": "UNLABELLED: Spidermonkey is a new component of the Datamonkey suite of phylogenetic tools that provides methods for detecting coevolving sites from a multiple alignment of homologous nucleotide or amino acid sequences. It reconstructs the substitution history of the alignment by maximum likelihood-based phylogenetic methods, and then analyzes the joint distribution of substitution events using Bayesian graphical models to identify significant associations among sites.\nAVAILABILITY: Spidermonkey is publicly available both as a web application at http://www.data-monkey.org and as a stand-alone component of the phylogenetic software package HyPhy, which is freely distributed on the web (http://www.hyphy.org) as precompiled binaries and open source.", + "year": "2008", + "author": "Poon, Art F Y and Lewis, Fraser I and Frost, Simon D W and Pond, Sergei L Kosakovsky", + "journal": "Bioinformatics" + }, + { + "id": "Duan:2008rp", + "title": "Population structure of the genes encoding the polymorphic Plasmodium falciparum apical membrane antigen 1: implications for vaccine design", + "abstract": "Immunization with the highly polymorphic Plasmodium falciparum apical membrane antigen 1 (PfAMA1) induces protection in animals but primarily against parasites that express the same or similar alleles. One strategy to overcome the obstacle of polymorphism is to combine PfAMA1 proteins representing major haplotypes into one vaccine. To determine the minimum number of haplotypes that would confer broad protection, we sequenced the coding region of PfAMA1 from 97 clones from around the world and 61 isolates from Mali, identifying 150 haplotypes for domains 1 to 3 that included previous sequences. A clustering algorithm grouped the 150 haplotypes into six populations that were independent of geographic location. Each of the six populations contained haplotypes predominantly of that population (predominant haplotypes) and haplotypes that were a mixture of haplotypes represented in other populations (admixed haplotypes). To determine the biological relevance of the populations identified through the clustering algorithm, antibodies induced against one predominant haplotype of population 1 (3D7) and one admixed haplotype of population 5 (FVO) were tested for their ability to block parasite invasion of erythrocytes. Parasites expressing PfAMA1s belonging to population 1 were efficiently inhibited by 3D7-specific antibodies, whereas parasites expressing PfAMA1s belonging to other populations were not. For FVO-specific antibodies, we observed growth inhibition against itself as well as isolates belonging to populations 3 and 6. Our data suggests that the inclusion of PfAMA1 sequences from each of the six populations may result in a vaccine that induces protective immunity against a broad range of malaria parasites.", + "year": "2008", + "author": "Duan, Junhui and Mu, Jianbing and Thera, Mahamadou Ali and Joy, Deirdre and Pond, Sergei L Kosakovsky and Diemert, David and Long, Carole and Zhou, Hong and Miura, Kazutoyo and Ouattara, Amed and Dolo, Amagana and Doumbo, Ogobara and Su, Xin-Zhuan and Miller, Louis", + "journal": "Proc Natl Acad Sci U S A" + }, + { + "id": "Kosakovsky-Pond:2008zl", + "title": "A maximum likelihood method for detecting directional evolution in protein sequences and its application to influenza A virus", + "abstract": "We develop a model-based phylogenetic maximum likelihood test for evidence of preferential substitution toward a given residue at individual positions of a protein alignment--directional evolution of protein sequences (DEPS). DEPS can identify both the target residue and sites evolving toward it, help detect selective sweeps and frequency-dependent selection--scenarios that confound most existing tests for selection, and achieve good power and accuracy on simulated data. We applied DEPS to alignments representing different genomic regions of influenza A virus (IAV), sampled from avian hosts (H5N1 serotype) and human hosts (H3N2 serotype), and identified multiple directionally evolving sites in 5/8 genomic segments of H5N1 and H3N2 IAV. We propose a simple descriptive classification of directionally evolving sites into 5 groups based on the temporal distribution of residue frequencies and document known functional correlates, such as immune escape or host adaptation.", + "year": "2008", + "author": "Pond, Sergei L Kosakovsky and Poon, Art F Y and Leigh Brown, Andrew J and Frost, Simon D W", + "journal": "Mol Biol Evol" + }, + { + "id": "Nickle:2008kv", + "title": "Comparison of immunogen designs that optimize peptide coverage: reply to Fischer et al", + "year": "2008", + "author": "Nickle, David C and Jojic, Nebojsa and Heckerman, David and Jojic, Vladimir and Kirovski, Darko and Rolland, Morgane and Pond, Sergei L Kosakovsky and Mullins, James I", + "journal": "PLoS Comput Biol" + }, + { + "id": "Kosakovsky-Pond:2008sh", + "title": "Estimating selection pressures on HIV-1 using phylogenetic likelihood models", + "abstract": "Human immunodeficiency virus (HIV-1) can rapidly evolve due to selection pressures exerted by HIV-specific immune responses, antiviral agents, and to allow the virus to establish infection in different compartments in the body. Statistical models applied to HIV-1 sequence data can help to elucidate the nature of these selection pressures through comparisons of non-synonymous (or amino acid changing) and synonymous (or amino acid preserving) substitution rates. These models also need to take into account the non-independence of sequences due to their shared evolutionary history. We review how we have developed these methods and have applied them to characterize the evolution of HIV-1 in vivo. To illustrate our methods, we present an analysis of compartment-specific evolution of HIV-1 env in blood and cerebrospinal fluid and of site-to-site variation in the gag gene of subtype C HIV-1.", + "year": "2008", + "author": "Kosakovsky Pond, S L and Poon, A F Y and Zarate, S and Smith, D M and Little, S J and Pillai, S K and Ellis, R J and Wong, J K and Leigh Brown, A J and Richman, D D and Frost, S D W", + "journal": "Stat Med" + }, + { + "id": "Little:2008wy", + "title": "Persistence of transmitted drug resistance among subjects with primary human immunodeficiency virus infection", + "abstract": "Following interruption of antiretroviral therapy among individuals with acquired drug resistance, preexisting drug-sensitive virus emerges relatively rapidly. In contrast, wild-type virus is not archived in individuals infected with drug-resistant human immunodeficiency virus (HIV) and thus cannot emerge rapidly in the absence of selective drug pressure. Fourteen recently HIV-infected patients with transmitted drug-resistant virus were followed for a median of 2.1 years after the estimated date of infection (EDI) without receiving antiretroviral therapy. HIV drug resistance and pol replication capacity (RC) in longitudinal plasma samples were assayed. Resistance mutations were characterized as pure populations or mixtures. The mean time to first detection of a mixture of wild-type and drug-resistant viruses was 96 weeks (1.8 years) (95% confidence interval, 48 to 192 weeks) after the EDI. The median time to loss of detectable drug resistance using population-based assays ranged from 4.1 years (conservative estimate) to longer than the lifetime of the individual (less conservative estimate). The transmission of drug-resistant virus was not associated with virus with reduced RC. Sexual transmission of HIV selects for highly fit drug-resistant variants that persist for years. The prolonged persistence of transmitted drug resistance strongly supports the routine use of HIV resistance genotyping for all newly diagnosed individuals.", + "year": "2008", + "author": "Little, Susan J and Frost, Simon D W and Wong, Joseph K and Smith, Davey M and Pond, Sergei L Kosakovsky and Ignacio, Caroline C and Parkin, Neil T and Petropoulos, Christos J and Richman, Douglas D", + "journal": "J Virol" + }, + { + "id": "Gorbach:2008ws", + "title": "Antiretroviral drug resistance and risk behavior among recently HIV-infected men who have sex with men", + "abstract": "OBJECTIVES: Examine associations among behaviors including substance use during sexual encounters, and transmitted HIV drug resistance in recently HIV-infected men who have sex with men (MSM).\nMETHODS: Between 2002 and 2006, 117 recently HIV-infected MSM completed questionnaires regarding their 3 most recent sexual partners. Serum samples were tested for the presence of genotypic and phenotypic HIV drug resistance. Logistic regression analysis was used to assess the association of substance use, behaviors, and resistance to at least 1 class of HIV drugs.\nRESULTS: The mean age of participants was 35 years; 71% identified as white and 19% as Hispanic. Sixty (51%) reported substance use during sexual activity in the past 12 months. A total of 12.5% of 112 had genotypic drug resistance to at least 1 class of antiretroviral medications, and 14% of 117 had phenotypic drug resistance. Substances used during sexual activity associated with phenotypic drug resistance in multivariate models included any substance use (adjusted odds ratio [aOR] = 4.21, 95% confidence interval [CI]: 1.13 to 15.68), polysubstance use (aOR = 5.64, 95% CI: 1.62 to 19.60), methamphetamine (aOR = 4.00, 95% CI: 1.19 to 13.38), 3,4-methylenedioxy-N-methylamphetamine (MDMA)/Ecstasy (aOR = 7.16, 95% CI: 1.40 to 36.59), and gamma-hydroxyl butyrate (GHB) (aOR = 6.98, 95% CI: 1.82 to 26.80). The genotype analysis was similar.\nCONCLUSIONS: Among these recently HIV-infected MSM, methamphetamine use during sexual activity and use of other substances, such as MDMA and GHB, was associated with acquired drug-resistant virus. No other behaviors associated with acquisition of drug-resistant HIV.", + "year": "2008", + "author": "Gorbach, Pamina M and Drumright, Lydia N and Javanbakht, Marjan and Pond, Sergei L and Woelk, Christopher H and Daar, Eric S and Little, Susan J", + "journal": "J Acquir Immune Defic Syndr" + }, + { + "id": "Poon:2007ht", + "title": "An evolutionary-network model reveals stratified interactions in the V3 loop of the HIV-1 envelope", + "abstract": "The third variable loop (V3) of the human immunodeficiency virus type 1 (HIV-1) envelope is a principal determinant of antibody neutralization and progression to AIDS. Although it is undoubtedly an important target for vaccine research, extensive genetic variation in V3 remains an obstacle to the development of an effective vaccine. Comparative methods that exploit the abundance of sequence data can detect interactions between residues of rapidly evolving proteins such as the HIV-1 envelope, revealing biological constraints on their variability. However, previous studies have relied implicitly on two biologically unrealistic assumptions: (1) that founder effects in the evolutionary history of the sequences can be ignored, and; (2) that statistical associations between residues occur exclusively in pairs. We show that comparative methods that neglect the evolutionary history of extant sequences are susceptible to a high rate of false positives (20%-40%). Therefore, we propose a new method to detect interactions that relaxes both of these assumptions. First, we reconstruct the evolutionary history of extant sequences by maximum likelihood, shifting focus from extant sequence variation to the underlying substitution events. Second, we analyze the joint distribution of substitution events among positions in the sequence as a Bayesian graphical model, in which each branch in the phylogeny is a unit of observation. We perform extensive validation of our models using both simulations and a control case of known interactions in HIV-1 protease, and apply this method to detect interactions within V3 from a sample of 1,154 HIV-1 envelope sequences. Our method greatly reduces the number of false positives due to founder effects, while capturing several higher-order interactions among V3 residues. By mapping these interactions to a structural model of the V3 loop, we find that the loop is stratified into distinct evolutionary clusters. We extend our model to detect interactions between the V3 and C4 domains of the HIV-1 envelope, and account for the uncertainty in mapping substitutions to the tree with a parametric bootstrap.", + "year": "2007", + "author": "Poon, Art F Y and Lewis, Fraser I and Pond, Sergei L Kosakovsky and Frost, Simon D W", + "journal": "PLoS Comput Biol" + }, + { + "id": "Miller:2007dg", + "title": "28-way vertebrate alignment and conservation track in the UCSC Genome Browser", + "abstract": "This article describes a set of alignments of 28 vertebrate genome sequences that is provided by the UCSC Genome Browser. The alignments can be viewed on the Human Genome Browser (March 2006 assembly) at http://genome.ucsc.edu, downloaded in bulk by anonymous FTP from http://hgdownload.cse.ucsc.edu/goldenPath/hg18/multiz28way, or analyzed with the Galaxy server at http://g2.bx.psu.edu. This article illustrates the power of this resource for exploring vertebrate and mammalian evolution, using three examples. First, we present several vignettes involving insertions and deletions within protein-coding regions, including a look at some human-specific indels. Then we study the extent to which start codons and stop codons in the human sequence are conserved in other species, showing that start codons are in general more poorly conserved than stop codons. Finally, an investigation of the phylogenetic depth of conservation for several classes of functional elements in the human genome reveals striking differences in the rates and modes of decay in alignability. Each functional class has a distinctive period of stringent constraint, followed by decays that allow (for the case of regulatory regions) or reject (for coding regions and ultraconserved elements) insertions and deletions.", + "year": "2007", + "author": "Miller, Webb and Rosenbloom, Kate and Hardison, Ross C and Hou, Minmei and Taylor, James and Raney, Brian and Burhans, Richard and King, David C and Baertsch, Robert and Blankenberg, Daniel and Pond, Sergei L Kosakovsky and Nekrutenko, Anton and Giardine, Belinda and Harris, Robert S and Tyekucheva, Svitlana and Diekhans, Mark and Pringle, Thomas H and Murphy, William J and Lesk, Arthur and Weinstock, George M and Lindblad-Toh, Kerstin and Gibbs, Richard A and Lander, Eric S and Siepel, Adam and Haussler, David and Kent, W James", + "journal": "Genome Res" + }, + { + "id": "Poon:2007mb", + "title": "Mapping protease inhibitor resistance to human immunodeficiency virus type 1 sequence polymorphisms within patients", + "abstract": "Resistance genotyping provides an important resource for the clinical management of patients infected with human immunodeficiency virus type 1 (HIV-1). However, resistance to protease (PR) inhibitors (PIs) is a complex phenotype shaped by interactions among nearly half of the residues in HIV-1 PR. Previous studies of the genetic basis of PI resistance focused on fixed substitutions among populations of HIV-1, i.e., host-specific adaptations. Consequently, they are susceptible to a high false discovery rate due to founder effects. Here, we employ sequencing \"mixtures\" (i.e., ambiguous base calls) as a site-specific marker of genetic variation within patients that is independent of the phylogeny. We demonstrate that the transient response to selection by PIs is manifested as an excess of nonsynonymous mixtures. Using a sample of 5,651 PR sequences isolated from both PI-naive and -treated patients, we analyze the joint distribution of mixtures and eight PIs as a Bayesian network, which distinguishes residue-residue interactions from direct associations with PIs. We find that selection for resistance is associated with the emergence of nonsynonymous mixtures in two distinct groups of codon sites clustered along the substrate cleft and distal regions of PR, respectively. Within-patient evolution at several positions is independent of PIs, including those formerly postulated to be involved in resistance. These positions are under strong positive selection in the PI-naive patient population, implying that other factors can produce spurious associations with resistance, e.g., mutational escape from the immune response.", + "year": "2007", + "author": "Poon, Art F Y and Pond, Sergei L Kosakovsky and Richman, Douglas D and Frost, Simon D W", + "journal": "J Virol" + }, + { + "id": "Szklarczyk:2007qb", + "title": "Rapid asymmetric evolution of a dual-coding tumor suppressor INK4a/ARF locus contradicts its function", + "abstract": "INK4a/ARF tumor suppressor locus encodes two protein products, INK4a and ARF, essential for controlling tumorigenesis and mutated in more than half of human cancers. There is no resemblance between the two proteins: their coding regions are assembled by alternative splicing of two mutually exclusive 5' exons into a constitutive one containing overlapping out-of-phase reading frames. We show that the dual-coding arrangement conflicts with the high cost of mutations within INK4a/ARF. Unexpectedly, the locus evolves rapidly and asymmetrically, with ARF accumulating the majority of amino acid replacements. Rapid evolution drives both INK4a and ARF proteins out of sync with other members of the RB and p53 tumor suppressor pathways, both of which are controlled by the locus. Yet, the asymmetric behavior may be an intrinsic property of dual-coding exons: INK4a/ARF closely mimics the evolution of 90 newly identified genes with similar dual-coding structure. Thus, the strong link between mutations in INK4a/ARF and cancer may be a direct consequence of the architecture of the locus.", + "year": "2007", + "author": "Szklarczyk, Radek and Heringa, Jaap and Pond, Sergei L Kosakovsky and Nekrutenko, Anton", + "journal": "Proc Natl Acad Sci U S A" + }, + { + "id": "Nickle:2007kk", + "title": "HIV-specific probabilistic models of protein evolution", + "abstract": "Comparative sequence analyses, including such fundamental bioinformatics techniques as similarity searching, sequence alignment and phylogenetic inference, have become a mainstay for researchers studying type 1 Human Immunodeficiency Virus (HIV-1) genome structure and evolution. Implicit in comparative analyses is an underlying model of evolution, and the chosen model can significantly affect the results. In general, evolutionary models describe the probabilities of replacing one amino acid character with another over a period of time. Most widely used evolutionary models for protein sequences have been derived from curated alignments of hundreds of proteins, usually based on mammalian genomes. It is unclear to what extent these empirical models are generalizable to a very different organism, such as HIV-1-the most extensively sequenced organism in existence. We developed a maximum likelihood model fitting procedure to a collection of HIV-1 alignments sampled from different viral genes, and inferred two empirical substitution models, suitable for describing between-and within-host evolution. Our procedure pools the information from multiple sequence alignments, and provided software implementation can be run efficiently in parallel on a computer cluster. We describe how the inferred substitution models can be used to generate scoring matrices suitable for alignment and similarity searches. Our models had a consistently superior fit relative to the best existing models and to parameter-rich data-driven models when benchmarked on independent HIV-1 alignments, demonstrating evolutionary biases in amino-acid substitution that are unique to HIV, and that are not captured by the existing models. The scoring matrices derived from the models showed a marked difference from common amino-acid scoring matrices. The use of an appropriate evolutionary model recovered a known viral transmission history, whereas a poorly chosen model introduced phylogenetic error. We argue that our model derivation procedure is immediately applicable to other organisms with extensive sequence data available, such as Hepatitis C and Influenza A viruses.", + "year": "2007", + "author": "Nickle, David C and Heath, Laura and Jensen, Mark A and Gilbert, Peter B and Mullins, James I and Pond, Sergei L Kosakovsky", + "journal": "PLoS One" + }, + { + "id": "Woelk:2007xc", + "title": "Evolution of the interferon alpha gene family in eutherian mammals", + "abstract": "Interferon alpha (IFNA) genes code for proteins with important signaling roles during the innate immune response. Phylogenetically, IFNA family members in eutherians (placental mammals) cluster together in a species-specific manner except for closely related species (i.e. Homo sapiens and Pan troglodytes) where gene-specific clustering is evident. Previous research has been unable to clarify whether gene conversion or recent gene duplication accounts for gene-specific clustering, partly because the similarity of members of the IFNA family within species has made it historically difficult to identify the exact composition of IFNA gene families. IFNA gene families were fully characterized in recently available genomes from Canis familiaris, Macaca mulatta, P. troglodytes and Rattus norvegicus, and combined with previously characterized IFNA gene families from H. sapiens and Mus musculus, for the analysis of both whole and partial gene conversion events using a variety of statistical methods. Gene conversion was inferred in every eutherian species analyzed and comparison of the IFNA gene family locus between primate species revealed independent gene duplication in M. mulatta. Thus, both gene conversion and gene duplication have shaped the evolution of the IFNA gene family in eutherian species. Scenarios may be envisaged whereby the increased production of a specific IFN-alpha protein would be beneficial against a particular pathogenic infection. Gene conversion, similar to duplication, provides a mechanism by which the protein product of a specific IFNA gene can be increased.", + "year": "2007", + "author": "Woelk, Christopher H and Frost, Simon D W and Richman, Douglas D and Higley, Prentice E and Pond, Sergei L Kosakovsky", + "journal": "Gene" + }, + { + "id": "Chung:2007vg", + "title": "A first look at ARFome: dual-coding genes in mammalian genomes", + "abstract": "Coding of multiple proteins by overlapping reading frames is not a feature one would associate with eukaryotic genes. Indeed, codependency between codons of overlapping protein-coding regions imposes a unique set of evolutionary constraints, making it a costly arrangement. Yet in cases of tightly coexpressed interacting proteins, dual coding may be advantageous. Here we show that although dual coding is nearly impossible by chance, a number of human transcripts contain overlapping coding regions. Using newly developed statistical techniques, we identified 40 candidate genes with evolutionarily conserved overlapping coding regions. Because our approach is conservative, we expect mammals to possess more dual-coding genes. Our results emphasize that the skepticism surrounding eukaryotic dual coding is unwarranted: rather than being artifacts, overlapping reading frames are often hallmarks of fascinating biology.", + "year": "2007", + "author": "Chung, Wen-Yu and Wadhawan, Samir and Szklarczyk, Radek and Pond, Sergei L Kosakovsky and Nekrutenko, Anton", + "journal": "PLoS Comput Biol" + }, + { + "id": "Mazumder:2007um", + "title": "Computational analysis and identification of amino acid sites in dengue E proteins relevant to development of diagnostics and vaccines", + "abstract": "We have identified 72 completely conserved amino acid residues in the E protein of major groups of the Flavivirus genus by computational analyses. In the dengue species we have identified 12 highly conserved sequence regions, 186 negatively selected sites, and many dengue serotype-specific negatively selected sites. The flavivirus-conserved sites included residues involved in forming six disulfide bonds crucial for the structural integrity of the protein, the fusion motif involved in viral infectivity, and the interface residues of the oligomers. The structural analysis of the E protein showed 19 surface-exposed non-conserved residues, 128 dimer or trimer interface residues, and regions, which undergo major conformational change during trimerization. Eleven consensus T(h)-cell epitopes common to all four dengue serotypes were predicted. Most of these corresponded to dengue-conserved regions or negatively selected sites. Of special interest are six singular sites (N(37), Q(211), D(215), P(217), H(244), K(246)) in dengue E protein that are conserved, are part of the predicted consensus T(h)-cell epitopes and are exposed in the dimer or trimer. We propose these sites and corresponding epitopic regions as potential candidates for prioritization by experimental biologists for development of diagnostics and vaccines that may be difficult to circumvent by natural or man-made alteration of dengue virus.", + "year": "2007", + "author": "Mazumder, Raja and Hu, Zhang-Zhi and Vinayaka, C R and Sagripanti, Jose-Luis and Frost, Simon D W and Pond, Sergei L Kosakovsky and Wu, Cathy H", + "journal": "Virus Genes" + }, + { + "id": "Nickle:2007on", + "title": "Coping with viral diversity in HIV vaccine design", + "abstract": "The ability of human immunodeficiency virus type 1 (HIV-1) to develop high levels of genetic diversity, and thereby acquire mutations to escape immune pressures, contributes to the difficulties in producing a vaccine. Possibly no single HIV-1 sequence can induce sufficiently broad immunity to protect against a wide variety of infectious strains, or block mutational escape pathways available to the virus after infection. The authors describe the generation of HIV-1 immunogens that minimizes the phylogenetic distance of viral strains throughout the known viral population (the center of tree [COT]) and then extend the COT immunogen by addition of a composite sequence that includes high-frequency variable sites preserved in their native contexts. The resulting COT(+) antigens compress the variation found in many independent HIV-1 isolates into lengths suitable for vaccine immunogens. It is possible to capture 62% of the variation found in the Nef protein and 82% of the variation in the Gag protein into immunogens of three gene lengths. The authors put forward immunogen designs that maximize representation of the diverse antigenic features present in a spectrum of HIV-1 strains. These immunogens should elicit immune responses against high-frequency viral strains as well as against most mutant forms of the virus.", + "year": "2007", + "author": "Nickle, David C and Rolland, Morgane and Jensen, Mark A and Pond, Sergei L Kosakovsky and Deng, Wenjie and Seligman, Mark and Heckerman, David and Mullins, James I and Jojic, Nebojsa", + "journal": "PLoS Comput Biol" + }, + { + "id": "Zarate:2007mw", + "title": "Comparative study of methods for detecting sequence compartmentalization in human immunodeficiency virus type 1", + "abstract": "Human immunodeficiency virus (HIV) infects different organs and tissues. During these infection events, subpopulations of HIV type 1 (HIV-1) develop and, if viral trafficking is restricted between subpopulations, the viruses can follow independent evolutionary histories, i.e., become compartmentalized. This phenomenon is usually detected via comparative sequence analysis and has been reported for viruses isolated from the central nervous system (CNS) and the genital tract. Several approaches have been proposed to study the compartmentalization of HIV sequences, but to date, no rigorous comparison of the most commonly employed methods has been made. In this study, we systematically compared inferences made by six different methods for detecting compartmentalization based on three data sets: (i) a sample of 45 patients with sequences gathered from the CNS, (ii) sequences from the female genital tract of 18 patients, and (iii) a set of simulated sequences. We found that different methods often reached contradictory conclusions. Methods based on the topology of a phylogenetic tree derived from clonal sequences were generally more sensitive in detecting compartmentalization than those that relied solely upon pairwise genetic distances between sequences. However, as the branching structure in a phylogenetic tree is often uncertain, especially for short, low-diversity, or recombinant sequences, tree-based approaches may need to be modified to take phylogenetic uncertainty into account. Given the frequently discordant predictions of different methods and the strengths and weaknesses of each particular methodology, we recommend that a suite of several approaches be used for reliable inference of compartmentalized population structure.", + "year": "2007", + "author": "Zarate, Selene and Pond, Sergei L Kosakovsky and Shapshak, Paul and Frost, Simon D W", + "journal": "J Virol" + }, + { + "id": "Poon:2007vy", + "title": "Adaptation to human populations is revealed by within-host polymorphisms in HIV-1 and hepatitis C virus", + "abstract": "CD8(+) cytotoxic T-lymphocytes (CTLs) perform a critical role in the immune control of viral infections, including those caused by human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV). As a result, genetic variation at CTL epitopes is strongly influenced by host-specific selection for either escape from the immune response, or reversion due to the replicative costs of escape mutations in the absence of CTL recognition. Under strong CTL-mediated selection, codon positions within epitopes may immediately \"toggle\" in response to each host, such that genetic variation in the circulating virus population is shaped by rapid adaptation to immune variation in the host population. However, this hypothesis neglects the substantial genetic variation that accumulates in virus populations within hosts. Here, we evaluate this quantity for a large number of HIV-1- (n > or = 3,000) and HCV-infected patients (n > or = 2,600) by screening bulk RT-PCR sequences for sequencing \"mixtures\" (i.e., ambiguous nucleotides), which act as site-specific markers of genetic variation within each host. We find that nonsynonymous mixtures are abundant and significantly associated with codon positions under host-specific CTL selection, which should deplete within-host variation by driving the fixation of the favored variant. Using a simple model, we demonstrate that this apparently contradictory outcome can be explained by the transmission of unfavorable variants to new hosts before they are removed by selection, which occurs more frequently when selection and transmission occur on similar time scales. Consequently, the circulating virus population is shaped by the transmission rate and the disparity in selection intensities for escape or reversion as much as it is shaped by the immune diversity of the host population, with potentially serious implications for vaccine design.", + "year": "2007", + "author": "Poon, Art F Y and Pond, Sergei L Kosakovsky and Bennett, Phil and Richman, Douglas D and Leigh Brown, Andrew J and Frost, Simon D W", + "journal": "PLoS Pathog" + }, + { + "id": "Noviello:2007tb", + "title": "Maintenance of Nef-mediated modulation of major histocompatibility complex class I and CD4 after sexual transmission of human immunodeficiency virus type 1", + "abstract": "Viruses encounter changing selective pressures during transmission between hosts, including host-specific immune responses and potentially varying functional demands on specific proteins. The human immunodeficiency virus type 1 Nef protein performs several functions potentially important for successful infection, including immune escape via down-regulation of class I major histocompatibility complex (MHC-I) and direct enhancement of viral infectivity and replication. Nef is also a major target of the host cytotoxic T-lymphocyte (CTL) response. To examine the impact of changing selective pressures on Nef functions following sexual transmission, we analyzed genetic and functional changes in nef clones from six transmission events. Phylogenetic analyses indicated that the diversity of nef was similar in both sources and acutely infected recipients, the patterns of selection across transmission were variable, and regions of Nef associated with distinct functions evolved similarly in sources and recipients. These results weighed against the selection of specific Nef functions by transmission or during acute infection. Measurement of Nef function provided no evidence that the down-regulation of either CD4 or MHC-I was optimized by transmission or during acute infection, although rare nef clones from sources that were impaired in these activities were not detected in recipients. Nef-specific CTL activity was detected as early as 3 weeks after infection and appeared to be an evolutionary force driving the diversification of nef. Despite the change in selective pressure between the source and recipient immune systems and concomitant genetic diversity, the majority of Nef proteins maintained robust abilities to down-regulate MHC-I and CD4. These data suggest that both functions are important for the successful establishment of infection in a new host.", + "year": "2007", + "author": "Noviello, C M and Pond, S L Kosakovsky and Lewis, M J and Richman, D D and Pillai, S K and Yang, O O and Little, S J and Smith, D M and Guatelli, J C", + "journal": "J Virol" + }, + { + "id": "Lemey:2007yt", + "title": "Synonymous substitution rates predict HIV disease progression as a result of underlying replication dynamics", + "abstract": "Upon HIV transmission, some patients develop AIDS in only a few months, while others remain disease free for 20 or more years. This variation in the rate of disease progression is poorly understood and has been attributed to host genetics, host immune responses, co-infection, viral genetics, and adaptation. Here, we develop a new \"relaxed-clock\" phylogenetic method to estimate absolute rates of synonymous and nonsynonymous substitution through time. We identify an unexpected association between the synonymous substitution rate of HIV and disease progression parameters. Since immune activation is the major determinant of HIV disease progression, we propose that this process can also determine viral generation times, by creating favourable conditions for HIV replication. These conclusions may apply more generally to HIV evolution, since we also observed an overall low synonymous substitution rate for HIV-2, which is known to be less pathogenic than HIV-1 and capable of tempering the detrimental effects of immune activation. Humoral immune responses, on the other hand, are the major determinant of nonsynonymous rate changes through time in the envelope gene, and our relaxed-clock estimates support a decrease in selective pressure as a consequence of immune system collapse.", + "year": "2007", + "author": "Lemey, Philippe and Pond, Sergei L Kosakovsky and Drummond, Alexei J and Pybus, Oliver G and Shapiro, Beth and Barroso, Helena and Taveira, Nuno and Rambaut, Andrew", + "journal": "PLoS Comput Biol" + }, + { + "id": "Poon:2007nu", + "title": "Evolutionary interactions between N-linked glycosylation sites in the HIV-1 envelope", + "abstract": "The addition of asparagine (N)-linked polysaccharide chains (i.e., glycans) to the gp120 and gp41 glycoproteins of human immunodeficiency virus type 1 (HIV-1) envelope is not only required for correct protein folding, but also may provide protection against neutralizing antibodies as a \"glycan shield.\" As a result, strong host-specific selection is frequently associated with codon positions where nonsynonymous substitutions can create or disrupt potential N-linked glycosylation sites (PNGSs). Moreover, empirical data suggest that the individual contribution of PNGSs to the neutralization sensitivity or infectivity of HIV-1 may be critically dependent on the presence or absence of other PNGSs in the envelope sequence. Here we evaluate how glycan-glycan interactions have shaped the evolution of HIV-1 envelope sequences by analyzing the distribution of PNGSs in a large-sequence alignment. Using a \"covarion\"-type phylogenetic model, we find that the rates at which individual PNGSs are gained or lost vary significantly over time, suggesting that the selective advantage of having a PNGS may depend on the presence or absence of other PNGSs in the sequence. Consequently, we identify specific interactions between PNGSs in the alignment using a new paired-character phylogenetic model of evolution, and a Bayesian graphical model. Despite the fundamental differences between these two methods, several interactions are jointly identified by both. Mapping these interactions onto a structural model of HIV-1 gp120 reveals that negative (exclusive) interactions occur significantly more often between colocalized glycans, while positive (inclusive) interactions are restricted to more distant glycans. Our results imply that the adaptive repertoire of alternative configurations in the HIV-1 glycan shield is limited by functional interactions between the N-linked glycans. This represents a potential vulnerability of rapidly evolving HIV-1 populations that may provide useful glycan-based targets for neutralizing antibodies.", + "year": "2007", + "author": "Poon, Art F Y and Lewis, Fraser I and Pond, Sergei L Kosakovsky and Frost, Simon D W", + "journal": "PLoS Comput Biol" + }, + { + "id": "Kosakovsky-Pond:2006qh", + "title": "GARD: a genetic algorithm for recombination detection", + "abstract": "MOTIVATION: Phylogenetic and evolutionary inference can be severely misled if recombination is not accounted for, hence screening for it should be an essential component of nearly every comparative study. The evolution of recombinant sequences can not be properly explained by a single phylogenetic tree, but several phylogenies may be used to correctly model the evolution of non-recombinant fragments.\nRESULTS: We developed a likelihood-based model selection procedure that uses a genetic algorithm to search multiple sequence alignments for evidence of recombination breakpoints and identify putative recombinant sequences. GARD is an extensible and intuitive method that can be run efficiently in parallel. Extensive simulation studies show that the method nearly always outperforms other available tools, both in terms of power and accuracy and that the use of GARD to screen sequences for recombination ensures good statistical properties for methods aimed at detecting positive selection.\nAVAILABILITY: Freely available http://www.datamonkey.org/GARD/", + "year": "2006", + "author": "Pond, Sergei L Kosakovsky and Posada, David and Gravenor, Michael B and Woelk, Christopher H and Frost, Simon D W", + "journal": "Bioinformatics" + }, + { + "id": "Kosakovsky-Pond:2007mf", + "title": "Evolutionary model selection with a genetic algorithm: a case study using stem RNA", + "abstract": "The choice of a probabilistic model to describe sequence evolution can and should be justified. Underfitting the data through the use of overly simplistic models may miss out on interesting phenomena and lead to incorrect inferences. Overfitting the data with models that are too complex may ascribe biological meaning to statistical artifacts and result in falsely significant findings. We describe a likelihood-based approach for evolutionary model selection. The procedure employs a genetic algorithm (GA) to quickly explore a combinatorially large set of all possible time-reversible Markov models with a fixed number of substitution rates. When applied to stem RNA data subject to well-understood evolutionary forces, the models found by the GA 1) capture the expected overall rate patterns a priori; 2) fit the data better than the best available models based on a priori assumptions, suggesting subtle substitution patterns not previously recognized; 3) cannot be rejected in favor of the general reversible model, implying that the evolution of stem RNA sequences can be explained well with only a few substitution rate parameters; and 4) perform well on simulated data, both in terms of goodness of fit and the ability to estimate evolutionary rates. We also investigate the utility of several distance measures for comparing and contrasting inferred evolutionary models. Using widely available small computer clusters, our approach allows, for the first time, to evaluate the performance of existing RNA evolutionary models by comparing them with a large pool of candidate models and to validate common modeling assumptions. In addition, the new method provides the foundation for rigorous selection and comparison of substitution models for other types of sequence data.", + "year": "2007", + "author": "Pond, Sergei L Kosakovsky and Mannino, Frank V and Gravenor, Michael B and Muse, Spencer V and Frost, Simon D W", + "journal": "Mol Biol Evol" + }, + { + "id": "Sorhannus:2006ja", + "title": "Evidence for positive selection on a sexual reproduction gene in the diatom genus Thalassiosira (Bacillariophyta)", + "abstract": "Single likelihood ancestor counting (SLAC), fixed effects likelihood (FEL), and several random effects likelihood (REL) methods were utilized to identify positively and negatively selected sites in sexually induced gene 1 (Sig1) of four different Thalassiosira species. The SLAC analysis did not find any sites affected by positive selection but suggested 13 sites influenced by negative selection. The SLAC approach may be too conservative because of low sequence divergence. The FEL and REL analyses revealed over 60 negatively selected sites and two positively selected sites that were unique to each method. The REL method may not be able to reliably identify individual sites under selection when applied to short sequences with low divergence. Instead, we proposed a new alignment-wide test for adaptive evolution based on codon models with variation in synonymous and nonsynonymous substitution rates among sites and found evidence for diversifying evolution without relying on site-by-site testing. The performance of the FEL and REL approaches was evaluated by subjecting the tests to a type I error rate simulation analysis, using the specific characteristics of the Sig1 data set. Simulation results indicated that the FEL test had reasonable Type I errors, while REL might have been too liberal, suggesting that the two positively selected sites identified by FEL (codons 94 and 174) are not likely to be false positives. The evolution of these codon sites, one of which is located in functional domain II, appears to be associated with divergence among the three major Thalassiosira lineages.", + "year": "2006", + "author": "Sorhannus, Ulf and Pond, Sergei L Kosakovsky", + "journal": "J Mol Evol" + }, + { + "id": "Kosakovsky-Pond:2006qt", + "title": "Automated phylogenetic detection of recombination using a genetic algorithm", + "abstract": "The evolution of homologous sequences affected by recombination or gene conversion cannot be adequately explained by a single phylogenetic tree. Many tree-based methods for sequence analysis, for example, those used for detecting sites evolving nonneutrally, have been shown to fail if such phylogenetic incongruity is ignored. However, it may be possible to propose several phylogenies that can correctly model the evolution of nonrecombinant fragments. We propose a model-based framework that uses a genetic algorithm to search a multiple-sequence alignment for putative recombination break points, quantifies the level of support for their locations, and identifies sequences or clades involved in putative recombination events. The software implementation can be run quickly and efficiently in a distributed computing environment, and various components of the methods can be chosen for computational expediency or statistical rigor. We evaluate the performance of the new method on simulated alignments and on an array of published benchmark data sets. Finally, we demonstrate that prescreening alignments with our method allows one to analyze recombinant sequences for positive selection.", + "year": "2006", + "author": "Pond, Sergei L Kosakovsky and Posada, David and Gravenor, Michael B and Woelk, Christopher H and Frost, Simon D W", + "journal": "Mol Biol Evol" + }, + { + "id": "Pond:2006gn", + "title": "Adaptation to different human populations by HIV-1 revealed by codon-based analyses", + "abstract": "Several codon-based methods are available for detecting adaptive evolution in protein-coding sequences, but to date none specifically identify sites that are selected differentially in two populations, although such comparisons between populations have been historically useful in identifying the action of natural selection. We have developed two fixed effects maximum likelihood methods: one for identifying codon positions showing selection patterns that persist in a population and another for detecting whether selection is operating differentially on individual codons of a gene sampled from two different populations. Applying these methods to two HIV populations infecting genetically distinct human hosts, we have found that few of the positively selected amino acid sites persist in the population; the other changes are detected only at the tips of the phylogenetic tree and appear deleterious in the long term. Additionally, we have identified seven amino acid sites in protease and reverse transcriptase that are selected differentially in the two samples, demonstrating specific population-level adaptation of HIV to human populations.", + "year": "2006", + "author": "Pond, Sergei L Kosakovsky and Frost, Simon D W and Grossman, Zehava and Gravenor, Michael B and Richman, Douglas D and Brown, Andrew J Leigh", + "journal": "PLoS Comput Biol" + }, + { + "id": "Pillai:2006gc", + "title": "Genetic attributes of cerebrospinal fluid-derived HIV-1 env", + "abstract": "HIV-1 often invades the CNS during primary infection, eventually resulting in neurological disorders in up to 50% of untreated patients. The CNS is a distinct viral reservoir, differing from peripheral tissues in immunological surveillance, target cell characteristics and antiretroviral penetration. Neurotropic HIV-1 likely develops distinct genotypic characteristics in response to this unique selective environment. We sought to catalogue the genetic features of CNS-derived HIV-1 by analysing 456 clonal RNA sequences of the C2-V3 env subregion generated from CSF and plasma of 18 chronically infected individuals. Neuropsychological performance of all subjects was evaluated and summarized as a global deficit score. A battery of phylogenetic, statistical and machine learning tools was applied to these data to identify genetic features associated with HIV-1 neurotropism and neurovirulence. Eleven of 18 individuals exhibited significant viral compartmentalization between blood and CSF (P < 0.01, Slatkin-Maddison test). A CSF-specific genetic signature was identified, comprising positions 9, 13 and 19 of the V3 loop. The residue at position 5 of the V3 loop was highly correlated with neurocognitive deficit (P < 0.0025, Fisher's exact test). Antibody-mediated HIV-1 neutralizing activity was significantly reduced in CSF with respect to autologous blood plasma (P < 0.042, Student's t-test). Accordingly, CSF-derived sequences exhibited constrained diversity and contained fewer glycosylated and positively selected sites. Our results suggest that there are several genetic features that distinguish CSF- and plasma-derived HIV-1 populations, probably reflecting altered cellular entry requirements and decreased immune pressure in the CNS. Furthermore, neurological impairment may be influenced by mutations within the viral V3 loop sequence.", + "year": "2006", + "author": "Pillai, Satish K and Pond, Sergei L Kosakovsky and Liu, Yang and Good, Benjamin M and Strain, Matthew C and Ellis, Ronald J and Letendre, Scott and Smith, Davey M and Gunthard, Huldrych F and Grant, Igor and Marcotte, Thomas D and McCutchan, J Allen and Richman, Douglas D and Wong, Joseph K", + "journal": "Brain" + }, + { + "id": "Huelsenbeck:2006wk", + "title": "A Dirichlet process model for detecting positive selection in protein-coding DNA sequences", + "abstract": "Most methods for detecting Darwinian natural selection at the molecular level rely on estimating the rates or numbers of nonsynonymous and synonymous changes in an alignment of protein-coding DNA sequences. In some of these methods, the nonsynonymous rate of substitution is allowed to vary across the sequence, permitting the identification of single amino acid positions that are under positive natural selection. However, it is unclear which probability distribution should be used to describe how the nonsynonymous rate of substitution varies across the sequence. One widely used solution is to model variation in the nonsynonymous rate across the sequence as a mixture of several discrete or continuous probability distributions. Unfortunately, there is little population genetics theory to inform us of the appropriate probability distribution for among-site variation in the nonsynonymous rate of substitution. Here, we describe an approach to modeling variation in the nonsynonymous rate of substitution by using a Dirichlet process mixture model. The Dirichlet process allows there to be a countably infinite number of nonsynonymous rate classes and is very flexible in accommodating different potential distributions for the nonsynonymous rate of substitution. We implemented the model in a fully Bayesian approach, with all parameters of the model considered as random variables.", + "year": "2006", + "author": "Huelsenbeck, John P and Jain, Sonia and Frost, Simon W D and Pond, Sergei L Kosakovsky", + "journal": "Proc Natl Acad Sci U S A" + }, + { + "id": "Frost:2005uz", + "title": "Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection", + "abstract": "HIV type 1 (HIV-1) can rapidly escape from neutralizing antibody responses. The genetic basis of this escape in vivo is poorly understood. We compared the pattern of evolution of the HIV-1 env gene between individuals with recent HIV infection whose virus exhibited either a low or a high rate of escape from neutralizing antibody responses. We demonstrate that the rate of viral escape at a phenotypic level is highly variable among individuals, and is strongly correlated with the rate of amino acid substitutions. We show that dramatic escape from neutralizing antibodies can occur in the relative absence of changes in glycosylation or insertions and deletions (\"indels\") in the envelope; conversely, changes in glycosylation and indels occur even in the absence of neutralizing antibody responses. Comparison of our data with the predictions of a mathematical model support a mechanism in which escape from neutralizing antibodies occurs via many amino acid substitutions, with low cross-neutralization between closely related viral strains. Our results suggest that autologous neutralizing antibody responses may play a pivotal role in the diversification of HIV-1 envelope during the early stages of infection.", + "year": "2005", + "author": "Frost, Simon D W and Wrin, Terri and Smith, Davey M and Pond, Sergei L Kosakovsky and Liu, Yang and Paxinos, Ellen and Chappey, Colombe and Galovich, Justin and Beauchaine, Jeff and Petropoulos, Christos J and Little, Susan J and Richman, Douglas D", + "journal": "Proc Natl Acad Sci U S A" + }, + { + "id": "Pond:2005ya", + "title": "Site-to-site variation of synonymous substitution rates", + "abstract": "We develop a new model for studying the molecular evolution of protein-coding DNA sequences. In contrast to existing models, we incorporate the potential for site-to-site heterogeneity of both synonymous and nonsynonymous substitution rates. We demonstrate that within-gene heterogeneity of synonymous substitution rates appears to be common. Using the new family of models, we investigate the utility of a variety of new statistical inference procedures, and we pay particular attention to issues surrounding the detection of sites undergoing positive selection. We discuss how failure to model synonymous rate variation in the model can lead to misidentification of sites as positively selected.", + "year": "2005", + "author": "Pond, Sergei L Kosakovsky and Muse, Spencer V", + "journal": "Mol Biol Evol" + }, + { + "id": "Pillai:2005mn", + "title": "Codon volatility does not reflect selective pressure on the HIV-1 genome", + "abstract": "Codon volatility is defined as the proportion of a codon's point-mutation neighbors that encode different amino acids. The cumulative volatility of a gene in relation to its associated genome was recently reported to be an indicator of selection pressure. We used this approach to measure selection on all available full-length HIV-1 subtype B genomes in the Los Alamos HIV Sequence Database, and compared these estimates against those obtained via established likelihood- and distance-based comparative methods. Volatility failed to correlate with the results of any of the comparative methods demonstrating that it is not a reliable indicator of selection pressure.", + "year": "2005", + "author": "Pillai, Satish K and Pond, Sergei L Kosakovsky and Woelk, Christopher H and Richman, Douglas D and Smith, Davey M", + "journal": "Virology" + }, + { + "id": "Frost:2005er", + "title": "Characterization of human immunodeficiency virus type 1 (HIV-1) envelope variation and neutralizing antibody responses during transmission of HIV-1 subtype B", + "abstract": "We analyzed neutralization sensitivity and genetic variation of transmitted subtype B human immunodeficiency virus type 1 (HIV-1) in eight recently infected men who have sex with men and the virus from the six subjects who infected them. In contrast to reports of heterosexual transmission of subtype C HIV-1, in which the transmitted virus appears to be more neutralization sensitive, we demonstrate that in our study population, relatively few phenotypic changes in neutralization sensitivity or genotypic changes in envelope occurred during transmission of subtype B HIV-1. We suggest that limited genetic variation within the infecting host reduces the likelihood of selective transmission of neutralization-sensitive HIV.", + "year": "2005", + "author": "Frost, Simon D W and Liu, Yang and Pond, Sergei L Kosakovsky and Chappey, Colombe and Wrin, Terri and Petropoulos, Christos J and Little, Susan J and Richman, Douglas D", + "journal": "J Virol" + }, + { + "id": "Pond:2005ph", + "title": "Datamonkey: rapid detection of selective pressure on individual sites of codon alignments", + "abstract": "UNLABELLED: Datamonkey is a web interface to a suite of cutting edge maximum likelihood-based tools for identification of sites subject to positive or negative selection. The methods range from very fast data exploration to the some of the most complex models available in public domain software, and are implemented to run in parallel on a cluster of computers.\nAVAILABILITY: http://www.datamonkey.org. In the future, we plan to expand the collection of available analytic tools, and provide a package for installation on other systems.", + "year": "2005", + "author": "Pond, Sergei L Kosakovsky and Frost, Simon D W", + "journal": "Bioinformatics" + }, + { + "id": "Kosakovsky-Pond:2005fm", + "title": "Not so different after all: a comparison of methods for detecting amino acid sites under selection", + "abstract": "We consider three approaches for estimating the rates of nonsynonymous and synonymous changes at each site in a sequence alignment in order to identify sites under positive or negative selection: (1) a suite of fast likelihood-based \"counting methods\" that employ either a single most likely ancestral reconstruction, weighting across all possible ancestral reconstructions, or sampling from ancestral reconstructions; (2) a random effects likelihood (REL) approach, which models variation in nonsynonymous and synonymous rates across sites according to a predefined distribution, with the selection pressure at an individual site inferred using an empirical Bayes approach; and (3) a fixed effects likelihood (FEL) method that directly estimates nonsynonymous and synonymous substitution rates at each site. All three methods incorporate flexible models of nucleotide substitution bias and variation in both nonsynonymous and synonymous substitution rates across sites, facilitating the comparison between the methods. We demonstrate that the results obtained using these approaches show broad agreement in levels of Type I and Type II error and in estimates of substitution rates. Counting methods are well suited for large alignments, for which there is high power to detect positive and negative selection, but appear to underestimate the substitution rate. A REL approach, which is more computationally intensive than counting methods, has higher power than counting methods to detect selection in data sets of intermediate size but may suffer from higher rates of false positives for small data sets. A FEL approach appears to capture the pattern of rate variation better than counting methods or random effects models, does not suffer from as many false positives as random effects models for data sets comprising few sequences, and can be efficiently parallelized. Our results suggest that previously reported differences between results obtained by counting methods and random effects models arise due to a combination of the conservative nature of counting-based methods, the failure of current random effects models to allow for variation in synonymous substitution rates, and the naive application of random effects models to extremely sparse data sets. We demonstrate our methods on sequence data from the human immunodeficiency virus type 1 env and pol genes and simulated alignments.", + "year": "2005", + "author": "Pond, Sergei L Kosakovsky and Frost, Simon D W", + "journal": "Mol Biol Evol" + }, + { + "id": "Pillai:2005we", + "title": "Semen-specific genetic characteristics of human immunodeficiency virus type 1 env", + "abstract": "Human immunodeficiency virus type 1 (HIV-1) in the male genital tract may comprise virus produced locally in addition to virus transported from the circulation. Virus produced in the male genital tract may be genetically distinct, due to tissue-specific cellular characteristics and immunological pressures. HIV-1 env sequences derived from paired blood and semen samples from the Los Alamos HIV Sequence Database were analyzed to ascertain a male genital tract-specific viral signature. Machine learning algorithms could predict seminal tropism based on env sequences with accuracies exceeding 90%, suggesting that a strong genetic signature does exist for virus replicating in the male genital tract. Additionally, semen-derived viral populations exhibited constrained diversity (P < 0.05), decreased levels of positive selection (P < 0.025), decreased CXCR4 coreceptor utilization, and altered glycosylation patterns. Our analysis suggests that the male genital tract represents a distinct selective environment that contributes to the apparent genetic bottlenecks associated with the sexual transmission of HIV-1.", + "year": "2005", + "author": "Pillai, Satish K and Good, Benjamin and Pond, Sergei L Kosakovsky and Wong, Joseph K and Strain, Matt C and Richman, Douglas D and Smith, Davey M", + "journal": "J Virol" + }, + { + "id": "Kosakovsky-Pond:2004vh", + "title": "Column sorting: rapid calculation of the phylogenetic likelihood function", + "abstract": "Likelihood applications have become a central approach for molecular evolutionary analyses since the first computationally tractable treatment two decades ago. Although Felsenstein's original pruning algorithm makes likelihood calculations feasible, it is usually possible to take advantage of repetitive structure present in the data to arrive at even greater computational reductions. In particular, alignment columns with certain similarities have components of the likelihood calculation that are identical and need not be recomputed if columns are evaluated in an optimal order. We develop an algorithm for exploiting this speed improvement via an application of graph theory. The reductions provided by the method depend on both the tree and the data, but typical savings range between 15%and 50%. Real-data examples with time reductions of 80%have been identified. The overhead costs associated with implementing the algorithm are minimal, and they are recovered in all but the smallest data sets. The modifications will provide faster likelihood algorithms, which will allow likelihood methods to be applied to larger sets of taxa and to include more thorough searches of the tree topology space.", + "year": "2004", + "author": "Pond, Sergei L Kosakovsky and Muse, Spencer V", + "journal": "Syst Biol" + }, + { + "id": "Pond:2005wl", + "title": "A genetic algorithm approach to detecting lineage-specific variation in selection pressure", + "abstract": "The ratio of nonsynonymous (dN) to synonymous (dS) substitution rates, omega, provides a measure of selection at the protein level. Models have been developed that allow omega to vary among lineages. However, these models require the lineages in which differential selection has acted to be specified a priori. We propose a genetic algorithm approach to assign lineages in a phylogeny to a fixed number of different classes of omega, thus allowing variable selection pressure without a priori specification of particular lineages. This approach can identify models with a better fit than a single-ratio model, and with fits that are better than (in an information theoretic sense) a fully local model, in which all lineages are assumed to evolve under different values of omega, but with far fewer parameters. By averaging over models which explain the data reasonably well, we can assess the robustness of our conclusions to uncertainty in model estimation. Our approach can also be used to compare results from models in which branch classes are specified a priori with a wide range of credible models. We illustrate our methods on primate lysozyme sequences and compare them with previous methods applied to the same data sets.", + "year": "2005", + "author": "Pond, Sergei L Kosakovsky and Frost, Simon D W", + "journal": "Mol Biol Evol" + }, + { + "id": "Pond:2005ez", + "title": "HyPhy: hypothesis testing using phylogenies", + "abstract": "UNLABELLED: The HyPhypackage is designed to provide a flexible and unified platform for carrying out likelihood-based analyses on multiple alignments of molecular sequence data, with the emphasis on studies of rates and patterns of sequence evolution.\nAVAILABILITY: http://www.hyphy.org\nCONTACT: muse@stat.ncsu.edu\nSUPPLEMENTARY INFORMATION: HyPhydocumentation and tutorials are available at http://www.hyphy.org.", + "year": "2005", + "author": "Pond, Sergei L Kosakovsky and Frost, Simon D W and Muse, Spencer V", + "journal": "Bioinformatics" + }, + { + "id": "Pond:2005oh", + "title": "A simple hierarchical approach to modeling distributions of substitution rates", + "abstract": "Genetic sequence data typically exhibit variability in substitution rates across sites. In practice, there is often too little variation to fit a different rate for each site in the alignment, but the distribution of rates across sites may not be well modeled using simple parametric families. Mixtures of different distributions can capture more complex patterns of rate variation, but are often parameter-rich and difficult to fit. We present a simple hierarchical model in which a baseline rate distribution, such as a gamma distribution, is discretized into several categories, the quantiles of which are estimated using a discretized beta distribution. Although this approach involves adding only two extra parameters to a standard distribution, a wide range of rate distributions can be captured. Using simulated data, we demonstrate that a \"beta-\" model can reproduce the moments of the rate distribution more accurately than the distribution used to simulate the data, even when the baseline rate distribution is misspecified. Using hepatitis C virus and mammalian mitochondrial sequences, we show that a beta- model can fit as well or better than a model with multiple discrete rate categories, and compares favorably with a model which fits a separate rate category to each site. We also demonstrate this discretization scheme in the context of codon models specifically aimed at identifying individual sites undergoing adaptive or purifying evolution.", + "year": "2005", + "author": "Pond, Sergei L Kosakovsky and Frost, Simon D W", + "journal": "Mol Biol Evol" + }, + { + "id": "Israel:2002ye", + "title": "Evolution of duplicated alpha-tubulin genes in ciliates", + "abstract": "Ciliates provide a powerful system to analyze the evolution of duplicated alpha-tubulin genes in the context of single-celled organisms. Genealogical analyses of ciliate alpha-tubulin sequences reveal five apparently recent gene duplications. Comparisons of paralogs in different ciliates implicate differing patterns of substitutions (e.g., ratios of replacement/synonymous nucleotides and radical/conservative amino acids) following duplication. Most substitutions between paralogs in Euplotes crassus, Halteria grandinella and Paramecium tetraurelia are synonymous. In contrast, alpha-tubulin paralogs within Stylonychia lemnae and Chilodonella uncinata are evolving at significantly different rates and have higher ratios of both replacement substitutions to synonymous substitutions and radical amino acid changes to conservative amino acid changes. Moreover, the amino acid substitutions in C. uncinata and S. lemnae paralogs are limited to short stretches that correspond to functionally important regions of the alpha-tubulin protein. The topology of ciliate alpha-tubulin genealogies are inconsistent with taxonomy based on morphology and other molecular markers, which may be due to taxonomic sampling, gene conversion, unequal rates of evolution, or asymmetric patterns of gene duplication and loss.", + "year": "2002", + "author": "Israel, Rachel L and Pond, Sergei L Kosakovsky and Muse, Spencer V and Katz, Laura A", + "journal": "Evolution" + }, + { + "id": "Zhang:2001eh", + "title": "A survey of the molecular evolutionary dynamics of twenty-five multigene families from four grass taxa", + "abstract": "We surveyed the molecular evolutionary characteristics of 25 plant gene families, with the goal of better understanding general processes in plant gene family evolution. The survey was based on 247 GenBank sequences representing four grass species (maize, rice, wheat, and barley). For each gene family, orthology and paralogy relationships were uncertain. Recognizing this uncertainty, we characterized the molecular evolution of each gene family in four ways. First, we calculated the ratio of nonsynonymous to synonymous substitutions (d(N)/d(S)) both on branches of gene phylogenies and across codons. Our results indicated that the d(N)/d(S) ratio was statistically heterogeneous across branches in 17 of 25 (68%) gene families. The vast majority of d(N)/d(S) estimates were <1.0, suggestive of selective constraint on amino acid replacements, and no estimates were >1.0, either across phylogenetic lineages or across codons. Second, we tested separately for nonsynonymous and synonymous molecular clocks. Sixty-eight percent of gene families rejected a nonsynonymous molecular clock, and 52% of gene families rejected a synonymous molecular clock. Thus, most gene families in this study deviated from clock-like evolution at either synonymous or nonsynonymous sites. Third, we calculated the effective number of codons and the proportion of G+C synonymous sites for each sequence in each gene family. One or both quantities vary significantly within 18 of 25 gene families. Finally, we tested for gene conversion, and only six gene families provided evidence of gene conversion events. Altogether, evolution for these 25 gene families is marked by selective constraint that varies among gene family members, a lack of molecular clock at both synonymous and nonsynonymous sites, and substantial variation in codon usage.", + "year": "2001", + "author": "Zhang, L and Pond, S K and Gaut, B S", + "journal": "J Mol Evol" + } +] \ No newline at end of file diff --git a/eslint.config.mjs b/eslint.config.mjs new file mode 100644 index 0000000..8f2d79b --- /dev/null +++ b/eslint.config.mjs @@ -0,0 +1,17 @@ +import { defineConfig, globalIgnores } from "eslint/config"; +import nextVitals from "eslint-config-next/core-web-vitals"; + +const eslintConfig = defineConfig([ + ...nextVitals, + // Override default ignores of eslint-config-next. + globalIgnores([ + // Default ignores of eslint-config-next: + ".next/**", + "out/**", + "build/**", + "next-env.d.ts", + "backup/**", + ]), +]); + +export default eslintConfig; diff --git a/jsconfig.json b/jsconfig.json new file mode 100644 index 0000000..b8d6842 --- /dev/null +++ b/jsconfig.json @@ -0,0 +1,7 @@ +{ + "compilerOptions": { + "paths": { + "@/*": ["./src/*"] + } + } +} diff --git a/next.config.js b/next.config.js new file mode 100644 index 0000000..824ba0a --- /dev/null +++ b/next.config.js @@ -0,0 +1,9 @@ +/** @type {import('next').NextConfig} */ +const nextConfig = { + output: 'export', + images: { + unoptimized: true, + }, +}; + +module.exports = nextConfig; diff --git a/package-lock.json b/package-lock.json index a7c20d1..40c2cb2 100644 --- a/package-lock.json +++ b/package-lock.json @@ -1,11588 +1,6537 @@ { - "name": "LabSite", + "name": "nextjs-app", "version": "0.1.0", - "lockfileVersion": 1, + "lockfileVersion": 3, "requires": true, - "dependencies": { - "@babel/runtime": { - "version": "7.10.5", - "resolved": "https://registry.npmjs.org/@babel/runtime/-/runtime-7.10.5.tgz", - "integrity": "sha512-otddXKhdNn7d0ptoFRHtMLa8LqDxLYwTjB4nYgM1yy5N6gU/MUf8zqyyLltCH3yAVitBzmwK4us+DD0l/MauAg==", - "requires": { - 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}, "dependencies": { - "@fortawesome/fontawesome-free": "^5.15.3", - "ajv": "^6.12.6", - "babel": "^6.23.0", - "babel-loader": "^7.1.4", - "babel-preset-es2015": "^6.24.1", - "babel-preset-react": "^6.24.1", - "babel-preset-stage-1": "^6.24.1", - "bootstrap": "^4.1.0", - "express": "^4.16.3", - "font-awesome": "4.x", - "fsevents": "^2.3.2", - "jquery": "^1.9.1", - "react": "^16.3.1", - "react-announcement": "^1.1.2", - "react-dom": "^16.3.1", - "react-router": "^4.2.0", - "react-scripts": "1.1.4", - "reactstrap": "^5.0.0", - "supervisor": "^0.12.0" + "next": "16.2.6", + "react": "19.2.4", + "react-dom": "19.2.4" }, - "scripts": { - "start": "react-scripts start", - "build": "react-scripts build", - "test": "react-scripts test --env=jsdom", - "eject": "react-scripts eject" + "devDependencies": { + "@tailwindcss/postcss": "^4", + "eslint": "^9", + "eslint-config-next": "16.2.6", + "tailwindcss": "^4" } } diff --git a/postcss.config.js b/postcss.config.js new file mode 100644 index 0000000..19afca4 --- /dev/null +++ b/postcss.config.js @@ -0,0 +1,7 @@ +const config = { + plugins: { + "@tailwindcss/postcss": {}, + }, +}; + +module.exports = config; diff --git a/public/file.svg b/public/file.svg new file mode 100644 index 0000000..004145c --- /dev/null +++ b/public/file.svg @@ -0,0 +1 @@ + \ No newline at end of file diff --git a/public/globe.svg b/public/globe.svg new file mode 100644 index 0000000..567f17b --- /dev/null +++ b/public/globe.svg @@ -0,0 +1 @@ + \ No newline at end of file diff --git a/public/images/members/Avery.jpeg b/public/images/members/Avery.jpeg new file mode 100644 index 0000000..2748c64 Binary files /dev/null and b/public/images/members/Avery.jpeg differ diff --git a/public/images/members/Brittany.jpeg b/public/images/members/Brittany.jpeg new file mode 100644 index 0000000..0ff8d71 Binary files /dev/null and b/public/images/members/Brittany.jpeg differ diff --git a/public/images/members/HV.jpg b/public/images/members/HV.jpg new file mode 100644 index 0000000..822fa8f Binary files /dev/null and b/public/images/members/HV.jpg differ diff --git a/public/images/members/Hannah.jpeg b/public/images/members/Hannah.jpeg new file mode 100644 index 0000000..521b629 Binary files /dev/null and b/public/images/members/Hannah.jpeg differ diff --git a/public/images/members/Sergei.jpeg b/public/images/members/Sergei.jpeg new file mode 100644 index 0000000..907d811 Binary files /dev/null and b/public/images/members/Sergei.jpeg differ diff --git a/public/images/members/Steven.jpeg b/public/images/members/Steven.jpeg new file mode 100644 index 0000000..b0db177 Binary files /dev/null and b/public/images/members/Steven.jpeg differ diff --git a/public/images/members/pixelated/Sergei.jpeg b/public/images/members/pixelated/Sergei.jpeg new file mode 100644 index 0000000..a39bb3a Binary files /dev/null and b/public/images/members/pixelated/Sergei.jpeg differ diff --git a/public/images/members/pixelated/Sergei.jpg b/public/images/members/pixelated/Sergei.jpg new file mode 100644 index 0000000..a39bb3a Binary files /dev/null and b/public/images/members/pixelated/Sergei.jpg differ diff --git a/public/images/members/pixelated/Steven.jpg b/public/images/members/pixelated/Steven.jpg new file mode 100644 index 0000000..cbf9390 Binary files /dev/null and b/public/images/members/pixelated/Steven.jpg differ diff --git a/public/images/projects/Alignment.jpeg b/public/images/projects/Alignment.jpeg new file mode 100644 index 0000000..4ef5712 Binary files /dev/null and b/public/images/projects/Alignment.jpeg differ diff --git a/public/images/projects/CovidDash.jpeg b/public/images/projects/CovidDash.jpeg new file mode 100644 index 0000000..b580904 Binary files /dev/null and b/public/images/projects/CovidDash.jpeg differ diff --git a/public/images/projects/Datamonkey.jpeg b/public/images/projects/Datamonkey.jpeg new file mode 100644 index 0000000..62fcfc4 Binary files /dev/null and b/public/images/projects/Datamonkey.jpeg differ diff --git a/public/images/projects/Galaxy.jpeg b/public/images/projects/Galaxy.jpeg new file mode 100644 index 0000000..fb2dd2e Binary files /dev/null and b/public/images/projects/Galaxy.jpeg differ diff --git a/public/images/projects/Galaxylogo.svg b/public/images/projects/Galaxylogo.svg new file mode 100644 index 0000000..cd63200 --- /dev/null +++ b/public/images/projects/Galaxylogo.svg @@ -0,0 +1 @@ +galaxy-hivGalaxy \ No newline at end of file diff --git a/public/images/projects/HIVNGS.jpeg b/public/images/projects/HIVNGS.jpeg new file mode 100644 index 0000000..2b6cef0 Binary files /dev/null and b/public/images/projects/HIVNGS.jpeg differ diff --git a/public/images/projects/Hyphy.jpeg b/public/images/projects/Hyphy.jpeg new file mode 100644 index 0000000..f92c16a Binary files /dev/null and b/public/images/projects/Hyphy.jpeg differ diff --git a/public/images/projects/Phylotree.jpeg b/public/images/projects/Phylotree.jpeg new file mode 100644 index 0000000..e7f3f73 Binary files /dev/null and b/public/images/projects/Phylotree.jpeg differ diff --git a/public/images/projects/Trace.jpeg b/public/images/projects/Trace.jpeg new file mode 100644 index 0000000..20a6795 Binary files /dev/null and b/public/images/projects/Trace.jpeg differ diff --git a/public/images/projects/Vision.jpeg b/public/images/projects/Vision.jpeg new file mode 100644 index 0000000..e567678 Binary files /dev/null and b/public/images/projects/Vision.jpeg differ diff --git a/public/next.svg b/public/next.svg new file mode 100644 index 0000000..5174b28 --- /dev/null +++ b/public/next.svg @@ -0,0 +1 @@ + \ No newline at end of file diff --git a/public/vercel.svg b/public/vercel.svg new file mode 100644 index 0000000..7705396 --- /dev/null +++ b/public/vercel.svg @@ -0,0 +1 @@ + \ No newline at end of file diff --git a/public/window.svg b/public/window.svg new file mode 100644 index 0000000..b2b2a44 --- /dev/null +++ b/public/window.svg @@ -0,0 +1 @@ + \ No newline at end of file diff --git a/src/app/favicon.ico b/src/app/favicon.ico new file mode 100644 index 0000000..718d6fe Binary files /dev/null and b/src/app/favicon.ico differ diff --git a/src/app/former/page.js b/src/app/former/page.js new file mode 100644 index 0000000..e4bdb13 --- /dev/null +++ b/src/app/former/page.js @@ -0,0 +1,51 @@ +import formerMembers from '@/data/former.json'; +import PageContainer from '@/components/PageContainer'; +import Card from '@/components/Card'; + +export default function FormerMembersPage() { + const separator = " // "; + + return ( + +

+ [PAST_CONTRIBUTORS_AND_RESEARCHERS] +

+ +
+
+ {formerMembers.map(member => ( + +
+

+ {member.title}{separator}{member.years} +

+

+ [NEXT_STATION]: {member.next} +

+
+ {Object.entries(member.links).map(([type, url]) => ( + + [{type.toUpperCase()}] + + ))} +
+
+
+ ))} +
+
+ +
+ + RETURN_TO_CURRENT_TEAM + +
+
+ ); +} diff --git a/src/app/globals.css b/src/app/globals.css new file mode 100644 index 0000000..bd95423 --- /dev/null +++ b/src/app/globals.css @@ -0,0 +1,130 @@ +@import "tailwindcss"; + +@theme { + --font-heading: var(--font-press-start); + --font-body: var(--font-vt323); + --font-mono: var(--font-share-tech-mono); + --font-pixelify: var(--font-pixelify); + --font-inter: sans-serif; + + /* 80s Palette */ + --color-retro-green: #689d6a; + --color-retro-blue: #458588; + --color-retro-amber: #d79921; + --color-retro-purple: #b16286; + --color-retro-bg: #282828; + --color-retro-fg: #ebdbb2; + + /* 90s Palette */ + --color-mgs-bg: #0a0f0a; + --color-mgs-panel: rgba(16, 24, 16, 0.85); + --color-mgs-green: #00ff41; + --color-mgs-blue: #00a8ff; + --color-mgs-red: #ff3e3e; + --color-mgs-border: #2d4c2d; + + /* 2000s Palette */ + --color-me-bg: #050a0f; + --color-me-orange: #ff9d00; + --color-me-blue: #00f2ff; + + /* 2010s Palette */ + --color-hero-bg: #f5f5f5; + --color-hero-yellow: #ffcc00; + --color-hero-cyan: #00ffff; + --color-hero-dark: #1a1a1a; + + /* 2020s AI Assistant Palette */ + --color-ai-bg: #0f111a; + --color-ai-sidebar: #171923; + --color-ai-bubble-user: #2d3139; + --color-ai-bubble-ai: #1e212b; + --color-ai-accent: #4a9eff; + --color-ai-gradient: linear-gradient(135deg, #4a9eff 0%, #a855f7 100%); + + --shadow-retro: 4px 4px 0px 0px rgba(0, 0, 0, 1); + --shadow-mgs: 0 0 15px rgba(0, 255, 65, 0.2); + --shadow-me: 0 0 20px rgba(255, 157, 0, 0.15); + --shadow-hero: 8px 8px 0px 0px rgba(0, 0, 0, 1); + --shadow-ai: 0 4px 20px rgba(0, 0, 0, 0.3); + + /* Animations */ + --animate-chew: chew 0.6s ease-in-out infinite; + --animate-banana-shrink: shrink 5s ease-in forwards; + --animate-scene-fade: fadeOut 1s ease-out 6s forwards; + --animate-hologram-flicker: hologramFade 3s ease-in-out infinite; + --animate-typing: typing 1.5s infinite; + + @keyframes chew { 0%, 100% { transform: scaleY(1); } 50% { transform: scaleY(0.6); } } + @keyframes shrink { 0% { transform: scale(1); opacity: 0.6; } 80% { transform: scale(0.2); opacity: 0.4; } 100% { transform: scale(0); opacity: 0; } } + @keyframes fadeOut { from { opacity: 1; } to { opacity: 0; visibility: hidden; } } + @keyframes hologramFade { 0%, 100% { opacity: 1; } 50% { opacity: 0.85; } } + @keyframes typing { 0%, 100% { opacity: 0.3; } 50% { opacity: 1; } } +} + +:root { --background: #282828; --foreground: #ebdbb2; } +[data-theme='90s'] { --background: #0a0f0a; --foreground: #00ff41; } +[data-theme='2000s'] { --background: #050a0f; --foreground: #ff9d00; } +[data-theme='2010s'] { --background: #f5f5f5; --foreground: #1a1a1a; } +[data-theme='2020s'] { --background: #0f111a; --foreground: #e2e8f0; } + +body { + background-color: var(--background); + color: var(--foreground); + transition: background-color 0.5s, color 0.3s; + min-height: 100vh; + margin: 0; + overflow-x: hidden; +} + +/* 80s Specifics */ +.theme-80s { font-family: var(--font-vt323), monospace; image-rendering: pixelated; } +.theme-80s h1, .theme-80s h2, .theme-80s h3 { font-family: var(--font-press-start), cursive; text-transform: uppercase; } +.theme-80s.crt::before { + content: " "; display: block; position: fixed; top: 0; left: 0; bottom: 0; right: 0; + background: linear-gradient(rgba(18, 16, 16, 0) 50%, rgba(0, 0, 0, 0.1) 50%), linear-gradient(90deg, rgba(255, 0, 0, 0.02), rgba(0, 255, 0, 0.01), rgba(0, 0, 255, 0.02)); + z-index: 9999; background-size: 100% 3px, 3px 100%; pointer-events: none; opacity: 0.8; position: fixed; +} + +/* 90s Specifics */ +.theme-90s { font-family: var(--font-share-tech-mono), monospace; image-rendering: pixelated; } +.theme-90s::after { + content: " "; display: block; position: fixed; top: 0; left: 0; bottom: 0; right: 0; + background: linear-gradient(rgba(0, 255, 65, 0.03) 50%, transparent 50%); + background-size: 100% 2px; z-index: 9998; pointer-events: none; +} + +/* 2010s Specifics */ +.theme-2010s { font-family: var(--font-share-tech-mono), sans-serif; image-rendering: pixelated; } +.hero-panel { background: white; border: 4px solid #000; box-shadow: 8px 8px 0px 0px #ffcc00; position: relative; } +.hero-button { background: #ffcc00; border: 3px solid #000; color: #000; font-weight: 900; box-shadow: 4px 4px 0px 0px #000; } + +/* 2020s AI Specifics */ +.theme-2020s { font-family: ui-sans-serif, system-ui, sans-serif; image-rendering: auto; } +.ai-bubble { + border-radius: 1.5rem; + padding: 1.25rem; + max-width: 85%; + box-shadow: 0 4px 12px rgba(0, 0, 0, 0.1); + border: 1px solid rgba(255, 255, 255, 0.05); +} +.ai-bubble-user { background-color: #2d3139; align-self: flex-end; border-bottom-right-radius: 0.25rem; } +.ai-bubble-ai { background-color: #1e212b; align-self: flex-start; border-bottom-left-radius: 0.25rem; } + +.ai-sidebar { + background-color: #171923; + border-right: 1px solid rgba(255, 255, 255, 0.1); +} + +.ai-glow { + background: linear-gradient(135deg, #4a9eff, #a855f7); + -webkit-background-clip: text; + -webkit-text-fill-color: transparent; + background-clip: text; +} + +/* Base Panel Styles */ +.mgs-panel { background: rgba(16, 24, 16, 0.9); border: 1px solid #2d4c2d; position: relative; overflow: hidden; } +.me-panel { background: rgba(255, 157, 0, 0.03); border: 1px solid rgba(255, 157, 0, 0.2); clip-path: polygon(0 0, 95% 0, 100% 5%, 100% 100%, 5% 100%, 0 95%); } +.pixel-border { border: 4px solid var(--foreground); } +.pixel-button { background-color: #458588; border: 4px solid #1d2021; box-shadow: 4px 4px 0px 0px #ebdbb2; } diff --git a/src/app/layout.js b/src/app/layout.js new file mode 100644 index 0000000..1e564b5 --- /dev/null +++ b/src/app/layout.js @@ -0,0 +1,43 @@ +import { Press_Start_2P, VT323, Share_Tech_Mono, Pixelify_Sans } from "next/font/google"; +import "./globals.css"; +import { ThemeProvider } from "@/components/ThemeContext"; + +const pressStart2P = Press_Start_2P({ + variable: "--font-press-start", + weight: "400", + subsets: ["latin"], +}); + +const vt323 = VT323({ + variable: "--font-vt323", + weight: "400", + subsets: ["latin"], +}); + +const shareTechMono = Share_Tech_Mono({ + variable: "--font-share-tech-mono", + weight: "400", + subsets: ["latin"], +}); + +const pixelify = Pixelify_Sans({ + variable: "--font-pixelify", + subsets: ["latin"], +}); + +export const metadata = { + title: "ACME Lab | Acme Computational Molecular Evolution Group", + description: "High-performance software and statistical models for molecular evolution, phylogenetics, and epidemiology.", +}; + +export default function RootLayout({ children }) { + return ( + + + + {children} + + + + ); +} diff --git a/src/app/members/page.js b/src/app/members/page.js new file mode 100644 index 0000000..c580f96 --- /dev/null +++ b/src/app/members/page.js @@ -0,0 +1,38 @@ +import members from '@/data/members.json'; +import PageContainer from '@/components/PageContainer'; +import Card from '@/components/Card'; + +export default function MembersPage() { + return ( + +
+ {members.map(member => ( + +
+ {member.image ? ( + {member.name} + ) : ( +
+ [NO_IMAGE] +
+ )} +
+

{member.title}

+

{member.bio}

+
+ {Object.entries(member.links).map(([type, url]) => ( + + [{type}] + + ))} +
+
+ ))} +
+
+ ); +} diff --git a/src/app/page.js b/src/app/page.js new file mode 100644 index 0000000..2a77a0c --- /dev/null +++ b/src/app/page.js @@ -0,0 +1,212 @@ +'use client'; +import Navbar from '@/components/Navbar'; +import Card from '@/components/Card'; +import EraSelectionSplash from '@/components/EraSelectionSplash'; +import { useTheme } from '@/components/ThemeContext'; +import Link from 'next/link'; + +export default function Home() { + const { theme, mounted, hasSelectedTheme } = useTheme(); + + if (!mounted) return
; + + // Show splash if theme hasn't been chosen yet + if (!hasSelectedTheme) { + return ; + } + + return ( +
+ + +
+
+ {theme === '2020s' ? ( +
+
+

How can I help you today?

+

Discover the research and tools of the ACME Laboratory.

+
+ +
+ {[ + { title: "Browse Publications", desc: "Show me the research archive and statistics.", href: "/papers" }, + { title: "Meet the Team", desc: "Who are the current and former strike force members?", href: "/members" }, + { title: "Access Software", desc: "What tools are available in the arsenal?", href: "/projects" }, + { title: "View Collaborations", desc: "Tell me about the lab's alliance network.", href: "/projects" } + ].map((item, i) => ( + +

{item.title}

+

{item.desc}

+ + ))} +
+ +
+
+
Type a command to explore the lab...
+
+
+
+
+
+
+ ) : ( + <> +
+ {theme === '90s' &&
ESTABLISHING_UPLINK...
} + {theme === '2000s' &&
LOCATING_STRIKE_TEAM...
} + {theme === '2010s' &&
NEW QUEST DISCOVERED:
} + +

+ ACME_LAB:
+ COMPUTATIONAL_MOLECULAR_EVOLUTION +

+
+ +
+

+ STATISTICAL_MODELS & SOFTWARE_TOOLS
FOR COMPARATIVE_SEQUENCE_ANALYSIS +

+ + +

+ We develop and apply high-performance computational tools for the comparative analysis of sequence data. + Our methods are universally applicable across all domains of life. + While measurably evolving pathogens are our primary focus and "top customers," + our framework is used to interrogate evolutionary questions anywhere on the tree of life. +

+
+ [SCOPE]: UNIVERSAL + [PRIMARY_FOCUS]: PATHOGENS + [STATUS]: ACTIVE +
+
+
+ + )} +
+ + {theme !== '2020s' && ( + <> +
+ +
    +
  • {">"} MOLECULAR_EPIDEMIOLOGY
  • +
  • {">"} VIRAL_DYNAMICS
  • +
  • {">"} PHYLOGENETIC_METHODS
  • +
  • {">"} HIGH_PERFORMANCE_COMPUTING
  • +
  • {">"} DATA_VISUALIZATION
  • +
+
+ + +

Our lab maintains a suite of open-source tools utilized by researchers worldwide:

+
+ {['HYPHY', 'DATAMONKEY', 'HIV-TRACE'].map(tool => ( + + {tool} + + ))} +
+
+
+ +
+
+

SELECT_DESTINATION

+
+ {theme === '2010s' ? 'THE_TEAM' : '> MEET_THE_TEAM'} + + {theme === '2010s' ? 'PROJECTS' : '> EXPLORE_PROJECTS'} + + {theme === '2010s' ? 'RESEARCH' : '> READ_RESEARCH'} +
+
+
+ + )} +
+ +
+

© 2026 ACME_LAB // RE-DESIGNED FOR THE_NEXT_DECADE

+

+ INSTITUTE_FOR_GENOMICS_AND_EVOLUTIONARY_MEDICINE // TEMPLE_UNIVERSITY +

+
+
+ ); +} diff --git a/src/app/papers/page.js b/src/app/papers/page.js new file mode 100644 index 0000000..2c5512d --- /dev/null +++ b/src/app/papers/page.js @@ -0,0 +1,309 @@ +'use client'; +import Card from '@/components/Card'; +import papers from '@/data/papers.json'; +import currentMembers from '@/data/members.json'; +import formerMembers from '@/data/former.json'; +import PageContainer from '@/components/PageContainer'; +import { useTheme } from '@/components/ThemeContext'; + +export default function PapersPage() { + const { theme } = useTheme(); + const categories = ["METHODS", "SURVEILLANCE", "VIRAL_DYNAMICS", "ADAPTATION"]; + const allLabMembers = [...currentMembers, ...formerMembers]; + + // 1. Count by Category + const categoryCounts = categories.map(cat => ({ + name: cat, + count: papers.filter(p => p.category === cat).length + })); + + // 2. Member Contributions & Network Extent + const memberContributions = allLabMembers.map(member => { + const lastName = member.name.split(' ').pop().toLowerCase(); + const count = papers.filter(p => { + const authors = p.authors.toLowerCase(); + return authors.includes(lastName); + }).length; + return { name: member.name, count }; + }).filter(m => m.count > 0).sort((a, b) => b.count - a.count); + + // Collaboration Network: Total unique co-authors + const uniqueAuthors = new Set(); + papers.forEach(p => { + const authors = p.authors.split(/ and |; |, /); + authors.forEach(a => { + const trimmed = a.trim(); + if (trimmed && trimmed.length > 2) { + uniqueAuthors.add(trimmed.toLowerCase()); + } + }); + }); + + const legendaryPapers = papers.filter(p => p.isLegendary); + const recentPapers = papers.filter(p => p.isRecent); + + return ( + + {/* STATISTICS_HUD */} +
+
+
+

DASHBOARD_STATS

+
+
+ +
+ {/* Category Breakdown */} + +
+ {categoryCounts.map(cat => ( +
+ [{cat.name}] + {cat.count} +
+ ))} +
+
+ + {/* Group Contribution Level */} + +
+

[ACTIVE_CONTRIBUTORS]

+
+ {memberContributions.map(m => ( +
+ {m.name.split(' ').pop().toUpperCase()} + {m.count} logs +
+ ))} +
+
+
+ + {/* Collaborative Network */} + +
+
+ {uniqueAuthors.size}+ +
+

UNIQUE_CO-AUTHORS

+

+ Our collaborative network spans global institutions, merging expertise across biology, + math, and computer science. +

+
+
+
+
+ + {/* Hall of Fame */} +
+
+
+

HALL_OF_FAME

+
+
+
+ {legendaryPapers.map(paper => ( + + ))} +
+
+ + {/* Recent Quests */} +
+
+
+

LATEST_QUESTS

+
+
+
+ {recentPapers.map(paper => ( + + ))} +
+
+ +
+

+ Our full bibliography spans decades of research in molecular evolution and bioinformatics. +

+ + ACCESS_FULL_MASTER_LOG + +
+
+ ); +} + +function PaperCard({ paper, theme, isLegendarySection }) { + const isLegendary = paper.isLegendary; + const separator = " // "; + + if (theme === '2020s') { + return ( +
+
+ {paper.year}{separator}{paper.category} + {isLegendary && Featured} +
+

{paper.title}

+

{paper.authors}

+
+ {paper.journal} + View DOI +
+
+ ); + } + + if (theme === '2000s') { + return ( +
+
+

+ {paper.year}{separator}{paper.category} +

+ {isLegendary &&
LEGENDARY_STATUS
} +
+
+

{paper.title}

+

{paper.authors}

+
+ {paper.journal} + UPLINK_DOI +
+
+
+ ); + } + + if (theme === '90s') { + return ( +
+
+

+ {paper.year}{separator}{paper.category} +

+
FILE_REF: {paper.id.slice(0,8)}
+
+
+

{paper.title}

+

{paper.authors}

+
+ {paper.journal} + VIEW_DOI +
+
+
+ ); + } + + const borderColor = isLegendarySection ? 'border-retro-amber' : 'border-retro-green'; + const titleColor = isLegendarySection ? 'text-retro-amber' : 'text-retro-fg'; + + return ( +
+ {isLegendarySection && ( +
+ )} + +
+ + [{paper.category}]{separator}{paper.year} + + {paper.stats && ( + + ★ {paper.stats.toUpperCase()} + + )} +
+ +

+ {paper.title} +

+ +
+

+ {paper.authors} +

+

+ {paper.journal.toUpperCase()} +

+ +
+ + DOI_LINK + +
+
+
+ ); +} diff --git a/src/app/projects/page.js b/src/app/projects/page.js new file mode 100644 index 0000000..1ffb14f --- /dev/null +++ b/src/app/projects/page.js @@ -0,0 +1,194 @@ +'use client'; +import Card from '@/components/Card'; +import projects from '@/data/projects.json'; +import PageContainer from '@/components/PageContainer'; +import { useTheme } from '@/components/ThemeContext'; +import Link from 'next/link'; + +export default function ProjectsPage() { + const { theme } = useTheme(); + + return ( + +
+ {projects.map(project => ( +
+ {/* Character Portrait */} +
+
+ {project.image ? ( + {project.name} + ) : ( +
+ [DATA_EMPTY] +
+ )} + {/* Class Badge */} +
+ {project.class} +
+
+ + {/* Visual Stat Bars */} +
+ {Object.entries(project.stats).slice(0, 3).map(([key, val]) => ( +
+
+ {key} + {val} +
+
+
+
+
+ ))} +
+
+ + {/* Data Card */} +
+ +
+ {/* Attributes */} +
+ {Object.entries(project.stats).map(([key, val]) => ( +
+ [{key}] + {val} +
+ ))} +
+ + {/* Description */} +

+ {project.description} +

+ + {/* Special Powers */} +
+

+ SPECIAL_ABILITIES +

+
+ {project.powers.map(power => ( +
+ + {power.name} + + + {power.desc} + +
+ ))} +
+
+ + {/* Action Buttons */} +
+ {Object.entries(project.links).map(([type, url]) => ( + + {type === 'github' ? 'ACCESS_SOURCE' : `DEPLOY_${type.toUpperCase()}`} + + ))} +
+
+
+
+
+ ))} +
+ + {/* Collaborations & Other Projects */} +
+ +
+
+

+ STRATEGIC_COLLABORATIONS +

+
+

+ We are close collaborators with the Galaxy Project. + Many of our tools are integrated into Galaxy's high-performance infrastructure, providing scalable, reproducible analysis for the global research community. +

+
+
+
+

+ ADDITIONAL_PROJECTS +

+
+

+ Our arsenal contains dozens of other utilities, libraries, and pipelines. From + Bcell-Phylo to FLEA, we maintain a vast network + of open-source repositories. +

+ +
+
+
+
+
+ + ); +} diff --git a/src/components/Card.js b/src/components/Card.js new file mode 100644 index 0000000..978d219 --- /dev/null +++ b/src/components/Card.js @@ -0,0 +1,78 @@ +'use client'; +import { useTheme } from './ThemeContext'; + +export default function Card({ title, children, className = "" }) { + const { theme } = useTheme(); + + if (theme === '2010s') { + return ( +
+ {title && ( +
+
+ {title} +
+
+ )} +
+ {children} +
+
+ ); + } + + if (theme === '2000s') { + return ( +
+ {title && ( +
+

+ {title} +

+
+
+ )} +
+ {children} +
+
+
+
+ ); + } + + if (theme === '90s') { + return ( +
+ {title && ( +
+

+ {title} +

+
+
+
+
+
+ )} +
+ {children} +
+
+
+ ); + } + + return ( +
+ {title && ( +

+ {title} +

+ )} +
+ {children} +
+
+ ); +} diff --git a/src/components/EraSelectionSplash.js b/src/components/EraSelectionSplash.js new file mode 100644 index 0000000..1c4b2b6 --- /dev/null +++ b/src/components/EraSelectionSplash.js @@ -0,0 +1,118 @@ +'use client'; +import { useTheme } from './ThemeContext'; + +export default function EraSelectionSplash() { + const { toggleTheme } = useTheme(); + + const eras = [ + { + id: '80s', + label: '1985 Terminal', + desc: 'The Archean Era of computing. Muted 8-bit terminal for early molecular modeling.', + previewClass: 'bg-black border-2 border-retro-green text-retro-green font-heading text-[8px] flex items-center justify-center p-4 text-center' + }, + { + id: '90s', + label: '1998 Tactical', + desc: 'The Cambrian Explosion of data. High-tech bio-surveillance HUD for pathogen tracking.', + previewClass: 'bg-[#0a0f0a] border-2 border-[#2d4c2d] text-[#00ff41] font-mono text-[10px] flex flex-col items-center justify-center p-4' + }, + { + id: '2000s', + label: '2007 Omni-tool', + desc: 'The Genomic Mesozoic. Holographic interfaces for deep phylogenomic exploration.', + previewClass: 'bg-[#050a0f] border-2 border-[#ff9d00]/30 text-[#ff9d00] font-mono text-[10px] flex items-center justify-center p-4 italic font-black shadow-[0_0_15px_rgba(255,157,0,0.2)]' + }, + { + id: '2010s', + label: '2012 Vault Hunter', + desc: 'The Cenozoic of Cloud Computing. Cel-shaded action UI for high-throughput research.', + previewClass: 'bg-[#ffcc00] border-4 border-black text-black font-black uppercase text-[10px] flex items-center justify-center p-4 skew-x-[-5deg]' + }, + { + id: '2020s', + label: '2024 AI Assistant', + desc: 'The Anthropocene of Artificial Intelligence. Modern conversational research environments.', + previewClass: 'bg-[#0f111a] border border-white/10 text-white font-sans text-xs flex items-center justify-start p-4 rounded-xl shadow-xl' + } + ]; + + return ( +
+
+
+ ACME_LAB +
+ +

+ EVOLUTIONARY_EPOCH_STABILIZED +

+ +
+

+ ACME LAB // Computational Molecular Evolution +

+

+ [INITIATING_VISUAL_ONTOLOGY_SELECT] // THE DATA REMAINS CONSTANT, BUT THE INTERFACE EVOLVES. + PLEASE CHOOSE YOUR PREFERRED RESEARCH_EPOCH. +

+
+
+ +
+ {eras.map((era) => ( + + ))} +
+ +
+
+ ACME_LAB // MULTI-ERA_INTERFACE_SYSTEM // v4.0.0_STABLE +
+
+ The ACME Laboratory for Computational Molecular Evolution develops and applies high-performance + statistical models to measure the evolutionary dynamics of measurable pathogens. + Universal methodology across all domains of life. +
+
+
+ ); +} diff --git a/src/components/Navbar.js b/src/components/Navbar.js new file mode 100644 index 0000000..8c68eb3 --- /dev/null +++ b/src/components/Navbar.js @@ -0,0 +1,226 @@ +'use client'; +import Link from 'next/link'; +import { useTheme } from './ThemeContext'; +import { useState } from 'react'; + +function ThemeToggle({ theme, toggleTheme, showDropdown, setShowDropdown }) { + const eras = [ + { id: '80s', label: '1985 Terminal' }, + { id: '90s', label: '1998 Tactical' }, + { id: '2000s', label: '2007 Omni-tool' }, + { id: '2010s', label: '2012 Vault Hunter' }, + { id: '2020s', label: '2024 AI Assistant' } + ]; + + return ( +
+ + {showDropdown && ( +
+ {eras.map(era => ( + + ))} +
+ )} +
+ ); +} + +export default function Navbar() { + const { theme, toggleTheme } = useTheme(); + const [showDropdown, setShowDropdown] = useState(false); + + const navItems = [ + { label: 'PROJECTS', href: '/projects' }, + { label: 'TEAM', href: '/members' }, + { label: 'ALUMNI', href: '/former' }, + { label: 'PAPERS', href: '/papers' }, + ]; + + if (theme === '2020s') { + return ( + + ); + } + + if (theme === '2010s') { + return ( + + ); + } + + if (theme === '2000s') { + return ( + + ); + } + + if (theme === '90s') { + return ( + + ); + } + + return ( + + ); +} diff --git a/src/components/PageContainer.js b/src/components/PageContainer.js new file mode 100644 index 0000000..0be37a1 --- /dev/null +++ b/src/components/PageContainer.js @@ -0,0 +1,79 @@ +'use client'; +import { useTheme } from './ThemeContext'; +import Navbar from './Navbar'; + +export default function PageContainer({ children, title, titleColorClass = "text-retro-amber" }) { + const { theme, mounted } = useTheme(); + + if (!mounted) return
; + + return ( +
+ +
+ {title && ( +
+ {theme === '90s' &&
FILE_TYPE: RESEARCH_LOG
} + {theme === '2000s' &&
CODEX_ENTRY // {title}
} + {theme === '2010s' &&
ACTIVE_QUEST: {title}
} + {theme === '2020s' && ( +
+
+

User Prompt:

+

Show me information about {title.toLowerCase()}.

+
+
+ )} + + {theme !== '2020s' && ( +

+ {title} +

+ )} +
+ )} + + {theme === '2020s' ? ( +
+
+
+
+
AI
+ Assistant Response +
+ {children} +
+
+ ) : children} +
+ +
+

© 2026 ACME_LAB // RE-DESIGNED FOR THE_NEXT_DECADE

+

+ INSTITUTE_FOR_GENOMICS_AND_EVOLUTIONARY_MEDICINE // TEMPLE_UNIVERSITY +

+
+
+ ); +} diff --git a/src/components/ThemeContext.js b/src/components/ThemeContext.js new file mode 100644 index 0000000..5664b0d --- /dev/null +++ b/src/components/ThemeContext.js @@ -0,0 +1,66 @@ +'use client'; +import { createContext, useContext, useState, useEffect, useMemo } from 'react'; + +const ThemeContext = createContext(); + +export function ThemeProvider({ children }) { + const [state, setState] = useState({ + theme: '80s', + mounted: false, + hasSelectedTheme: false + }); + + useEffect(() => { + const savedTheme = localStorage.getItem('labsite-theme'); + // eslint-disable-next-line react-hooks/set-state-in-effect + setState({ + theme: savedTheme || '80s', + mounted: true, + hasSelectedTheme: !!savedTheme + }); + }, []); + + useEffect(() => { + if (!state.mounted) return; + + const root = document.documentElement; + root.setAttribute('data-theme', state.theme); + localStorage.setItem('labsite-theme', state.theme); + + document.body.classList.remove('theme-80s', 'theme-90s', 'theme-2000s', 'theme-2010s', 'theme-2020s', 'crt'); + document.body.classList.add(`theme-${state.theme}`); + + if (state.theme === '80s' && state.hasSelectedTheme) { + document.body.classList.add('crt'); + } + }, [state.theme, state.mounted, state.hasSelectedTheme]); + + const toggleTheme = (newTheme) => { + setState(prev => ({ + ...prev, + theme: newTheme, + hasSelectedTheme: true + })); + }; + + const value = useMemo(() => ({ + theme: state.theme, + toggleTheme, + mounted: state.mounted, + hasSelectedTheme: state.hasSelectedTheme + }), [state.theme, state.mounted, state.hasSelectedTheme]); + + return ( + + {children} + + ); +} + +export const useTheme = () => { + const context = useContext(ThemeContext); + if (!context) { + throw new Error('useTheme must be used within a ThemeProvider'); + } + return context; +}; diff --git a/src/data/former.json b/src/data/former.json new file mode 100644 index 0000000..c2248fa --- /dev/null +++ b/src/data/former.json @@ -0,0 +1,83 @@ +[ + { + "id": "avery", + "name": "Avery Selberg", + "title": "PhD Student", + "years": "2021-2025", + "next": "Postdoctoral Researcher, UPenn (Mathieson Lab)", + "links": { + "github": "https://github.com/agselberg", + "googlescholar": "https://scholar.google.com/citations?user=OhvxIl8AAAAJ&hl=en" + } + }, + { + "id": "jordan", + "name": "Jordan Zehr", + "title": "PhD Student", + "years": "2018-2023", + "next": "Postdoctoral Associate, Cornell (Baker Institute)", + "links": { + "website": "http://phdbioinform.cst.temple.edu/people/students" + } + }, + { + "id": "alex", + "name": "Alexander Lucaci", + "title": "PhD Student", + "years": "2019-2023", + "next": "Postdoctoral Associate, Weill Cornell (Mason Lab)", + "links": { + "website": "https://aglucaci.github.io" + } + }, + { + "id": "sadie", + "name": "Sadie Wisotsky", + "title": "Postdoctoral Researcher", + "years": "2018-2020", + "next": "Scientist, INOVIO Pharmaceuticals", + "links": { + "github": "https://github.com/srwis", + "linkedin": "https://linkedin.com/in/sadie-wisotsky" + } + }, + { + "id": "stella", + "name": "Stella Park", + "title": "PhD Student", + "years": "2018-2020", + "next": "Lab Manager, UPenn (Huang Lab)", + "links": {} + }, + { + "id": "brittany", + "name": "Brittany Rife Magalis", + "title": "Postdoctoral Researcher", + "years": "2017-2019", + "next": "Assistant Professor, University of Louisville", + "links": { + "googlescholar": "https://scholar.google.com/citations?user=0FrSeQgAAAAJ&hl=en" + } + }, + { + "id": "stephanie", + "name": "Stephanie Spielman", + "title": "Postdoctoral Researcher", + "years": "2016-2018", + "next": "Data Scientist, Childhood Cancer Data Lab", + "links": { + "website": "http://sjspielman.org", + "github": "https://github.com/sjspielman" + } + }, + { + "id": "kemal", + "name": "Kemal Eren", + "title": "Graduate Student", + "years": "2013-2017", + "next": "Computer Vision Research Engineer, Ancera", + "links": { + "website": "http://www.kemaleren.com" + } + } +] diff --git a/src/data/members.json b/src/data/members.json new file mode 100644 index 0000000..31fe248 --- /dev/null +++ b/src/data/members.json @@ -0,0 +1,85 @@ +[ + { + "id": "sergei", + "name": "Sergei Pond", + "title": "Principal Investigator", + "image": "/images/members/pixelated/Sergei.jpg", + "bio": "Professor of Biology at Temple University, Associate Dean for Research and Innovation.", + "links": { + "twitter": "https://twitter.com/sergeilkp", + "github": "https://github.com/spond", + "linkedin": "https://www.linkedin.com/in/sergei-kosakovsky-pond-8a429/", + "googlescholar": "https://scholar.google.com/citations?user=SP6nj-QAAAAJ&hl=en" + } + }, + { + "id": "steven", + "name": "Steven Weaver", + "title": "Senior Programming Analyst", + "image": "/images/members/pixelated/Steven.jpg", + "bio": "Expert in bioinformatics software development and high-performance computing.", + "links": { + "twitter": "https://twitter.com/stvnwvr?lang=en", + "github": "https://github.com/stevenweaver", + "linkedin": "https://www.linkedin.com/in/steven-weaver-6308a59/", + "googlescholar": "https://scholar.google.com/citations?user=A2ImcaUAAAAJ&hl=en&authuser=1" + } + }, + { + "id": "danielle", + "name": "Danielle Callan", + "title": "Developer", + "image": null, + "bio": "Bioinformatics software developer focusing on lab tools and infrastructure.", + "links": { + "github": "https://github.com/d-callan" + } + }, + { + "id": "hanna-v", + "name": "Hanna Verdonk", + "title": "Postdoctoral Researcher", + "image": "/images/members/HV.jpg", + "bio": "Specializing in molecular evolution and codon substitution models.", + "links": { + "twitter": "https://twitter.com/hannahverdonk", + "github": "https://github.com/hverdonk", + "linkedin": "https://www.linkedin.com/in/hannahverdonk/", + "googlescholar": "https://scholar.google.com/citations?user=Wob8Un8AAAAJ&hl=en&oi=ao" + } + }, + { + "id": "hanna-k", + "name": "Hannah Kim", + "title": "PhD Candidate", + "image": "/images/members/Hannah.jpeg", + "bio": "Working on viral evolution and bioinformatics methods at iGEM.", + "links": { + "twitter": "https://twitter.com/hannahincompbio", + "github": "https://github.com/hannahkimincompbio", + "linkedin": "https://www.linkedin.com/in/hannahkimincompbio/", + "website": "https://hannahkimincompbio.github.io/", + "googlescholar": "https://scholar.google.com/citations?user=JUPwQRYAAAAJ&hl=en" + } + }, + { + "id": "gigi", + "name": "Gigi Brown", + "title": "PhD Student", + "image": null, + "bio": "Bioinformatics PhD student at Temple University.", + "links": { + "website": "https://igem.temple.edu/people/students" + } + }, + { + "id": "daria", + "name": "Daria Chalkova", + "title": "PhD Student", + "image": null, + "bio": "Bioinformatics PhD student at Temple University.", + "links": { + "website": "https://igem.temple.edu/people/students" + } + } +] diff --git a/src/data/papers.json b/src/data/papers.json new file mode 100644 index 0000000..4c22909 --- /dev/null +++ b/src/data/papers.json @@ -0,0 +1,2734 @@ +[ + { + "id": "Selberg:2026aa", + "year": 2026, + "authors": "Selberg, Avery G and Clark, Nathan and Nekrutenko, Anton and Chikina, Maria and Kosakovsky Pond, Sergei L", + "title": "MoleRate: comparing molecular relative evolutionary rates to detect convergent evolution", + "journal": "Evolution", + "doi": "", + "abstract": "In comparative evolutionary genomics, faster or slower evolution of a particular gene, site, or branch in a phylogenetic tree, when compared to the appropriate average, has been interpreted as evidence of conservation, functional importance, or adaptation. With large consortia generating hundreds of genomes, there is an opportunity to interrogate these datasets for evidence of accelerated or reduced evolutionary rates in protein-coding genes associated with the presence or absence of a given phenotype (e.g., marine vs. terrestrial, nocturnal vs. diurnal). Such rate shifts can reflect the molecular basis of convergent phenotypic adaptation when they occur repeatedly across independent lineages. Here, we introduce an explicit phylogenetic rate test, MoleRate, for acceleration or reduction of nucleotide or protein evolutionary rates in focal lineages vs. the rest of the phylogeny. Compared to existing methods, MoleRate offers execution, explicit likelihood-based hypothesis testing, and the ability to detect and filter out potentially aberrant signal from single lineages. We demonstrate MoleRate's performance on simulated and empirical data, and apply it to several mammalian phenotypes. We also highlight its visualization capabilities, which enable exploration and communication of results. These analyses show that MoleRate detects biologically significant enrichments in selective pressure on specific functions related to the given phenotype, and that enrichments in selective pressure related to the given phenotype, absent when random lineages are tested.", + "category": "ADAPTATION", + "isRecent": true, + "isLegendary": false + }, + { + "id": "Havens:2026aa", + "year": 2026, + "authors": "Havens, Jennifer L and Kosakovsky Pond, Sergei L and Zehr, Jordan D and Pekar, Jonathan E and Parker, Edyth and Worobey, Michael and Andersen, Kristian G and Wertheim, Joel O", + "title": "Dynamics of natural selection preceding human viral epidemics and pandemics", + "journal": "Cell", + "doi": "", + "abstract": "Using a phylogenetic framework to characterize natural selection, we investigate the hypothesis that zoonotic viruses require adaptation prior to zoonosis to sustain human-to-human transmission. Examining the zoonotic emergence of Ebola virus, Marburg virus, mpox virus, influenza A virus, and SARS-CoV-2, we find no evidence of a change in selection intensity immediately prior to outbreaks in humans compared with typical selection within reservoir hosts. We found a change in selection on SARS-CoV in an intermediate host. We conclude that extensive pre-zoonotic adaptation is not necessary for human-to-human transmission of zoonotic viruses. In contrast, the reemergence of H1N1 influenza A virus in 1977 was preceded by a shift in selection intensity, consistent with the hypothesis of passage in a laboratory setting. Holistic phylogenetic analysis of selection regimes can be used to detect evolutionary signals of host switching or laboratory passage, providing insight into the circumstances of past and future viral emergence.", + "category": "SURVEILLANCE", + "isRecent": true, + "isLegendary": false + }, + { + "id": "Melendez-Vazquez:2025aa", + "year": 2025, + "authors": "Melendez-Vazquez, Fernando and Lucaci, Alexander G and Selberg, Avery and Clavel, Julien and Rincon-Sandoval, Melissa and Santaquiteria, Aintzane and White, William T and Drabeck, Danielle and Carnevale, Giorgio and Duarte-Ribeiro, Emanuell and Miya, Masaki and Westneat, Mark W and Baldwin, Carole C and Hughes, Lily C and Ort{\\'\\i}, Guillermo and Kosakovsky Pond, Sergei L and Betancur-R, Ricardo and Arcila, Dahiana", + "title": "Ecological interactions and genomic innovation fueled the evolution of ray-finned fish endothermy", + "journal": "Sci Adv", + "doi": "", + "abstract": "Endothermy has independently evolved in several vertebrate lineages but remains rare among fishes. Using an integrated approach combining phylogenomic and ecomorphological data for 1051 ray-finned fishes, a time-dependent evolutionary model, and comparative genomic analyses of 205 marine vertebrates, we show that ecological interactions with modern cetaceans coincided with the evolution of endothermy in ray-finned fishes during the Eocene-Miocene. This result is supported by evidence of temporal and geographical overlap between cetaceans and endothermic fish lineages in the fossil record, as well as correlations between cetacean diversification and the origin of endothermy in fishes. Phylogenetic comparative analyses identified correlations between endothermy, large body sizes, and specialized swimming modes while challenging diet specialization and depth range expansion hypotheses. Comparative genomic analyses identified several genes under selection in endothermic lineages, including carnmt1 (involved in fatty acid metabolism) and dcaf6 (associated with development). Our findings advance the understanding of how ecological interactions and genomic factors shape key adaptations.", + "category": "ADAPTATION", + "isRecent": true, + "isLegendary": false + }, + { + "id": "Selberg:2025aa", + "year": 2025, + "authors": "Selberg, Avery and Clark, Nathan L and Sackton, Timothy B and Muse, Spencer V and Lucaci, Alexander G and Weaver, Steven and Nekrutenko, Anton and Chikina, Maria and Pond, Sergei L Kosakovsky", + "title": "Minus the Error: Testing for Positive Selection in the Presence of Residual Alignment Errors", + "journal": "bioRxiv", + "doi": "", + "abstract": "Positive selection is an evolutionary process which increases the frequency of advantageous mutations because they confer a fitness benefit. Inferring the past action of positive selection on protein-coding sequences is fundamental for deciphering phenotypic diversity and the emergence of novel traits. With the advent of genome-wide comparative genomic datasets, researchers can analyze selection not only at the level of individual genes but also globally, delivering systems-level insights into evolutionary dynamics. However, genome-scale datasets are generated with automated pipelines and imperfect curation that does not eliminate all sequencing, annotation, and alignment errors. Positive selection inference methods are highly sensitive to such errors. We present BUSTED-E: a method designed to detect positive selection for amino acid diversification while concurrently identifying some alignment errors. This method builds on the flexible branch-site random effects model (BUSTED) for fitting distributions of dN/dS, with a critical modification: it incorporates an \"error-sink\" component to represent an abiological evolutionary regime. Using several genome-scale biological datasets that were extensively filtered using state-of-the art automated alignment tools, we show that BUSTED-E identifies pervasive residual alignment errors, produces more realistic estimates of positive selection, reduces bias, and improves biological interpretation. The BUSTED-E model promises to be a more stringent filter to identify positive selection in genome-wide contexts, thus enabling further characterization and validation of the most biologically relevant cases.", + "category": "ADAPTATION", + "isRecent": true, + "isLegendary": false + }, + { + "id": "Makova:2024aa", + "year": 2024, + "authors": "Makova, Kateryna D and Pickett, Brandon D and Harris, Robert S and Hartley, Gabrielle A and Cechova, Monika and Pal, Karol and Nurk, Sergey and Yoo, DongAhn and Li, Qiuhui and Hebbar, Prajna and McGrath, Barbara C and Antonacci, Francesca and Aubel, Margaux and Biddanda, Arjun and Borchers, Matthew and Bornberg-Bauer, Erich and Bouffard, Gerard G and Brooks, Shelise Y and Carbone, Lucia and Carrel, Laura and Carroll, Andrew and Chang, Pi-Chuan and Chin, Chen-Shan and Cook, Daniel E and Craig, Sarah J C and de Gennaro, Luciana and Diekhans, Mark and Dutra, Amalia and Garcia, Gage H and Grady, Patrick G S and Green, Richard E and Haddad, Diana and Hallast, Pille and Harvey, William T and Hickey, Glenn and Hillis, David A and Hoyt, Savannah J and Jeong, Hyeonsoo and Kamali, Kaivan and Pond, Sergei L Kosakovsky and LaPolice, Troy M and Lee, Charles and Lewis, Alexandra P and Loh, Yong-Hwee E and Masterson, Patrick and McGarvey, Kelly M and McCoy, Rajiv C and Medvedev, Paul and Miga, Karen H and Munson, Katherine M and Pak, Evgenia and Paten, Benedict and Pinto, Brendan J and Potapova, Tamara and Rhie, Arang and Rocha, Joana L and Ryabov, Fedor and Ryder, Oliver A and Sacco, Samuel and Shafin, Kishwar and Shepelev, Valery A and Slon, Viviane and Solar, Steven J and Storer, Jessica M and Sudmant, Peter H and Sweetalana and Sweeten, Alex and Tassia, Michael G and Thibaud-Nissen, Fran{\\c c}oise and Ventura, Mario and Wilson, Melissa A and Young, Alice C and Zeng, Huiqing and Zhang, Xinru and Szpiech, Zachary A and Huber, Christian D and Gerton, Jennifer L and Yi, Soojin V and Schatz, Michael C and Alexandrov, Ivan A and Koren, Sergey and O'Neill, Rachel J and Eichler, Evan E and Phillippy, Adam M", + "title": "The complete sequence and comparative analysis of ape sex chromosomes", + "journal": "Nature", + "doi": "", + "abstract": "Apes possess two sex chromosomes-the male-specific Y chromosome and the X chromosome, which is present in both males and females. The Y chromosome is crucial for male reproduction, with deletions being linked to infertility1. The X chromosome is vital for reproduction and cognition2. Variation in mating patterns and brain function among apes suggests corresponding differences in their sex chromosomes. However, owing to their repetitive nature and incomplete reference assemblies, ape sex chromosomes have been challenging to study. Here, using the methodology developed for the telomere-to-telomere (T2T) human genome, we produced gapless assemblies of the X and Y chromosomes for five great apes (bonobo (Pan paniscus), chimpanzee (Pan troglodytes), western lowland gorilla (Gorilla gorilla gorilla), Bornean orangutan (Pongo pygmaeus) and Sumatran orangutan (Pongo abelii)) and a lesser ape (the siamang gibbon (Symphalangus syndactylus)), and untangled the intricacies of their evolution. Compared with the X chromosomes, the ape Y chromosomes vary greatly in size and have low alignability and high levels of structural rearrangements-owing to the accumulation of lineage-specific ampliconic regions, palindromes, transposable elements and satellites. Many Y chromosome genes expand in multi-copy families and some evolve under purifying selection. Thus, the Y chromosome exhibits dynamic evolution, whereas the X chromosome is more stable. Mapping short-read sequencing data to these assemblies revealed diversity and selection patterns on sex chromosomes of more than 100 individual great apes. These reference assemblies are expected to inform human evolution and conservation genetics of non-human apes, all of which are endangered species.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Council:2025aa", + "year": 2025, + "authors": "Council, Olivia D and Tyers, Lynn and Moeser, Matthew and Sondgeroth, Amy and Spielvogel, Ean and Richardson, Brian D and Doolabh, Deelan and Zhou, Shuntai and Emery, Ann and Archin, Nancie M and Shook-Sa, Bonnie and Margolis, David M and Abdool Karim, Salim S and Kosakovsky Pond, Sergei and Garrett, Nigel and Abrahams, Melissa-Rose and Joseph, Sarah B and Williamson, Carolyn and Swanstrom, Ronald", + "title": "The persistent pool of HIV-1-infected cells is formed episodically during untreated infection", + "journal": "J Virol", + "doi": "", + "abstract": "Previous studies have shown that the majority of long-lived cells harboring persistent HIV-1 proviral genomes originates from viruses circulating in the year prior to antiretroviral therapy (ART) initiation, but a smaller proportion originates from viruses circulating much earlier in untreated infection. These observations suggest that discrete biological factors influence the entry and persistence of viruses into the persistent proviral pool, and there may be periods earlier in untreated infection with increased seeding. Therefore, we examined the timing of formation of the long-lived pool of infected cells that persists during ART in seven women (after a median of 5.1 years of suppressive ART) by comparing the phylogenetic distance between unique 3' half genome on-ART proviral sequences and longitudinally sampled pre-ART viral RNA sequences, focusing on the period >1 year prior to ART initiation (i.e., the \"early\" proviral pool). We constructed models of continuous entry into the persistent proviral pool prior to ART initiation and analyzed the fit of our experimentally derived data to these models. We found that the pattern of persistent proviral pool formation in five of seven participants is incongruent with a model of continuous entry, implying that persistent proviral pool formation can occur episodically during untreated infection. Notably, increased entry into the persistent proviral pool was not universally observed during acute infection, and the timing of enhanced early entry differed across the participants.IMPORTANCECells harboring HIV-1 proviruses that persist on antiretroviral therapy (ART) constitute the main barrier to an HIV-1 cure. Recent work has elucidated that the majority of persisting proviruses harbor HIV-1 variants circulating near the time of ART initiation, whether the proviruses are intact or defective, though a portion forms earlier in untreated infection. We examined the formation of the \"early-forming\" persistent proviral pool and found that in 5/7 participants, persistent proviral pool formation was episodic, rather than continuous, suggesting that there are host/biological factors that periodically enhance the formation of the persistent proviral pool. Further characterization of these factors will aid in the development of methods to abrogate their effect, thereby reducing the size of the persistent proviral pool.", + "category": "VIRAL_DYNAMICS", + "isRecent": true, + "isLegendary": false + }, + { + "id": "Tyers:2025aa", + "year": 2025, + "authors": "Tyers, Lynn and Moeser, Matthew and Ntuli, Jean and Council, Olivia and Zhou, Shuntai and Spielvogel, Ean and Sondgeroth, Amy and Adams, Craig and Thebus, Ruwayhida and Yssel, Anna and Karim, Salim Abdool and Garrett, Nigel and Pond, Sergei Kosakovsky and Williamson, Carolyn and Swanstrom, Ronald and Abrahams, Melissa-Rose and Joseph, Sarah B", + "title": "HIV-1 Rebound Virus Consists of a Small Number of Lineages That Entered the Reservoir Close to ART Initiation", + "journal": "bioRxiv", + "doi": "", + "abstract": "HIV-1 persists as a latent reservoir during suppressive antiretroviral therapy (ART). Viral rebound occurs upon ART interruption, posing a challenge to cure efforts. Characterizing viral populations fuelling rebound is imperative to curing HIV-1. We used longitudinal samples collected pretherapy from women in the CAPRISA 002 cohort to create an evolutionary timeline to determine the pretherapy timepoint when the rebound virus originally entered the long-lived reservoir. Participants (N=10) were untreated for an average of 5 years then on ART for an average of 2 years before viral rebound (defined as >1000 RNA copies/ml). env sequences were used to characterize the longitudinal pre-ART evolving viral RNA population, the proviral DNA reservoir during ART, and viral RNA in the plasma during rebound. For each participant, between 1 and 3 major viral lineages were identified in the plasma during rebound. A total of 20 rebound virus lineages were examined for the 10 participants, and 19 were found to have entered the reservoir around the time of therapy initiation. The one lineage estimated to enter the reservoir more than a year before therapy was observed in a participant who was untreated for more than 8 years, yet retained moderate CD4 T cell counts. Analysis of the viral DNA reservoir, from which the rebound viruses emanated, revealed that while 95% of rebounding lineages dated to the year before ART initiation, only 61% of unique proviruses dated to that time period. Strikingly, for three participants with DNA reservoirs dominated by viruses from earlier in untreated infection, only 33% of unique proviruses dated to the year before ART initiation, yet 83% of rebounding lineages dated to that time. Our results show that rebound virus almost exclusively comes from the portion of the latent reservoir that formed around the time of therapy initiation, even when the reservoir is composed of diverse sequences from across the pre-ART time period.", + "category": "VIRAL_DYNAMICS", + "isRecent": true, + "isLegendary": false + }, + { + "id": "Verdonk:2025aa", + "year": 2025, + "authors": "Verdonk, Hannah and Pivirotto, Alyssa and Pavinato, Vitor and Hey, Jody and Pond, Sergei L K", + "title": "A New Comparative Framework for Estimating Selection on Synonymous Substitutions", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Selection on synonymous codon usage is a well-known and widespread phenomenon, yet existing models often do not account for it or its effect on synonymous substitution rates. In this article, we develop and expand the capabilities of multiclass synonymous substitution (MSS) models, which account for such selection by partitioning synonymous substitutions into 2 or more classes and estimating a relative substitution rate for each class, while accounting for important confounders like mutation bias. We identify extensive heterogeneity among relative synonymous substitution rates in an empirical dataset of \u223c12,000 gene alignments from 12 Drosophila species. We validate model performance using data simulated under a forward population genetic simulation, demonstrating that MSS models are robust to model misspecification. MSS rates are significantly correlated with other covariates of selection on codon usage (population-level polymorphism data and tRNA abundance data), suggesting that models can detect weak signatures of selection on codon usage. With the MSS model, we can now study selection on synonymous substitutions in diverse taxa, independent of any a priori assumptions about the forces driving that selection.", + "category": "ADAPTATION", + "isRecent": true, + "isLegendary": false + }, + { + "id": "France:2025aa", + "year": 2025, + "authors": "France, Anne Marie and Hallmark, Camden J and Panneer, Nivedha and Billock, Rachael and Russell, Olivia O and Plaster, Mary and Alberti, Jessica and Nuthan, Fathima and Saduvala, Neeraja and Philpott, David and Ocfemia, M Cheryl Ba{\\~n}ez and Cope, Scott and Hernandez, Angela L and Pond, Sergei L Kosakovsky and Wertheim, Joel O and Weaver, Steven and Khader, Saja and Johnson, Kevin and Oster, Alexandra M", + "title": "Nationwide Implementation of HIV Molecular Cluster Detection by Centers for Disease Control and Prevention and State and Local Health Departments, United States", + "journal": "Emerg Infect Dis", + "doi": "", + "abstract": "Detecting and responding to clusters of rapid HIV transmission is a core HIV prevention strategy in the United States, guiding public health interventions and identifying gaps in prevention and care services. In 2016, the Centers for Disease Control and Prevention (CDC) initiated molecular cluster detection using data from 27 jurisdictions. During 2016-2023, CDC expanded sequence reporting nationwide and deployed Secure HIV-TRACE, an application supporting health department (HD) molecular cluster detection. CDC conducts molecular cluster detection quarterly; state and local HDs analyze local data monthly. HDs began routinely reporting clusters to CDC by using cluster report forms in 2020. During 2018-2023, CDC identified 404 molecular clusters of rapid HIV transmission; 325 (80%) involved multiple jurisdictions. During 2020-2023, HDs reported 298 molecular clusters to CDC; 249 were first detected by HDs. Expanding molecular cluster detection has provided a foundation for improving service delivery to networks experiencing rapid HIV transmission.", + "category": "SURVEILLANCE", + "isRecent": true, + "isLegendary": false + }, + { + "id": "Rincon-Sandoval:2024aa", + "year": 2024, + "authors": "Rincon-Sandoval, Melissa and De-Kayne, Rishi and Shank, Stephen D and Pirro, Stacy and Ko'ou, Alfred and Abueg, Linelle and Tracey, Alan and Mountcastle, Jackie and O'Toole, Brian and Balacco, Jennifer and Formenti, Giulio and Jarvis, Erich D and Arcila, Dahiana and Kosakovsky Pond, Sergei L and Davis, Aaron and Bloom, Devin D and Betancur-R, Ricardo", + "title": "Ecological diversification of sea catfishes is accompanied by genome-wide signatures of positive selection", + "journal": "Nat Commun", + "doi": "", + "abstract": "Habitat transitions have shaped the evolutionary trajectory of many clades. Sea catfishes (Ariidae) have repeatedly undergone ecological transitions, including colonizing freshwaters from marine environments, leading to an adaptive radiation in Australia and New Guinea alongside non-radiating freshwater lineages elsewhere. Here, we generate and analyze one long-read reference genome and 66 short-read whole genome assemblies, in conjunction with genomic data for 54 additional species. We investigate how three major ecological transitions have shaped genomic variation among ariids over their\u2009~\u200950\u2009million-year evolutionary history. Our results show that relatively younger freshwater lineages exhibit a higher incidence of positive selection than their more ancient marine counterparts. They also display a larger disparity in body shapes, a trend that correlates with a heightened occurrence of positive selection on genes associated with body size and elongation. Although positive selection in the Australia and New Guinea radiation does not stand out compared to non-radiating lineages overall, selection across the prolactin gene family during the marine-to-freshwater transition suggests that strong osmoregulatory adaptations may have facilitated their colonization and radiation. Our findings underscore the significant role of selection in shaping the genome and organismal traits in response to habitat shifts across macroevolutionary scales.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Zarate:2024aa", + "year": 2024, + "authors": "Zarate, Selene and Bertram, Miranda and Rodgers, Case and Reed, Kirsten and Pelzel-McCluskey, Angela and Gomez-Romero, Ninnet and Rodriguez, Luis L and Mayo, Christie and Mire, Chad and Pond, Sergei L Kosakovsky and Velazquez-Salinas, Lauro", + "title": "Phylogenomic Signatures of a Lineage of Vesicular Stomatitis Indiana Virus Circulating During the 2019-2020 Epidemic in the United States", + "journal": "Viruses", + "doi": "", + "abstract": "For the first time, we describe phylogenomic signatures of an epidemic lineage of vesicular stomatitis Indiana virus (VSIV). We applied multiple evolutionary analyses to a dataset of 87 full-length genome sequences representing the circulation of an epidemic VSIV lineage in the US between 2019 and 2020. Based on phylogenetic analyses, we predicted the ancestral relationship of this lineage with a specific group of isolates circulating in the endemic zone of Chiapas, Mexico. Subsequently, our findings indicate that the lineage diversified into at least four different subpopulations during its circulation in the US. We identified single nucleotide polymorphisms (SNPs) that differentiate viral subpopulations and assessed their potential relevance using comparative phylogenetic methods, highlighting the preponderance of synonymous mutations during the differentiation of these populations. Purifying selection was the main evolutionary force favoring the conservation of this epidemic phenotype, with P and G genes as the main drivers of the evolution of this lineage. Our analyses identified multiple codon sites under positive selection and the association of these sites with specific functional domains at P, M, G, and L proteins. Based on ancestral reconstruction analyses, we showed the potential relevance of some of the sites identified under positive selection to the adaptation of the epidemic lineage at the population level. Finally, using a representative group of viruses from Colorado, we established a positive correlation between genetic and geographical distances, suggesting that positive selection on specific codon positions might have favored the adaptation of different subpopulations to circulation in specific geographical settings. Collectively, our study reveals the complex dynamics that accompany the evolution of an epidemic lineage of VSIV in nature. Our analytical framework provides a model for conducting future evolutionary analyses. The ultimate goal is to support the implementation of an early warning system for vesicular stomatitis virus in the US, enabling early detection of epidemic precursors from Mexico.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Lucaci:2024aa", + "year": 2024, + "authors": "Lucaci, Alexander G and Brew, William E and Lamanna, Jason and Selberg, Avery and Carnevale, Vincenzo and Moore, Anna R and Kosakovsky Pond, Sergei L", + "title": "The evolution of mammalian Rem2: unraveling the impact of purifying selection and coevolution on protein function, and implications for human disorders", + "journal": "Front Bioinform", + "doi": "", + "abstract": "Rad And Gem-Like GTP-Binding Protein 2 (Rem2), a member of the RGK family of Ras-like GTPases, is implicated in Huntington's disease and Long QT Syndrome and is highly expressed in the brain and endocrine cells. We examine the evolutionary history of Rem2 identified in various mammalian species, focusing on the role of purifying selection and coevolution in shaping its sequence and protein structural constraints. Our analysis of Rem2 sequences across 175 mammalian species found evidence for strong purifying selection in 70% of non-invariant codon sites which is characteristic of essential proteins that play critical roles in biological processes and is consistent with Rem2's role in the regulation of neuronal development and function. We inferred epistatic effects in 50 pairs of codon sites in Rem2, some of which are predicted to have deleterious effects on human health. Additionally, we reconstructed the ancestral evolutionary history of mammalian Rem2 using protein structure prediction of extinct and extant sequences which revealed the dynamics of how substitutions that change the gene sequence of Rem2 can impact protein structure in variable regions while maintaining core functional mechanisms. By understanding the selective pressures, protein- and gene - interactions that have shaped the sequence and structure of the Rem2 protein, we gain a stronger understanding of its biological and functional constraints.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Weaver:2024aa", + "year": 2024, + "authors": "Weaver, Steven and D{\\'a}vila Conn, Vanessa M and Ji, Daniel and Verdonk, Hannah and {\\'A}vila-R{\\'\\i}os, Santiago and Leigh Brown, Andrew J and Wertheim, Joel O and Kosakovsky Pond, Sergei L", + "title": "AUTO-TUNE: selecting the distance threshold for inferring HIV transmission clusters", + "journal": "Front Bioinform", + "doi": "", + "abstract": "Molecular surveillance of viral pathogens and inference of transmission networks from genomic data play an increasingly important role in public health efforts, especially for HIV-1. For many methods, the genetic distance threshold used to connect sequences in the transmission network is a key parameter informing the properties of inferred networks. Using a distance threshold that is too high can result in a network with many spurious links, making it difficult to interpret. Conversely, a distance threshold that is too low can result in a network with too few links, which may not capture key insights into clusters of public health concern. Published research using the HIV-TRACE software package frequently uses the default threshold of 0.015 substitutions/site for HIV pol gene sequences, but in many cases, investigators heuristically select other threshold parameters to better capture the underlying dynamics of the epidemic they are studying. Here, we present a general heuristic scoring approach for tuning a distance threshold adaptively, which seeks to prevent the formation of giant clusters. We prioritize the ratio of the sizes of the largest and the second largest cluster, maximizing the number of clusters present in the network. We apply our scoring heuristic to outbreaks with different characteristics, such as regional or temporal variability, and demonstrate the utility of using the scoring mechanism's suggested distance threshold to identify clusters exhibiting risk factors that would have otherwise been more difficult to identify. For example, while we found that a 0.015 substitutions/site distance threshold is typical for US-like epidemics, recent outbreaks like the CRF07_BC subtype among men who have sex with men (MSM) in China have been found to have a lower optimal threshold of 0.005 to better capture the transition from injected drug use (IDU) to MSM as the primary risk factor. Alternatively, in communities surrounding Lake Victoria in Uganda, where there has been sustained heterosexual transmission for many years, we found that a larger distance threshold is necessary to capture a more risk factor-diverse population with sparse sampling over a longer period of time. Such identification may allow for more informed intervention action by respective public health officials.", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Zehr:2024aa", + "year": 2024, + "authors": "Zehr, Jordan D and Kosakovsky Pond, Sergei L and Shank, Stephen D and McQueary, Holly and Grenier, Jennifer K and Whittaker, Gary R and Stanhope, Michael J and Goodman, Laura B", + "title": "Positive selection, genetic recombination, and intra-host evolution in novel equine coronavirus genomes and other members of the Embecovirus subgenus", + "journal": "Microbiol Spectr", + "doi": "", + "abstract": "There are several examples of coronaviruses in the Betacoronavirus subgenus Embecovirus that have jumped from an animal to the human host. Studying how evolutionary factors shape coronaviruses in non-human hosts may provide insight into the coronavirus host-switching potential. Equids, such as horses and donkeys, are susceptible to equine coronaviruses (ECoVs). With increased testing prevalence, several ECoV genome sequences have become available for molecular evolutionary analyses, especially those from the United States of America (USA). To date, no analyses have been performed to characterize evolution within coding regions of the ECoV genome. Here, we obtain and describe four new ECoV genome sequences from infected equines from across the USA presenting clinical symptoms of ECoV, and infer ECoV-specific and Embecovirus-wide patterns of molecular evolution. Within two of the four data sets analyzed, we find evidence of intra-host evolution within the nucleocapsid (N) gene, suggestive of quasispecies development. We also identify 12 putative genetic recombination events within the ECoV genome, 11 of which fall in ORF1ab. Finally, we infer and compare sites subject to positive selection on the ancestral branch of each major Embecovirus member clade. Specifically, for the two currently identified human coronavirus (HCoV) embecoviruses that have spilled from animals to humans (HCoV-OC43 and HCoV-HKU1), we find that there are 42 and 2 such sites, respectively, perhaps reflective of the more complex ancestral evolutionary history of HCoV-OC43, which involves several different animal hosts.IMPORTANCEThe Betacoronavirus subgenus Embecovirus contains coronaviruses that not only pose a health threat to animals and humans, but also have jumped from animal to human host. Equids, such as horses and donkeys are susceptible to equine coronavirus (ECoV) infections. No studies have systematically examined evolutionary patterns within ECoV genomes. Our study addresses this gap and provides insight into intra-host ECoV evolution from infected horses. Further, we identify and report natural selection pattern differences between two embecoviruses that have jumped from animals to humans [human coronavirus OC43 and HKU1 (HCoV-OC43 and HCoV-HKU1, respectively)], and hypothesize that the differences observed may be due to the different animal host(s) that each virus circulated in prior to its jump into humans. Finally, we contribute four novel, high-quality ECoV genomes to the scientific community.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Inzaule:2023aa", + "year": 2023, + "authors": "Inzaule, Seth C and Siedner, Mark J and Little, Susan J and Avila-Rios, Santiago and Ayitewala, Alisen and Bosch, Ronald J and Calvez, Vincent and Ceccherini-Silberstein, Francesca and Charpentier, Charlotte and Descamps, Diane and Eshleman, Susan H and Fokam, Joseph and Frenkel, Lisa M and Gupta, Ravindra K and Ioannidis, John P A and Kaleebu, Pontiano and Kantor, Rami and Kassaye, Seble G and Pond, Sergei L Kosakovsky and Kouamou, Vinie and Kouyos, Roger D and Kuritzkes, Daniel R and Lessells, Richard and Marcelin, Anne-Genevieve and Mbuagbaw, Lawrence and Minalga, Brian and Ndembi, Nicaise and Neher, Richard A and Paredes, Roger and Pillay, Deenan and Raizes, Elliot G and Rhee, Soo-Yon and Richman, Douglas D and Ruxrungtham, Kiat and Sabeti, Pardis C and Schapiro, Jonathan M and Sirivichayakul, Sunee and Steegen, Kim and Sugiura, Wataru and van Zyl, Gert U and Vandamme, Anne-Mieke and Wensing, Annemarie M J and Wertheim, Joel O and Gunthard, Huldrych F and Jordan, Michael R and Shafer, Robert W", + "title": "Recommendations on data sharing in HIV drug resistance research", + "journal": "PLoS Med", + "doi": "", + "abstract": "\u2003*\u2002Human immunodeficiency virus (HIV) drug resistance has implications for antiretroviral treatment strategies and for containing the HIV pandemic because the development of HIV drug resistance leads to the requirement for antiretroviral drugs that may be less effective, less well-tolerated, and more expensive than those used in first-line regimens. \u2003*\u2002HIV drug resistance studies are designed to determine which HIV mutations are selected by antiretroviral drugs and, in turn, how these mutations affect antiretroviral drug susceptibility and response to future antiretroviral treatment regimens. \u2003*\u2002Such studies collectively form a vital knowledge base essential for monitoring global HIV drug resistance trends, interpreting HIV genotypic tests, and updating HIV treatment guidelines. \u2003*\u2002Although HIV drug resistance data are collected in many studies, such data are often not publicly shared, prompting the need to recommend best practices to encourage and standardize HIV drug resistance data sharing. \u2003*\u2002In contrast to other viruses, sharing HIV sequences from phylogenetic studies of transmission dynamics requires additional precautions as HIV transmission is criminalized in many countries and regions. \u2003*\u2002Our recommendations are designed to ensure that the data that contribute to HIV drug resistance knowledge will be available without undue hardship to those publishing HIV drug resistance studies and without risk to people living with HIV.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kosakovsky-Pond:2023aa", + "year": 2023, + "authors": "Pond, Sergei L Kosakovsky and Martin, Darren", + "title": "Anti-COVID drug accelerates viral evolution", + "journal": "Nature", + "doi": "", + "abstract": "", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Elli:2023aa", + "year": 2023, + "authors": "Elli, Stefano and Raffaini, Giuseppina and Guerrini, Marco and Pond, Sergei L Kosakovsky and Matrosovich, Mikhail", + "title": "Molecular modeling and phylogenetic analyses highlight the role of amino acid 347 of the {N1} subtype neuraminidase in influenza virus host range and interspecies adaptation", + "journal": "Front Microbiol", + "doi": "", + "abstract": "The N1 neuraminidases (NAs) of avian and pandemic human influenza viruses contain tyrosine and asparagine, respectively, at position 347 on the rim of the catalytic site; the biological significance of this difference is not clear. Here, we used molecular dynamics simulation to model the effects of amino acid 347 on N1 NA interactions with sialyllacto-N-tetraoses 6'SLN-LC and 3'SLN-LC, which represent NA substrates in humans and birds, respectively. Our analysis predicted that Y347 plays an important role in the NA preference for the avian-type substrates. The Y347N substitution facilitates hydrolysis of human-type substrates by resolving steric conflicts of the Neu5Ac2-6Gal moiety with the bulky side chain of Y347, decreasing the free energy of substrate binding, and increasing the solvation of the Neu5Ac2-6Gal bond. Y347 was conserved in all N1 NA sequences of avian influenza viruses in the GISAID EpiFlu database with two exceptions. First, the Y347F substitution was present in the NA of a specific H6N1 poultry virus lineage and was associated with the substitutions G228S and/or E190V/L in the receptor-binding site (RBS) of the hemagglutinin (HA). Second, the highly pathogenic avian H5N1 viruses of the Gs/Gd lineage contained sporadic variants with the NA substitutions Y347H/D, which were frequently associated with substitutions in the HA RBS. The Y347N substitution occurred following the introductions of avian precursors into humans and pigs with N/D347 conserved during virus circulation in these hosts. Comparative evolutionary analysis of site 347 revealed episodic positive selection across the entire tree and negative selection within most host-specific groups of viruses, suggesting that substitutions at NA position 347 occurred during host switches and remained under pervasive purifying selection thereafter. Our results elucidate the role of amino acid 347 in NA recognition of sialoglycan substrates and emphasize the significance of substitutions at position 347 as a marker of host range and adaptive evolution of influenza viruses.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Maurer-Alcala:2024aa", + "year": 2024, + "authors": "Maurer-Alcal{\\'a}, Xyrus X and Cote-L'Heureux, Auden and Pond, Sergei L Kosakovsky and Katz, Laura A", + "title": "Somatic genome architecture and molecular evolution are decoupled in \"young\" linage-specific gene families in ciliates", + "journal": "PLoS One", + "doi": "", + "abstract": "The evolution of lineage-specific gene families remains poorly studied across the eukaryotic tree of life, with most analyses focusing on the recent evolution of de novo genes in model species. Here we explore the origins of lineage-specific genes in ciliates, a ~1 billion year old clade of microeukaryotes that are defined by their division of somatic and germline functions into distinct nuclei. Previous analyses on conserved gene families have shown the effect of ciliates' unusual genome architecture on gene family evolution: extensive genome processing-the generation of thousands of gene-sized somatic chromosomes from canonical germline chromosomes-is associated with larger and more diverse gene families. To further study the relationship between ciliate genome architecture and gene family evolution, we analyzed lineage specific gene families from a set of 46 transcriptomes and 12 genomes representing x species from eight ciliate classes. We assess how the evolution lineage-specific gene families occurs among four groups of ciliates: extensive fragmenters with gene-size somatic chromosomes, non-extensive fragmenters with \"large'' multi-gene somatic chromosomes, Heterotrichea with highly polyploid somatic genomes and Karyorelictea with 'paradiploid' somatic genomes. Our analyses demonstrate that: 1) most lineage-specific gene families are found at shallow taxonomic scales; 2) extensive genome processing (i.e., gene unscrambling) during development likely influences the size and number of young lineage-specific gene families; and 3) the influence of somatic genome architecture on molecular evolution is increasingly apparent in older gene families. Altogether, these data highlight the influences of genome architecture on the evolution of lineage-specific gene families in eukaryotes.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Joseph:2024aa", + "year": 2024, + "authors": "Joseph, Sarah B and Abrahams, Melissa-Rose and Moeser, Matthew and Tyers, Lynn and Archin, Nancie M and Council, Olivia D and Sondgeroth, Amy and Spielvogel, Ean and Emery, Ann and Zhou, Shuntai and Doolabh, Deelan and Ismail, Sherazaan D and Karim, Salim Abdool and Margolis, David M and Pond, Sergei Kosakovsky and Garrett, Nigel and Swanstrom, Ronald and Williamson, Carolyn", + "title": "The timing of HIV-1 infection of cells that persist on therapy is not strongly influenced by replication competency or cellular tropism of the provirus", + "journal": "PLoS Pathog", + "doi": "", + "abstract": "People with HIV-1 (PWH) on antiretroviral therapy (ART) can maintain undetectable virus levels, but a small pool of infected cells persists. This pool is largely comprised of defective proviruses that may produce HIV-1 proteins but are incapable of making infectious virus, with only a fraction (~10%) of these cells harboring intact viral genomes, some of which produce infectious virus following ex vivo stimulation (i.e. inducible intact proviruses). A majority of the inducible proviruses that persist on ART are formed near the time of therapy initiation. Here we compared proviral DNA (assessed here as 3' half genomes amplified from total cellular DNA) and inducible replication competent viruses in the pool of infected cells that persists during ART to determine if the original infection of these cells occurred at comparable times prior to therapy initiation. Overall, the average percent of proviruses that formed late (i.e. around the time of ART initiation, 60%) did not differ from the average percent of replication competent inducible viruses that formed late (69%), and this was also true for proviral DNA that was hypermutated (57%). Further, there was no evidence that entry into the long-lived infected cell pool was impeded by the ability to use the CXCR4 coreceptor, nor was the formation of long-lived infected cells enhanced during primary infection, when viral loads are exceptionally high. We observed that infection of cells that transitioned to be long-lived was enhanced among people with a lower nadir CD4+ T cell count. Together these data suggest that the timing of infection of cells that become long-lived is impacted more by biological processes associated with immunodeficiency before ART than the replication competency and/or cellular tropism of the infecting virus or the intactness of the provirus. Further research is needed to determine the mechanistic link between immunodeficiency and the timing of infected cells transitioning to the long-lived pool, particularly whether this is due to differences in infected cell clearance, turnover rates and/or homeostatic proliferation before and after ART.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wirthlin:2024aa", + "year": 2024, + "authors": "Wirthlin, Morgan E and Schmid, Tobias A and Elie, Julie E and Zhang, Xiaomeng and Kowalczyk, Amanda and Redlich, Ruby and Shvareva, Varvara A and Rakuljic, Ashley and Ji, Maria B and Bhat, Ninad S and Kaplow, Irene M and Sch{\\\"a}ffer, Daniel E and Lawler, Alyssa J and Wang, Andrew Z and Phan, BaDoi N and Annaldasula, Siddharth and Brown, Ashley R and Lu, Tianyu and Lim, Byung Kook and Azim, Eiman and {Zoonomia Consortium} and Clark, Nathan L and Meyer, Wynn K and Pond, Sergei L Kosakovsky and Chikina, Maria and Yartsev, Michael M and Pfenning, Andreas R and Andrews, Gregory and Armstrong, Joel C and Bianchi, Matteo and Birren, Bruce W and Bredemeyer, Kevin R and Breit, Ana M and Christmas, Matthew J and Clawson, Hiram and Damas, Joana and Di Palma, Federica and Diekhans, Mark and Dong, Michael X and Eizirik, Eduardo and Fan, Kaili and Fanter, Cornelia and Foley, Nicole M and Forsberg-Nilsson, Karin and Garcia, Carlos J and Gatesy, John and Gazal, Steven and Genereux, Diane P and Goodman, Linda and Grimshaw, Jenna and Halsey, Michaela K and Harris, Andrew J and Hickey, Glenn and Hiller, Michael and Hindle, Allyson G and Hubley, Robert M and Hughes, Graham M and Johnson, Jeremy and Juan, David and Kaplow, Irene M and Karlsson, Elinor K and Keough, Kathleen C and Kirilenko, Bogdan and Koepfli, Klaus-Peter and Korstian, Jennifer M and Kowalczyk, Amanda and Kozyrev, Sergey V and Lawler, Alyssa J and Lawless, Colleen and Lehmann, Thomas and Levesque, Danielle L and Lewin, Harris A and Li, Xue and Lind, Abigail and Lindblad-Toh, Kerstin and Mackay-Smith, Ava and Marinescu, Voichita D and Marques-Bonet, Tomas and Mason, Victor C and Meadows, Jennifer R S and Meyer, Wynn K and Moore, Jill E and Moreira, Lucas R and Moreno-Santillan, Diana D and Morrill, Kathleen M and Muntan{\\'e}, Gerard and Murphy, William J and Navarro, Arcadi and Nweeia, Martin and Ortmann, Sylvia and Osmanski, Austin and Paten, Benedict and Paulat, Nicole S and Pfenning, Andreas R and Phan, BaDoi N and Pollard, Katherine S and Pratt, Henry E and Ray, David A and Reilly, Steven K and Rosen, Jeb R and Ruf, Irina and Ryan, Louise and Ryder, Oliver A and Sabeti, Pardis C and Sch{\\\"a}ffer, Daniel E and Serres, Aitor and Shapiro, Beth and Smit, Arian F A and Springer, Mark and Srinivasan, Chaitanya and Steiner, Cynthia and Storer, Jessica M and Sullivan, Kevin A M and Sullivan, Patrick F and Sundstr{\\\"o}m, Elisabeth and Supple, Megan A and Swofford, Ross and Talbot, Joy-El and Teeling, Emma and Turner-Maier, Jason and Valenzuela, Alejandro and Wagner, Franziska and Wallerman, Ola and Wang, Chao and Wang, Juehan and Weng, Zhiping and Wilder, Aryn P and Wirthlin, Morgan E and Xue, James R and Zhang, Xiaomeng", + "title": "Vocal learning-associated convergent evolution in mammalian proteins and regulatory elements", + "journal": "Science", + "doi": "", + "abstract": "Vocal production learning (\"vocal learning\") is a convergently evolved trait in vertebrates. To identify brain genomic elements associated with mammalian vocal learning, we integrated genomic, anatomical, and neurophysiological data from the Egyptian fruit bat (Rousettus aegyptiacus) with analyses of the genomes of 215 placental mammals. First, we identified a set of proteins evolving more slowly in vocal learners. Then, we discovered a vocal motor cortical region in the Egyptian fruit bat, an emergent vocal learner, and leveraged that knowledge to identify active cis-regulatory elements in the motor cortex of vocal learners. Machine learning methods applied to motor cortex open chromatin revealed 50 enhancers robustly associated with vocal learning whose activity tended to be lower in vocal learners. Our research implicates convergent losses of motor cortex regulatory elements in mammalian vocal learning evolution.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Langedijk:2024aa", + "year": 2024, + "authors": "Langedijk, Annefleur C and Vrancken, Bram and Lebbink, Robert Jan and Wilkins, Deidre and Kelly, Elizabeth J and Baraldi, Eugenio and Mascare{\\~n}as de Los Santos, Abiel Homero and Danilenko, Daria M and Choi, Eun Hwa and Palomino, Mar{\\'\\i}a Ang{\\'e}lica and Chi, Hsin and Keller, Christian and Cohen, Robert and Papenburg, Jesse and Pernica, Jeffrey and Greenough, Anne and Richmond, Peter and Martin{\\'o}n-Torres, Federico and Heikkinen, Terho and Stein, Renato T and Hosoya, Mitsuaki and Nunes, Marta C and Verwey, Charl and Evers, Anouk and Kragten-Tabatabaie, Leyla and Suchard, Marc A and Pond, Sergei L Kosakovsky and Poletto, Chiara and Colizza, Vittoria and Lemey, Philippe and Bont, Louis J and {INFORM-RSV Study Group}", + "title": "The genomic evolutionary dynamics and global circulation patterns of respiratory syncytial virus", + "journal": "Nat Commun", + "doi": "", + "abstract": "Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection in young children and the second leading cause of infant death worldwide. While global circulation has been extensively studied for respiratory viruses such as seasonal influenza, and more recently also in great detail for SARS-CoV-2, a lack of global multi-annual sampling of complete RSV genomes limits our understanding of RSV molecular epidemiology. Here, we capitalise on the genomic surveillance by the INFORM-RSV study and apply phylodynamic approaches to uncover how selection and neutral epidemiological processes shape RSV diversity. Using complete viral genome sequences, we show similar patterns of site-specific diversifying selection among RSVA and RSVB and recover the imprint of non-neutral epidemic processes on their genealogies. Using a phylogeographic approach, we provide evidence for air travel governing the global patterns of RSVA and RSVB spread, which results in a considerable degree of phylogenetic mixing across countries. Our findings highlight the potential of systematic global RSV genomic surveillance for transforming our understanding of global RSV spread.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Amendola:2022aa", + "year": 2022, + "authors": "Amendola, Antonella and Canuti, Marta and Bianchi, Silvia and Kumar, Sudhir and Fappani, Clara and Gori, Maria and Colzani, Daniela and Kosakovsky Pond, Sergei L and Miura, Sayaka and Baggieri, Melissa and Marchi, Antonella and Borghi, Elisa and Zuccotti, Gianvincenzo and Raviglione, Mario C and Magurano, Fabio and Tanzi, Elisabetta", + "title": "Molecular evidence for SARS-CoV-2 in samples collected from patients with morbilliform eruptions since late 2019 in Lombardy, northern Italy", + "journal": "Environ Res", + "doi": "", + "abstract": "As a reference laboratory for measles and rubella surveillance in Lombardy, we evaluated the association between SARS-CoV-2 infection and measles-like syndromes, providing preliminary evidence for undetected early circulation of SARS-CoV-2. Overall, 435 samples from 156 cases were investigated. RNA from oropharyngeal swabs (N = 148) and urine (N = 141) was screened with four hemi-nested PCRs and molecular evidence for SARS-CoV-2 infection was found in 13 subjects. Two of the positive patients were from the pandemic period (2/12, 16.7%, March 2020-March 2021) and 11 were from the pre-pandemic period (11/44, 25%, August 2019-February 2020). Sera (N = 146) were tested for anti-SARS-CoV-2 IgG, IgM, and IgA antibodies. Five of the RNA-positive individuals also had detectable anti-SARS-CoV-2 antibodies. No strong evidence of infection was found in samples collected between August 2018 and July 2019 from 100 patients. The earliest sample with evidence of SARS-CoV-2 RNA was from September 12, 2019, and the positive patient was also positive for anti-SARS-CoV-2 antibodies (IgG and IgM). Mutations typical of B.1 strains previously reported to have emerged in January 2020 (C3037T, C14408T, and A23403G), were identified in samples collected as early as October 2019 in Lombardy. One of these mutations (C14408T) was also identified among sequences downloaded from public databases that were obtained by others from samples collected in Brazil in November 2019. We conclude that a SARS-CoV-2 progenitor capable of producing a measles-like syndrome may have emerged in late June-late July 2019 and that viruses with mutations characterizing B.1 strain may have been spreading globally before the first Wuhan outbreak. Our findings should be complemented by high-throughput sequencing to obtain additional sequence information. We highlight the importance of retrospective surveillance studies in understanding the early dynamics of COVID-19 spread and we encourage other groups to perform retrospective investigations to seek confirmatory proofs of early SARS-CoV-2 circulation.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Lucaci:2022aa", + "year": 2022, + "authors": "Lucaci, Alexander G and Zehr, Jordan D and Shank, Stephen D and Bouvier, Dave and Ostrovsky, Alexander and Mei, Han and Nekrutenko, Anton and Martin, Darren P and Kosakovsky Pond, Sergei L", + "title": "RASCL: Rapid Assessment of Selection in CLades through molecular sequence analysis", + "journal": "PLoS One", + "doi": "", + "abstract": "An important unmet need revealed by the COVID-19 pandemic is the near-real-time identification of potentially fitness-altering mutations within rapidly growing SARS-CoV-2 lineages. Although powerful molecular sequence analysis methods are available to detect and characterize patterns of natural selection within modestly sized gene-sequence datasets, the computational complexity of these methods and their sensitivity to sequencing errors render them effectively inapplicable in large-scale genomic surveillance contexts. Motivated by the need to analyze new lineage evolution in near-real time using large numbers of genomes, we developed the Rapid Assessment of Selection within CLades (RASCL) pipeline. RASCL applies state of the art phylogenetic comparative methods to evaluate selective processes acting at individual codon sites and across whole genes. RASCL is scalable and produces automatically updated regular lineage-specific selection analysis reports: even for lineages that include tens or hundreds of thousands of sampled genome sequences. Key to this performance is (i) generation of automatically subsampled high quality datasets of gene/ORF sequences drawn from a selected \"query\" viral lineage; (ii) contextualization of these query sequences in codon alignments that include high-quality \"background\" sequences representative of global SARS-CoV-2 diversity; and (iii) the extensive parallelization of a suite of computationally intensive selection analysis tests. Within hours of being deployed to analyze a novel rapidly growing lineage of interest, RASCL will begin yielding JavaScript Object Notation (JSON)-formatted reports that can be either imported into third-party analysis software or explored in standard web-browsers using the premade RASCL interactive data visualization dashboard. By enabling the rapid detection of genome sites evolving under different selective regimes, RASCL is well-suited for near-real-time monitoring of the population-level selective processes that will likely underlie the emergence of future variants of concern in measurably evolving pathogens with extensive genomic surveillance.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Tzou:2022aa", + "year": 2022, + "authors": "Tzou, Philip L and Tao, Kaiming and Sahoo, Malaya K and Kosakovsky Pond, Sergei L and Pinsky, Benjamin A and Shafer, Robert W", + "title": "Sierra SARS-CoV-2 sequence and antiviral resistance analysis program", + "journal": "J Clin Virol", + "doi": "", + "abstract": "Although most laboratories are capable of employing established protocols to perform full-genome SARS-CoV-2 sequencing, many are unable to assess sequence quality, select appropriate mutation-detection thresholds, or report on the potential clinical significance of mutations in the targets of antiviral therapy METHODS: We describe the technical aspects and benchmark the performance of Sierra SARS-CoV-2, a program designed to perform these functions on user-submitted FASTQ and FASTA sequence files and lists of Spike mutations. Sierra SARS-CoV-2 indicates which sequences contain an unexpectedly large number of unusual mutations and which mutations are associated with reduced susceptibility to clinical stage mAbs, the RdRP inhibitor remdesivir, or the Mpro inhibitor nirmatrelvir RESULTS: To assess the performance of Sierra SARS-CoV-2 on FASTQ files, we applied it to 600 representative FASTQ sequences and compared the results to the COVID-19 EDGE program. To assess its performance on FASTA files, we applied it to nearly one million representative FASTA sequences and compared the results to the GISAID mutation annotation. To assess its performance on mutations lists, we applied it to 13,578 distinct Spike RBD mutation patterns and showed that exactly or partially matching annotations were available for 88% of patterns CONCLUSION: Sierra SARS-CoV-2 leverages previously published data to improve the quality control of submitted viral genomic data and to provide functional annotation on the impact of mutations in the targets of antiviral SARS-CoV-2 therapy. The program can be found at https://covdb.stanford.edu/sierra/sars2/ and its source code at https://github.com/hivdb/sierra-sars2.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Zehr:2023aa", + "year": 2023, + "authors": "Zehr, Jordan D and Kosakovsky Pond, Sergei L and Millet, Jean K and Olarte-Castillo, Ximena A and Lucaci, Alexander G and Shank, Stephen D and Ceres, Kristina M and Choi, Annette and Whittaker, Gary R and Goodman, Laura B and Stanhope, Michael J", + "title": "Natural selection differences detected in key protein domains between non-pathogenic and pathogenic feline coronavirus phenotypes", + "journal": "Virus Evol", + "doi": "", + "abstract": "Feline coronaviruses (FCoVs) commonly cause mild enteric infections in felines worldwide (termed feline enteric coronavirus [FECV]), with around 12 per cent\u2009developing into deadly feline infectious peritonitis (FIP; feline infectious peritonitis virus [FIPV]). Genomic differences between FECV and FIPV have been reported, yet the putative genotypic basis of the highly pathogenic phenotype remains unclear. Here, we used state-of-the-art molecular evolutionary genetic statistical techniques to identify and compare differences in natural selection pressure between FECV and FIPV sequences, as well as to identify FIPV- and FECV-specific signals of positive selection. We analyzed full-length FCoV protein coding genes thought to contain mutations associated with FIPV (Spike, ORF3abc, and ORF7ab). We identified two sites exhibiting differences in natural selection pressure between FECV and FIPV: one within the S1/S2 furin cleavage site (FCS) and the other within the fusion domain of Spike. We also found fifteen sites subject to positive selection associated with FIPV within Spike, eleven of which have not previously been suggested as possibly relevant to FIP development. These sites fall within Spike protein subdomains that participate in host cell receptor interaction, immune evasion, tropism shifts, host cellular entry, and viral escape. There were fourteen sites (twelve novel sites) within Spike under positive selection associated with the FECV phenotype, almost exclusively within the S1/S2 FCS and adjacent to C domain, along with a signal of relaxed selection in FIPV relative to FECV, suggesting that furin cleavage functionality may not be needed for FIPV. Positive selection inferred in ORF7b was associated with the FECV phenotype and included twenty-four positively selected sites, while ORF7b had signals of relaxed selection in FIPV. We found evidence of positive selection in ORF3c in FCoV-wide analyses, but no specific association with the FIPV or FECV phenotype. We hypothesize that some combination of mutations in FECV may contribute to FIP development, and that it is unlikely to be one singular 'switch' mutational event. This work expands our understanding of the complexities of FIP development and provides insights into how evolutionary forces may alter pathogenesis in coronavirus genomes.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Tao:2023aa", + "year": 2023, + "authors": "Tao, Kaiming and Rhee, Soo-Yon and Tzou, Philip L and Osman, Zachary A and Pond, Sergei L Kosakovsky and Holmes, Susan P and Shafer, Robert W", + "title": "HIV-1 Group M Capsid Amino Acid Variability: Implications for Sequence Quality Control of Genotypic Resistance Testing", + "journal": "Viruses", + "doi": "", + "abstract": "BACKGROUND: With the approval of the HIV-1 capsid inhibitor, lenacapavir, capsid sequencing will be required for managing lenacapavir-experienced individuals with detectable viremia. Successful sequence interpretation will require examining new capsid sequences in the context of previously published sequence data.\nMETHODS: We analyzed published HIV-1 group M capsid sequences from 21,012 capsid-inhibitor na{\\\"\\i}ve individuals to characterize amino acid variability at each position and influence of subtype and cytotoxic T lymphocyte (CTL) selection pressure. We determined the distributions of usual mutations, defined as amino acid differences from the group M consensus, with a prevalence \u2265 0.1%. Co-evolving mutations were identified using a phylogenetically-informed Bayesian graphical model method.\nRESULTS: 162 (70.1%) positions had no usual mutations (45.9%) or only conservative usual mutations with a positive BLOSUM62 score (24.2%). Variability correlated independently with subtype-specific amino acid occurrence (Spearman rho = 0.83; p < 1 \u00d7 10-9) and the number of times positions were reported to contain an HLA-associated polymorphism, an indicator of CTL pressure (rho = 0.43; p = 0.0002).\nCONCLUSIONS: Knowing the distribution of usual capsid mutations is essential for sequence quality control. Comparing capsid sequences from lenacapavir-treated and lenacapavir-na{\\\"\\i}ve individuals will enable the identification of additional mutations potentially associated with lenacapavir therapy.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Escalera-Zamudio:2023aa", + "year": 2023, + "authors": "Escalera-Zamudio, Marina and Kosakovsky Pond, Sergei L and Mart{\\'\\i}nez de la Vi{\\~n}a, Natalia and Guti{\\'e}rrez, Bernardo and Inward, Rhys P D and Th{\\'e}z{\\'e}, Julien and van Dorp, Lucy and Castel{\\'a}n-S{\\'a}nchez, Hugo G and Bowden, Thomas A and Pybus, Oliver G and Hulswit, Ruben J G", + "title": "Identification of Evolutionary Trajectories Shared across Human Betacoronaviruses", + "journal": "Genome Biol Evol", + "doi": "", + "abstract": "Comparing the evolution of distantly related viruses can provide insights into common adaptive processes related to shared ecological niches. Phylogenetic approaches, coupled with other molecular evolution tools, can help identify mutations informative on adaptation, although the structural contextualization of these to functional sites of proteins may help gain insight into their biological properties. Two zoonotic betacoronaviruses capable of sustained human-to-human transmission have caused pandemics in recent times (SARS-CoV-1 and SARS-CoV-2), although a third virus (MERS-CoV) is responsible for sporadic outbreaks linked to animal infections. Moreover, two other betacoronaviruses have circulated endemically in humans for decades (HKU1 and OC43). To search for evidence of adaptive convergence between established and emerging betacoronaviruses capable of sustained human-to-human transmission (HKU1, OC43, SARS-CoV-1, and SARS-CoV-2), we developed a methodological pipeline to classify shared nonsynonymous mutations as putatively denoting homoplasy (repeated mutations that do not share direct common ancestry) or stepwise evolution (sequential mutations leading towards a novel genotype). In parallel, we look for evidence of positive selection and draw upon protein structure data to identify potential biological implications. We find 30 candidate mutations, from which 4 (codon sites 18121 [nsp14/residue 28], 21623 [spike/21], 21635 [spike/25], and 23948 [spike/796]; SARS-CoV-2 genome numbering) further display evolution under positive selection and proximity to functional protein regions. Our findings shed light on potential mechanisms underlying betacoronavirus adaptation to the human host and pinpoint common mutational pathways that may occur during establishment of human endemicity.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Joyce:2023aa", + "year": 2023, + "authors": "Joyce, Collin and Murrell, Sasha and Murrell, Ben and Omorodion, Oluwarotimi and Ver, Lorena S and Carrico, Nancy and Bastidas, Raiza and Nedellec, Rebecca and Bick, Michael and Woehl, Jordan and Zhao, Fangzhu and Burns, Alison and Barman, Shawn and Appel, Michael and Ramos, Alejandra and Wickramasinghe, Lalinda and Eren, Kemal and Vollbrecht, Thomas and Smith, Davey M and Kosakovsky Pond, Sergei L and McBride, Ryan and Worth, Charli and Batista, Facundo and Sok, Devin and {IAVI Protocol C Investigators \\& The IAVI African HIV Research Network} and Poignard, Pascal and Briney, Bryan and Wilson, Ian A and Landais, Elise and Burton, Dennis R", + "title": "Antigen pressure from two founder viruses induces multiple insertions at a single antibody position to generate broadly neutralizing HIV antibodies", + "journal": "PLoS Pathog", + "doi": "", + "abstract": "Vaccination strategies aimed at maturing broadly neutralizing antibodies (bnAbs) from na{\\\"\\i}ve precursors are hindered by unusual features that characterize these Abs, including insertions and deletions (indels). Longitudinal studies of natural HIV infection cases shed light on the complex processes underlying bnAb development and have suggested a role for superinfection as a potential enhancer of neutralization breadth. Here we describe the development of a potent bnAb lineage that was elicited by two founder viruses to inform vaccine design. The V3-glycan targeting bnAb lineage (PC39-1) was isolated from subtype C-infected IAVI Protocol C elite neutralizer, donor PC39, and is defined by the presence of multiple independent insertions in CDRH1 that range from 1-11 amino acids in length. Memory B cell members of this lineage are predominantly atypical in phenotype yet also span the class-switched and antibody-secreting cell compartments. Development of neutralization breadth occurred concomitantly with extensive recombination between founder viruses before each virus separated into two distinct population \"arms\" that evolved independently to escape the PC39-1 lineage. Ab crystal structures show an extended CDRH1 that can help stabilize the CDRH3. Overall, these findings suggest that early exposure of the humoral system to multiple related Env molecules could promote the induction of bnAbs by focusing Ab responses to conserved epitopes.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Lucaci:2023aa", + "year": 2023, + "authors": "Lucaci, Alexander G and Zehr, Jordan D and Enard, David and Thornton, Joseph W and Kosakovsky Pond, Sergei L", + "title": "Evolutionary Shortcuts via Multinucleotide Substitutions and Their Impact on Natural Selection Analyses", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Inference and interpretation of evolutionary processes, in particular of the types and targets of natural selection affecting coding sequences, are critically influenced by the assumptions built into statistical models and tests. If certain aspects of the substitution process (even when they are not of direct interest) are presumed absent or are modeled with too crude of a simplification, estimates of key model parameters can become biased, often systematically, and lead to poor statistical performance. Previous work established that failing to accommodate multinucleotide (or multihit, MH) substitutions strongly biases dN/dS-based inference towards false-positive inferences of diversifying episodic selection, as does failing to model variation in the rate of synonymous substitution (SRV) among sites. Here, we develop an integrated analytical framework and software tools to simultaneously incorporate these sources of evolutionary complexity into selection analyses. We found that both MH and SRV are ubiquitous in empirical alignments, and incorporating them has a strong effect on whether or not positive selection is detected (1.4-fold reduction) and on the distributions of inferred evolutionary rates. With simulation studies, we show that this effect is not attributable to reduced statistical power caused by using a more complex model. After a detailed examination of 21 benchmark alignments and a new high-resolution analysis showing which parts of the alignment provide support for positive selection, we show that MH substitutions occurring along shorter branches in the tree explain a significant fraction of discrepant results in selection detection. Our results add to the growing body of literature which examines decades-old modeling assumptions (including MH) and finds them to be problematic for comparative genomic data analysis. Because multinucleotide substitutions have a significant impact on natural selection detection even at the level of an entire gene, we recommend that selection analyses of this type consider their inclusion as a matter of routine. To facilitate this procedure, we developed, implemented, and benchmarked a simple and well-performing model testing selection detection framework able to screen an alignment for positive selection with two biologically important confounding processes: site-to-site synonymous rate variation, and multinucleotide instantaneous substitutions.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Lucaci:2022wo", + "year": 2022, + "authors": "Lucaci, Alexander G and Zehr, Jordan D and Shank, Stephen D and Bouvier, Dave and Mei, Han and Nekrutenko, Anton and Martin, Darren P and Pond, Sergei L Kosakovsky", + "title": "RASCL: Rapid Assessment Of SARS-CoV-2 Clades Through Molecular Sequence Analysis", + "journal": "bioRxiv", + "doi": "", + "abstract": "An important component of efforts to manage the ongoing COVID19 pandemic is the R apid A ssessment of how natural selection contributes to the emergence and proliferation of potentially dangerous S ARS-CoV-2 lineages and CL ades (RASCL). The RASCL pipeline enables continuous comparative phylogenetics-based selection analyses of rapidly growing clade-focused genome surveillance datasets, such as those produced following the initial detection of potentially dangerous variants. From such datasets RASCL automatically generates down-sampled codon alignments of individual genes/ORFs containing contextualizing background reference sequences, analyzes these with a battery of selection tests, and outputs results as both machine readable JSON files, and interactive notebook-based visualizations.\nAVAILABILITY: RASCL is available from a dedicated repository at https://github.com/veg/RASCL and as a Galaxy workflow https://usegalaxy.eu/u/hyphy/w/rascl . Existing clade/variant analysis results are available here: https://observablehq.com/@aglucaci/rascl .\nCONTACT: Dr. Sergei L Kosakovsky Pond ( spond@temple.edu ).\nSUPPLEMENTARY INFORMATION: N/A.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wertheim:2022tz", + "year": 2022, + "authors": "Wertheim, Joel O and Wang, Jade C and Leelawong, Mindy and Martin, Darren P and Havens, Jennifer L and Chowdhury, Moinuddin A and Pekar, Jonathan E and Amin, Helly and Arroyo, Anthony and Awandare, Gordon A and Chow, Hoi Yan and Gonzalez, Edimarlyn and Luoma, Elizabeth and Morang'a, Collins M and Nekrutenko, Anton and Shank, Stephen D and Silver, Stefan and Quashie, Peter K and Rakeman, Jennifer L and Ruiz, Victoria and Torian, Lucia V and Vasylyeva, Tetyana I and Pond, Sergei L Kosakovsky and Hughes, Scott", + "title": "Detection of SARS-CoV-2 intra-host recombination during superinfection with Alpha and Epsilon variants in New York City", + "journal": "Nat Commun", + "doi": "", + "abstract": "Recombination is an evolutionary process by which many pathogens generate diversity and acquire novel functions. Although a common occurrence during coronavirus replication, detection of recombination is only feasible when genetically distinct viruses contemporaneously infect the same host. Here, we identify an instance of SARS-CoV-2 superinfection, whereby an individual was infected with two distinct viral variants: Alpha (B.1.1.7) and Epsilon (B.1.429). This superinfection was first noted when an Alpha genome sequence failed to exhibit the classic S gene target failure behavior used to track this variant. Full genome sequencing from four independent extracts reveals that Alpha variant alleles comprise around 75% of the genomes, whereas the Epsilon variant alleles comprise around 20% of the sample. Further investigation reveals the presence of numerous recombinant haplotypes spanning the genome, specifically in the spike, nucleocapsid, and ORF 8 coding regions. These findings support the potential for recombination to reshape SARS-CoV-2 genetic diversity.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Tegally:2022wf", + "year": 2022, + "authors": "Tegally, Houriiyah and Moir, Monika and Everatt, Josie and Giovanetti, Marta and Scheepers, Cathrine and Wilkinson, Eduan and Subramoney, Kathleen and Makatini, Zinhle and Moyo, Sikhulile and Amoako, Daniel G and Baxter, Cheryl and Althaus, Christian L and Anyaneji, Ugochukwu J and Kekana, Dikeledi and Viana, Raquel and Giandhari, Jennifer and Lessells, Richard J and Maponga, Tongai and Maruapula, Dorcas and Choga, Wonderful and Matshaba, Mogomotsi and Mbulawa, Mpaphi B and Msomi, Nokukhanya and {NGS-SA consortium} and Naidoo, Yeshnee and Pillay, Sureshnee and Sanko, Tomasz Janusz and San, James E and Scott, Lesley and Singh, Lavanya and Magini, Nonkululeko A and Smith-Lawrence, Pamela and Stevens, Wendy and Dor, Graeme and Tshiabuila, Derek and Wolter, Nicole and Preiser, Wolfgang and Treurnicht, Florette K and Venter, Marietjie and Chiloane, Georginah and McIntyre, Caitlyn and O'Toole, Aine and Ruis, Christopher and Peacock, Thomas P and Roemer, Cornelius and Pond, Sergei L Kosakovsky and Williamson, Carolyn and Pybus, Oliver G and Bhiman, Jinal N and Glass, Allison and Martin, Darren P and Jackson, Ben and Rambaut, Andrew and Laguda-Akingba, Oluwakemi and Gaseitsiwe, Simani and von Gottberg, Anne and de Oliveira, Tulio", + "title": "Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa", + "journal": "Nat Med", + "doi": "", + "abstract": "Three lineages (BA.1, BA.2 and BA.3) of the SARS-CoV-2 Omicron variant of concern predominantly drove South Africa's fourth COVID-19 wave. We have now identified two new lineages, BA.4 and BA.5, responsible for a fifth wave of infections. The spike proteins of BA.4 and BA.5 are identical, and comparable to BA.2 except for the addition of 69-70del (present in the Alpha variant and the BA.1 lineage), L452R (present in the Delta variant), F486V and the wild type amino acid at Q493.The two lineages only differ outside of the spike region. The 69-70 deletion in spike allows these lineages to be identified by the proxy marker of S-gene target failure, on the background of variants not possessing this feature . BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50% of sequenced cases in South Africa by the first week of April 2022. Using a multinomial logistic regression model, we estimate growth advantages for BA.4 and BA.5 of 0.08 (95% CI: 0.08 - 0.09) and 0.10 (95% CI: 0.09 - 0.11) per day respectively over BA.2 in South Africa. The continued discovery of genetically diverse Omicron lineages points to the hypothesis that a discrete reservoir, such as human chronic infections and/or animal hosts, is potentially contributing to further evolution and dispersal of the virus.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Lucaci:2022wa", + "year": 2022, + "authors": "Lucaci, Alexander G and Notaras, Michael J and Pond, Sergei L Kosakovsky and Colak, Dilek", + "title": "The evolution of BDNF is defined by strict purifying selection and prodomain spatial coevolution, but what does it mean for human brain disease?", + "journal": "Transl Psychiatry", + "doi": "", + "abstract": "Brain-Derived Neurotrophic Factor (BDNF) is an essential mediator of brain assembly, development, and maturation. BDNF has been implicated in a variety of brain disorders such as neurodevelopmental disorders (e.g., autism spectrum disorder), neuropsychiatric disorders (e.g., anxiety, depression, PTSD, and schizophrenia), and various neurodegenerative disorders (e.g., Parkinson's, Alzheimer's, etc.). To better understand the role of BDNF in disease, we sought to define the evolution of BDNF within Mammalia. We conducted sequence alignment and phylogenetic reconstruction of BDNF across a diverse selection of >160 mammalian species spanning ~177 million years of evolution. The selective evolutionary change was examined via several independent computational models of codon evolution including FEL (pervasive diversifying selection), MEME (episodic selection), and BGM (structural coevolution of sites within a single molecule). We report strict purifying selection in the main functional domain of BDNF (NGF domain, essentially comprising the mature BDNF protein). Additionally, we discover six sites in our homologous alignment which are under episodic selection in early regulatory regions (i.e. the prodomain) and 23 pairs of coevolving sites that are distributed across the entirety of BDNF. Coevolving BDNF sites exhibited complex spatial relationships and geometric features including triangular relations, acyclic graph networks, double-linked sites, and triple-linked sites, although the most notable pattern to emerge was that changes in the mature region of BDNF tended to coevolve along with sites in the prodomain. Thus, we propose that the discovery of both local and distal sites of coevolution likely reflects 'evolutionary fine-tuning' of BDNF's underlying regulation and function in mammals. This tracks with the observation that BDNF's mature domain (which encodes mature BDNF protein) is largely conserved, while the prodomain (which is linked to regulation and its own unique functionality) exhibits more pervasive and diversifying evolutionary selection. That said, the fact that negative purifying selection also occurs in BDNF's prodomain also highlights that this region also contains critical sites of sensitivity which also partially explains its disease relevance (via Val66Met and other prodomain variants). Taken together, these computational evolutionary analyses provide important context as to the origins and sensitivity of genetic changes within BDNF that may help to deconvolute the role of BDNF polymorphisms in human brain disorders.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Tao:2022wu", + "year": 2022, + "authors": "Tao, Kaiming and Tzou, Philip L and Pond, Sergei L Kosakovsky and Ioannidis, John P A and Shafer, Robert W", + "title": "Susceptibility of SARS-CoV-2 Omicron Variants to Therapeutic Monoclonal Antibodies: Systematic Review and Meta-analysis", + "journal": "Microbiol Spectr", + "doi": "", + "abstract": "SARS-CoV-2 Omicron variants contain many mutations in its spike receptor-binding domain, the target of all authorized monoclonal antibodies (MAbs). Determining the extent to which Omicron variants reduced MAb susceptibility is critical to preventing and treating COVID-19. We systematically reviewed PubMed and three preprint servers, last updated 11 April 2022, for the in vitro activity of authorized MAbs against the Omicron variants. Fifty-one studies were eligible, including 50 containing Omicron BA.1 susceptibility data and 17 containing Omicron BA.2 susceptibility data. The first two authorized MAb combinations, bamlanivimab/etesevimab and casirivimab/imdevimab, were largely inactive against the Omicron BA.1 and BA.2 variants. In 34 studies, sotrovimab displayed a median 4.0-fold (interquartile range [IQR]: 2.6 to 6.9) reduction in activity against Omicron BA.1, and in 12 studies, it displayed a median 17-fold (IQR: 13 to 30) reduction in activity against Omicron BA.2. In 15 studies, the combination cilgavimab/tixagevimab displayed a median 86-fold (IQR: 27 to 151) reduction in activity against Omicron BA.1, and in six studies, it displayed a median 5.4-fold (IQR: 3.7 to 6.9) reduction in activity against Omicron BA.2. In eight studies against Omicron BA.1 and six studies against Omicron BA.2, bebtelovimab displayed no reduction in activity. Disparate results between assays were common. For authorized MAbs, 51/268 (19.0%) results for wild-type control variants and 78/348 (22.4%) results for Omicron BA.1 and BA.2 variants were more than 4-fold below or 4-fold above the median result for that MAb. Highly disparate results between published assays indicate a need for improved MAb susceptibility test standardization or interassay calibration. IMPORTANCE Monoclonal antibodies (MAbs) targeting the SARS-CoV-2 spike protein are among the most effective measures for preventing and treating COVID-19. However, SARS-CoV-2 Omicron variants contain many mutations in their spike receptor-binding domains, the target of all authorized MAbs. Therefore, determining the extent to which Omicron variants reduced MAb susceptibility is critical to preventing and treating COVID-19. We identified 51 studies that reported the in vitro susceptibility of the two main Omicron variants BA.1 and BA.2 to therapeutic MAbs in advanced clinical development, including eight authorized individual MAbs and three authorized MAb combinations. We estimated the degree to which different MAbs displayed reduced activity against Omicron variants. The marked loss of activity of many MAbs against Omicron variants underscores the importance of developing MAbs that target conserved regions of spike. Highly disparate results between assays indicate the need for improved MAb susceptibility test standardization.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Benndorf:2022wd", + "year": 2022, + "authors": "Benndorf, Rainer and Velazquez, Ryan and Zehr, Jordan D and Pond, Sergei L Kosakovsky and Martin, Jody L and Lucaci, Alexander G", + "title": "Human HspB1, HspB3, HspB5 and HspB8: Shaping these disease factors during vertebrate evolution", + "journal": "Cell Stress Chaperones", + "doi": "", + "abstract": "Small heat shock proteins (sHSPs) emerged early in evolution and occur in all domains of life and nearly in all species, including humans. Mutations in four sHSPs (HspB1, HspB3, HspB5, HspB8) are associated with neuromuscular disorders. The aim of this study is to investigate the evolutionary forces shaping these sHSPs during vertebrate evolution. We performed comparative evolutionary analyses on a set of orthologous sHSP sequences, based on the ratio of non-synonymous: synonymous substitution rates for each codon. We found that these sHSPs had been historically exposed to different degrees of purifying selection, decreasing in this order: HspB8\u2009>\u2009HspB1, HspB5\u2009>\u2009HspB3. Within each sHSP, regions with different degrees of purifying selection can be discerned, resulting in characteristic selective pressure profiles. The conserved \u03b1-crystallin domains were exposed to the most stringent purifying selection compared to the flanking regions, supporting a 'dimorphic pattern' of evolution. Thus, during vertebrate evolution the different sequence partitions were exposed to different and measurable degrees of selective pressures. Among the disease-associated mutations, most are missense mutations primarily in HspB1 and to a lesser extent in the other sHSPs. Our data provide an explanation for this disparate incidence. Contrary to the expectation, most missense mutations cause dominant disease phenotypes. Theoretical considerations support a connection between the historic exposure of these sHSP genes to a high degree of purifying selection and the unusual prevalence of genetic dominance of the associated disease phenotypes. Our study puts the genetics of inheritable sHSP-borne diseases into the context of vertebrate evolution.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Zehr:2022tj", + "year": 2022, + "authors": "Zehr, Jordan D and Pond, Sergei L Kosakovsky and Martin, Darren P and Ceres, Kristina and Whittaker, Gary R and Millet, Jean K and Goodman, Laura B and Stanhope, Michael J", + "title": "Recent Zoonotic Spillover and Tropism Shift of a Canine Coronavirus Is Associated with Relaxed Selection and Putative Loss of Function in NTD Subdomain of Spike Protein", + "journal": "Viruses", + "doi": "", + "abstract": "A canine coronavirus (CCoV) has now been reported from two independent human samples from Malaysia (respiratory, collected in 2017-2018; CCoV-HuPn-2018) and Haiti (urine, collected in 2017); these two viruses were nearly genetically identical. In an effort to identify any novel adaptations associated with this apparent shift in tropism we carried out detailed evolutionary analyses of the spike gene of this virus in the context of related Alphacoronavirus 1 species. The spike 0-domain retains homology to CCoV2b (enteric infections) and Transmissible Gastroenteritis Virus (TGEV; enteric and respiratory). This domain is subject to relaxed selection pressure and an increased rate of molecular evolution. It contains unique amino acid substitutions, including within a region important for sialic acid binding and pathogenesis in TGEV. Overall, the spike gene is extensively recombinant, with a feline coronavirus type II strain serving a prominent role in the recombinant history of the virus. Molecular divergence time for a segment of the gene where temporal signal could be determined, was estimated at around 60 years ago. We hypothesize that the virus had an enteric origin, but that it may be losing that particular tropism, possibly because of mutations in the sialic acid binding region of the spike 0-domain.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Caraballo-Ortiz:2022aa", + "year": 2022, + "authors": "Caraballo-Ortiz, Marcos A and Miura, Sayaka and Sanderford, Maxwell and Dolker, Tenzin and Tao, Qiqing and Weaver, Steven and Pond, Sergei L K and Kumar, Sudhir", + "title": "TopHap: rapid inference of key phylogenetic structures from common haplotypes in large genome collections with limited diversity", + "journal": "Bioinformatics", + "doi": "", + "abstract": "MOTIVATION: Building reliable phylogenies from very large collections of sequences with a limited number of phylogenetically informative sites is challenging because sequencing errors and recurrent/backward mutations interfere with the phylogenetic signal, confounding true evolutionary relationships. Massive global efforts of sequencing genomes and reconstructing the phylogeny of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains exemplify these difficulties since there are only hundreds of phylogenetically informative sites but millions of genomes. For such datasets, we set out to develop a method for building the phylogenetic tree of genomic haplotypes consisting of positions harboring common variants to improve the signal-to-noise ratio for more accurate and fast phylogenetic inference of resolvable phylogenetic features.\nRESULTS: We present the TopHap approach that determines spatiotemporally common haplotypes of common variants and builds their phylogeny at a fraction of the computational time of traditional methods. We develop a bootstrap strategy that resamples genomes spatiotemporally to assess topological robustness. The application of TopHap to build a phylogeny of 68 057 SARS-CoV-2 genomes (68KG) from the first year of the pandemic produced an evolutionary tree of major SARS-CoV-2 haplotypes. This phylogeny is concordant with the mutation tree inferred using the co-occurrence pattern of mutations and recovers key phylogenetic relationships from more traditional analyses. We also evaluated alternative roots of the SARS-CoV-2 phylogeny and found that the earliest sampled genomes in 2019 likely evolved by four mutations of the most recent common ancestor of all SARS-CoV-2 genomes. An application of TopHap to more than 1 million SARS-CoV-2 genomes reconstructed the most comprehensive evolutionary relationships of major variants, which confirmed the 68KG phylogeny and provided evolutionary origins of major and recent variants of concern.\nAVAILABILITY AND IMPLEMENTATION: TopHap is available at https://github.com/SayakaMiura/TopHap.\nSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Martin:2022ui", + "year": 2022, + "authors": "Martin, Darren P and Lytras, Spyros and Lucaci, Alexander G and Maier, Wolfgang and Gr{\\\"u}ning, Bj{\\\"o}rn and Shank, Stephen D and Weaver, Steven and MacLean, Oscar A and Orton, Richard J and Lemey, Philippe and Boni, Maciej F and Tegally, Houriiyah and Harkins, Gordon W and Scheepers, Cathrine and Bhiman, Jinal N and Everatt, Josie and Amoako, Daniel G and San, James Emmanuel and Giandhari, Jennifer and Sigal, Alex and {NGS-SA} and Williamson, Carolyn and Hsiao, Nei-Yuan and von Gottberg, Anne and De Klerk, Arne and Shafer, Robert W and Robertson, David L and Wilkinson, Robert J and Sewell, B Trevor and Lessells, Richard and Nekrutenko, Anton and Greaney, Allison J and Starr, Tyler N and Bloom, Jesse D and Murrell, Ben and Wilkinson, Eduan and Gupta, Ravindra K and de Oliveira, Tulio and Pond, Sergei L Kosakovsky", + "title": "Selection Analysis Identifies Clusters of Unusual Mutational Changes in Omicron Lineage BA.1 That Likely Impact Spike Function", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Among the 30 nonsynonymous nucleotide substitutions in the Omicron S-gene are 13 that have only rarely been seen in other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of the S-gene at sites that will likely impact (1) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (2) interactions of Spike with ACE2 receptors, and (3) the priming of Spike for membrane fusion. We show here that, based on both the rarity of these 13 mutations in intrapatient sequencing reads and patterns of selection at the codon sites where the mutations occur in SARS-CoV-2 and related sarbecoviruses, prior to the emergence of Omicron the mutations would have been predicted to decrease the fitness of any virus within which they occurred. We further propose that the mutations in each of the three clusters therefore cooperatively interact to both mitigate their individual fitness costs, and, in combination with other mutations, adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron overall previously known SARS-CoV-2 lineages, it is crucial to determine both how such complex and highly adaptive mutation constellations were assembled within the Omicron S-gene, and why, despite unprecedented global genomic surveillance efforts, the early stages of this assembly process went completely undetected.", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Canuti:2022wv", + "year": 2022, + "authors": "Canuti, Marta and Bianchi, Silvia and Kolbl, Otto and Pond, Sergei L Kosakovsky and Kumar, Sudhir and Gori, Maria and Fappani, Clara and Colzani, Daniela and Borghi, Elisa and Zuccotti, Gianvincenzo and Raviglione, Mario C and Tanzi, Elisabetta and Amendola, Antonella", + "title": "Waiting for the truth: is reluctance in accepting an early origin hypothesis for SARS-CoV-2 delaying our understanding of viral emergence?", + "journal": "BMJ Glob Health", + "doi": "", + "abstract": "Two years after the start of the COVID-19 pandemic, key questions about the emergence of its aetiological agent (SARS-CoV-2) remain a matter of considerable debate. Identifying when SARS-CoV-2 began spreading among people is one of those questions. Although the current canonically accepted timeline hypothesises viral emergence in Wuhan, China, in November or December 2019, a growing body of diverse studies provides evidence that the virus may have been spreading worldwide weeks, or even months, prior to that time. However, the hypothesis of earlier SARS-CoV-2 circulation is often dismissed with prejudicial scepticism and experimental studies pointing to early origins are frequently and speculatively attributed to false-positive tests. In this paper, we critically review current evidence that SARS-CoV-2 had been circulating prior to December of 2019, and emphasise how, despite some scientific limitations, this hypothesis should no longer be ignored and considered sufficient to warrant further larger-scale studies to determine its veracity.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Tzou:2022wj", + "year": 2022, + "authors": "Tzou, Philip L and Tao, Kaiming and Pond, Sergei L Kosakovsky and Shafer, Robert W", + "title": "Coronavirus Resistance Database (CoV-RDB): SARS-CoV-2 susceptibility to monoclonal antibodies, convalescent plasma, and plasma from vaccinated persons", + "journal": "PLoS One", + "doi": "", + "abstract": "As novel SARS-CoV-2 variants with different patterns of spike protein mutations have emerged, the susceptibility of these variants to neutralization by antibodies has been rapidly assessed. However, neutralization data are generated using different approaches and are scattered across different publications making it difficult for these data to be located and synthesized. The Stanford Coronavirus Resistance Database (CoV-RDB; https://covdb.stanford.edu) is designed to house comprehensively curated published data on the neutralizing susceptibility of SARS-CoV-2 variants and spike mutations to monoclonal antibodies (mAbs), convalescent plasma (CP), and vaccinee plasma (VP). As of December 31, 2021, CoV-RDB encompassed 257 publications including 91 (35%) containing 9,070 neutralizing mAb susceptibility results, 131 (51%) containing 16,773 neutralizing CP susceptibility results, and 178 (69%) containing 33,540 neutralizing VP results. The database also records which spike mutations are selected during in vitro passage of SARS-CoV-2 in the presence of mAbs and which emerge in persons receiving mAbs as treatment. The CoV-RDB interface interactively displays neutralizing susceptibility data at different levels of granularity by filtering and/or aggregating query results according to one or more experimental conditions. The CoV-RDB website provides a companion sequence analysis program that outputs information about mutations present in a submitted sequence and that also assists users in determining the appropriate mutation-detection thresholds for identifying non-consensus amino acids. The most recent data underlying the CoV-RDB can be downloaded in its entirety from a GitHub repository in a documented machine-readable format.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Lytras:2022tz", + "year": 2022, + "authors": "Lytras, Spyros and Hughes, Joseph and Martin, Darren and Swanepoel, Phillip and de Klerk, Arn{\\'e} and Lourens, Rentia and Pond, Sergei L Kosakovsky and Xia, Wei and Jiang, Xiaowei and Robertson, David L", + "title": "Exploring the Natural Origins of SARS-CoV-2 in the Light of Recombination", + "journal": "Genome Biol Evol", + "doi": "", + "abstract": "The lack of an identifiable intermediate host species for the proximal animal ancestor of SARS-CoV-2, and the large geographical distance between Wuhan and where the closest evolutionary related coronaviruses circulating in horseshoe bats (members of the Sarbecovirus subgenus) have been identified, is fueling speculation on the natural origins of SARS-CoV-2. We performed a comprehensive phylogenetic study on SARS-CoV-2 and all the related bat and pangolin sarbecoviruses sampled so far. Determining the likely recombination events reveals a highly reticulate evolutionary history within this group of coronaviruses. Distribution of the inferred recombination events is nonrandom with evidence that Spike, the main target for humoral immunity, is beside a recombination hotspot likely driving antigenic shift events in the ancestry of bat sarbecoviruses. Coupled with the geographic ranges of their hosts and the sampling locations, across southern China, and into Southeast Asia, we confirm that horseshoe bats, Rhinolophus, are the likely reservoir species for the SARS-CoV-2 progenitor. By tracing the recombinant sequence patterns, we conclude that there has been relatively recent geographic movement and cocirculation of these viruses' ancestors, extending across their bat host ranges in China and Southeast Asia over the last 100\u2009years. We confirm that a direct proximal ancestor to SARS-CoV-2 has not yet been sampled, since the closest known relatives collected in Yunnan shared a common ancestor with SARS-CoV-2 approximately 40\u2009years ago. Our analysis highlights the need for dramatically more wildlife sampling to: 1) pinpoint the exact origins of SARS-CoV-2's animal progenitor, 2) the intermediate species that facilitated transmission from bats to humans (if there is one), and 3) survey the extent of the diversity in the related sarbecoviruses' phylogeny that present high risk for future spillovers.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "VIR", + "year": 2022, + "authors": "Maher, M Cyrus and Bartha, Istvan and Weaver, Steven and di Iulio, Julia and Ferri, Elena and Soriaga, Leah and Lempp, Florian A and Hie, Brian L and Bryson, Bryan and Berger, Bonnie and Robertson, David L and Snell, Gyorgy and Corti, Davide and Virgin, Herbert W and Pond, Sergei L Kosakovsky and Telenti, Amalio", + "title": "Predicting the mutational drivers of future SARS-CoV-2 variants of concern", + "journal": "Sci Transl Med", + "doi": "", + "abstract": "[Figure: see text].", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "matrosovichH3N2", + "year": 2021, + "authors": "West, Johanna and R{\\\"o}der, Juliane and Matrosovich, Tatyana and Beicht, Jana and Baumann, Jan and Mounogou Kouassi, Nancy and Doedt, Jennifer and Bovin, Nicolai and Zamperin, Gianpiero and Gastaldelli, Michele and Salviato, Annalisa and Bonfante, Francesco and Kosakovsky Pond, Sergei and Herfst, Sander and Fouchier, Ron and Wilhelm, Jochen and Klenk, Hans-Dieter and Matrosovich, Mikhail", + "title": "Characterization of changes in the hemagglutinin that accompanied the emergence of H3N2/1968 pandemic influenza viruses", + "journal": "PLoS Pathog", + "doi": "", + "abstract": "The hemagglutinin (HA) of A/H3N2 pandemic influenza viruses (IAVs) of 1968 differed from its inferred avian precursor by eight amino acid substitutions. To determine their phenotypic effects, we studied recombinant variants of A/Hong Kong/1/1968 virus containing either human-type or avian-type amino acids in the corresponding positions of HA. The precursor HA displayed receptor binding profile and high conformational stability typical for duck IAVs. Substitutions Q226L and G228S, in addition to their known effects on receptor specificity and replication, marginally decreased HA stability. Substitutions R62I, D63N, D81N and N193S reduced HA binding avidity. Substitutions R62I, D81N and A144G promoted viral replication in human airway epithelial cultures. Analysis of HA sequences revealed that substitutions D63N and D81N accompanied by the addition of N-glycans represent common markers of avian H3 HA adaptation to mammals. Our results advance understanding of genotypic and phenotypic changes in IAV HA required for avian-to-human adaptation and pandemic emergence.", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "GalaxyCOVID", + "year": 2021, + "authors": "Maier, Wolfgang and Bray, Simon and van den Beek, Marius and Bouvier, Dave and Coraor, Nathan and Miladi, Milad and Singh, Babita and De Argila, Jordi Rambla and Baker, Dannon and Roach, Nathan and Gladman, Simon and Coppens, Frederik and Martin, Darren P and Lonie, Andrew and Gr{\\\"u}ning, Bj{\\\"o}rn and Pond, Sergei L Kosakovsky and Nekrutenko, Anton", + "title": "Ready-to-use public infrastructure for global SARS-CoV-2 monitoring", + "journal": "Nat Biotechnol", + "doi": "", + "abstract": "", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "N501Y", + "year": 2021, + "authors": "Martin, Darren P and Weaver, Steven and Tegally, Houriiyah and San, James Emmanuel and Shank, Stephen D and Wilkinson, Eduan and Lucaci, Alexander G and Giandhari, Jennifer and Naidoo, Sureshnee and Pillay, Yeshnee and Singh, Lavanya and Lessells, Richard J and {NGS-SA} and {COVID-19 Genomics UK (COG-UK)} and Gupta, Ravindra K and Wertheim, Joel O and Nekturenko, Anton and Murrell, Ben and Harkins, Gordon W and Lemey, Philippe and MacLean, Oscar A and Robertson, David L and de Oliveira, Tulio and Pond, Sergei L Kosakovsky", + "title": "The emergence and ongoing convergent evolution of the SARS-CoV-2 N501Y lineages", + "journal": "Cell", + "doi": "", + "abstract": "The independent emergence late in 2020 of the B.1.1.7, B.1.351, and P.1 lineages of SARS-CoV-2 prompted renewed concerns about the evolutionary capacity of this virus to overcome public health interventions and rising population immunity. Here, by examining patterns of synonymous and non-synonymous mutations that have accumulated in SARS-CoV-2 genomes since the pandemic began, we find that the emergence of these three \"501Y lineages\" coincided with a major global shift in the selective forces acting on various SARS-CoV-2 genes. Following their emergence, the adaptive evolution of 501Y lineage viruses has involved repeated selectively favored convergent mutations at 35 genome sites, mutations we refer to as the 501Y meta-signature. The ongoing convergence of viruses in many other lineages on this meta-signature suggests that it includes multiple mutation combinations capable of promoting the persistence of diverse SARS-CoV-2 lineages in the face of mounting host immune recognition.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Tao:2021vv", + "year": 2021, + "authors": "Tao, Kaiming and Tzou, Philip L and Nouhin, Janin and Gupta, Ravindra K and de Oliveira, Tulio and Pond, Sergei L Kosakovsky and Fera, Daniela and Shafer, Robert W", + "title": "The biological and clinical significance of emerging SARS-CoV-2 variants", + "journal": "Nat Rev Genet", + "doi": "", + "abstract": "The past several months have witnessed the emergence of SARS-CoV-2 variants with novel spike protein mutations that are influencing the epidemiological and clinical aspects of the COVID-19 pandemic. These variants can increase rates of virus transmission and/or increase the risk of reinfection and reduce the protection afforded by neutralizing monoclonal antibodies and vaccination. These variants can therefore enable SARS-CoV-2 to continue its spread in the face of rising population immunity while maintaining or increasing its replication fitness. The identification of four rapidly expanding virus lineages since December 2020, designated variants of concern, has ushered in a new stage of the pandemic. The four variants of concern, the Alpha variant (originally identified in the UK), the Beta variant (originally identified in South Africa), the Gamma variant (originally identified in Brazil) and the Delta variant (originally identified in India), share several mutations with one another as well as with an increasing number of other recently identified SARS-CoV-2 variants. Collectively, these SARS-CoV-2 variants complicate the COVID-19 research agenda and necessitate additional avenues of laboratory, epidemiological and clinical research.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Mei:2021uw", + "year": 2021, + "authors": "Mei, Han and Pond, Sergei L Kosakovsky and Nekrutenko, Anton", + "title": "Stepwise evolution and exceptional conservation of ORF1a/b overlap in coronaviruses", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "The programmed frameshift element (PFE) rerouting translation from ORF1a to ORF1b is essential for propagation of coronaviruses. The combination of genomic features that make up PFE-the overlap between the two reading frames, a slippery sequence, as well as an ensemble of complex secondary structure elements-places severe constraints on this region as most possible nucleotide substitution may disrupt one or more of these elements. The vast amount of SARS-CoV-2 sequencing data generated within the past year provides an opportunity to assess evolutionary dynamics of PFE in great detail. Here we performed a comparative analysis of all available coronaviral genomic data available to date. We show that the overlap between ORF1a and ORF1b evolved as a set of discrete 7, 16, 22, 25, and 31 nucleotide stretches with a well defined phylogenetic specificity. We further examined sequencing data from over 1,500,000 complete genomes and 55,000 raw read datasets to demonstrate exceptional conservation and detect signatures of selection within the PFE region.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Maier:2021un", + "year": 2021, + "authors": "Maier, Wolfgang and Bray, Simon and van den Beek, Marius and Bouvier, Dave and Coraor, Nathaniel and Miladi, Milad and Singh, Babita and De Argila, Jordi Rambla and Baker, Dannon and Roach, Nathan and Gladman, Simon and Coppens, Frederik and Martin, Darren P and Lonie, Andrew and Gr{\\\"u}ning, Bj{\\\"o}rn and Pond, Sergei L Kosakovsky and Nekrutenko, Anton", + "title": "Freely accessible ready to use global infrastructure for SARS-CoV-2 monitoring", + "journal": "bioRxiv", + "doi": "", + "abstract": "The COVID-19 pandemic is the first global health crisis to occur in the age of big genomic data.Although data generation capacity is well established and sufficiently standardized, analytical capacity is not. To establish analytical capacity it is necessary to pull together global computational resources and deliver the best open source tools and analysis workflows within a ready to use, universally accessible resource. Such a resource should not be controlled by a single research group, institution, or country. Instead it should be maintained by a community of users and developers who ensure that the system remains operational and populated with current tools. A community is also essential for facilitating the types of discourse needed to establish best analytical practices. Bringing together public computational research infrastructure from the USA, Europe, and Australia, we developed a distributed data analysis platform that accomplishes these goals. It is immediately accessible to anyone in the world and is designed for the analysis of rapidly growing collections of deep sequencing datasets. We demonstrate its utility by detecting allelic variants in high-quality existing SARS-CoV-2 sequencing datasets and by continuous reanalysis of COG-UK data. All workflows, data, and documentation is available at https://covid19.galaxyproject.org .", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Cui:2021ui", + "year": 2021, + "authors": "Cui, Rongfeng and Tyers, Alexandra M and Malubhoy, Zahabiya Juzar and Wisotsky, Sadie and Valdesalici, Stefano and Henriette, Elvina and Pond, Sergei L Kosakovsky and Valenzano, Dario Riccardo", + "title": "Ancestral transoceanic colonization and recent population reduction in a nonannual killifish from the Seychelles archipelago", + "journal": "Mol Ecol", + "doi": "", + "abstract": "Whether freshwater fish colonize remote islands following tectonic or transoceanic dispersal remains an evolutionary puzzle. Integrating dating of known tectonic events with phylogenomics and current species distribution, we find that killifish species distribution is not explained by species dispersal by tectonic drift only. Investigating the colonization of a nonannual killifish (golden panchax, Pachypanchax playfairii) on the Seychelle islands, we found genetic support for transoceanic dispersal and experimentally discovered an adaptation to complete tolerance to seawater. At the macroevolutionary scale, despite their long-lasting isolation, nonannual golden panchax show stronger genome-wide purifying selection than annual killifishes from continental Africa. However, progressive decline in effective population size over a more recent timescale has probably led to the segregation of slightly deleterious mutations across golden panchax populations, which represents a potential threat for species preservation in the long term.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Escalera-Zamudio:2021vw", + "year": 2021, + "authors": "Escalera-Zamudio, Marina and Pond, Sergei L Kosakovsky and de la Vi{\\~n}a, Natalia Mart{\\'\\i}nez and Guti{\\'e}rrez, Bernardo and Th{\\'e}z{\\'e}, Julien and Bowden, Thomas A and Pybus, Oliver G and Hulswit, Ruben J G", + "title": "Identification of site-specific evolutionary trajectories shared across human betacoronaviruses", + "journal": "bioRxiv", + "doi": "", + "abstract": "Comparison of evolution among related viruses can provide insights into shared adaptive processes, for example following host switching to a mutual host species. Whilst phylogenetic methods can help identify mutations that may be important for evolutionary processes such as adaptation to a new host, these can be enhanced by positioning candidate mutations to known functional sites on protein structures. Over the past two decades, three zoonotic betacoronaviruses have significantly impacted human public health: SARS-CoV-1, MERS-CoV and SARS-CoV-2, whilst two other betacoronaviruses, HKU1 and OC43, have circulated endemically in the human population for over 100 years. In this study, we use a comparative approach to prospectively search for potentially evolutionarily-relevant mutations within the Orf1ab and S genes across betacoronavirus species that have demonstrated sustained human-to-human transmission (HKU1, OC43, SARS-CoV-1 and SARS-CoV-2). We used a combination of molecular evolution methods to identify 30 sites that display evidence of homoplasy and/or stepwise evolution, that may be suggestive of adaptation across emerging and endemic betacoronaviruses. Of these, seven sites also display evidence of being selectively relevant. Drawing upon known protein structure data, we find that four of the identified mutations [18121 (exonuclease/27), 21623 (spike/21), 21635 (spike/25) and 23948 (spike/796), in SARS-CoV-2 genome coordinates] are proximal to regions of known functionality. Our results provide a molecular-level context for common evolutionary pathways that betacoronaviruses may undergo during adaptation to the human host.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Radke:2021us", + "year": 2021, + "authors": "Radke, Emily E and Li, Zhi and Hernandez, David N and El Bannoudi, Hanane and Pond, Sergei L Kosakovsky and Shopsin, Bo and Lopez, Peter and Feny{\\\"o}, David and Silverman, Gregg J", + "title": "Diversity of Functionally Distinct Clonal Sets of Human Conventional Memory B Cells That Bind Staphylococcal Protein A", + "journal": "Front Immunol", + "doi": "", + "abstract": "Staphylococcus aureus, a common cause of serious and often fatal infections, is well-armed with secreted factors that disarm host immune defenses. Highly expressed in vivo during infection, Staphylococcal protein A (SpA) is reported to also contribute to nasal colonization that can be a prelude to invasive infection. Co-evolution with the host immune system has provided SpA with an Fc-antibody binding site, and a Fab-binding site responsible for non-immune superantigen interactions via germline-encoded surfaces expressed on many human BCRs. We wondered whether the recurrent exposures to S. aureus commonly experienced by adults, result in the accumulation of memory B-cell responses to other determinants on SpA. We therefore isolated SpA-specific class-switched memory B cells, and characterized their encoding VH : VL antibody genes. In SpA-reactive memory B cells, we confirmed a striking bias in usage for VH genes, which retain the surface that mediates the SpA-superantigen interaction. We postulate these interactions reflect co-evolution of the host immune system and SpA, which during infection results in immune recruitment of an extraordinarily high prevalence of B cells in the repertoire that subverts the augmentation of protective defenses. Herein, we provide the first evidence that human memory responses are supplemented by B-cell clones, and circulating-antibodies, that bind to SpA determinants independent of the non-immune Fc- and Fab-binding sites. In parallel, we demonstrate that healthy individuals, and patients recovering from S. aureus infection, both have circulating antibodies with these conventional binding specificities. These findings rationalize the potential utility of incorporating specially engineered SpA proteins into a protective vaccine.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Cui:2021wq", + "year": 2021, + "authors": "Cui, Rongfeng and Tyers, Alexandra M and Malubhoy, Zahabiya Juzar and Wisotsky, Sadie and Valdesalici, Stefano and Henriette, Elvina and Pond, Sergei L Kosakovsky and Valenzano, Dario Riccardo", + "title": "Ancestral transoceanic colonization and recent population reduction in a non-annual killifish from the Seychelles archipelago", + "journal": "Mol Ecol", + "doi": "", + "abstract": "Whether freshwater fish colonize remote islands following tectonic or transoceanic dispersal remains an evolutionary puzzle. Integrating dating of known tectonic events with phylogenomics and current species distribution, we find that killifish species distribution eludes species dispersal by tectonic drift only. Investigating the colonization of a non-annual killifish (Pachypanchax playfairii) on the Seychelle islands, we found genetic support for trans-oceanic dispersal and experimentally discovered an adaptation to complete tolerance to seawater. At the macroevolutionary scale, despite their long-lasting isolation, non-annual golden panchax show stronger genome-wide purifying selection than annual killifishes from continental Africa. However, progressive decline in effective population size in a more recent time-scale likely led to the segregation of slightly deleterious mutations across golden panchax populations, which represents a potential threat for species preservation on the long run.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "MacLean:2021aa", + "year": 2021, + "authors": "MacLean, Oscar A and Lytras, Spyros and Weaver, Steven and Singer, Joshua B and Boni, Maciej F and Lemey, Philippe and Pond, Sergei L Kosakovsky and Robertson, David L", + "title": "Natural selection in the evolution of SARS-CoV-2 in bats created a generalist virus and highly capable human pathogen", + "journal": "PLoS Biol", + "doi": "", + "abstract": "Virus host shifts are generally associated with novel adaptations to exploit the cells of the new host species optimally. Surprisingly, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has apparently required little to no significant adaptation to humans since the start of the Coronavirus Disease 2019 (COVID-19) pandemic and to October 2020. Here we assess the types of natural selection taking place in Sarbecoviruses in horseshoe bats versus the early SARS-CoV-2 evolution in humans. While there is moderate evidence of diversifying positive selection in SARS-CoV-2 in humans, it is limited to the early phase of the pandemic, and purifying selection is much weaker in SARS-CoV-2 than in related bat Sarbecoviruses. In contrast, our analysis detects evidence for significant positive episodic diversifying selection acting at the base of the bat virus lineage SARS-CoV-2 emerged from, accompanied by an adaptive depletion in CpG composition presumed to be linked to the action of antiviral mechanisms in these ancestral bat hosts. The closest bat virus to SARS-CoV-2, RmYN02 (sharing an ancestor about 1976), is a recombinant with a structure that includes differential CpG content in Spike; clear evidence of coinfection and evolution in bats without involvement of other species. While an undiscovered \"facilitating\" intermediate species cannot be discounted, collectively, our results support the progenitor of SARS-CoV-2 being capable of efficient human-human transmission as a consequence of its adaptive evolutionary history in bats, not humans, which created a relatively generalist virus.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Lucaci:2021aa", + "year": 2021, + "authors": "Lucaci, Alexander G and Wisotsky, Sadie R and Shank, Stephen D and Weaver, Steven and Pond, Sergei L Kosakovsky", + "title": "Extra base hits: Widespread empirical support for instantaneous multiple-nucleotide changes", + "journal": "PLoS One", + "doi": "", + "abstract": "Despite many attempts to introduce evolutionary models that permit substitutions to instantly alter more than one nucleotide in a codon, the prevailing wisdom remains that such changes are rare and generally negligible or are reflective of non-biological artifacts, such as alignment errors. Codon models continue to posit that only single nucleotide change have non-zero rates. Here, we develop and test a simple hierarchy of codon-substitution models with non-zero evolutionary rates for only one-nucleotide (1H), one- and two-nucleotide (2H), or any (3H) codon substitutions. Using over 42, 000 empirical alignments, we find widespread statistical support for multiple hits: 61% of alignments prefer models with 2H allowed, and 23%-with 3H allowed. Analyses of simulated data suggest that these results are not likely to be due to simple artifacts such as model misspecification or alignment errors. Further modeling reveals that synonymous codon island jumping among codons encoding serine, especially along short branches, contributes significantly to this 3H signal. While serine codons were prominently involved in multiple-hit substitutions, there were other common exchanges contributing to better model fit. It appears that a small subset of sites in most alignments have unusual evolutionary dynamics not well explained by existing model formalisms, and that commonly estimated quantities, such as dN/dS ratios may be biased by model misspecification. Our findings highlight the need for continued evaluation of assumptions underlying workhorse evolutionary models and subsequent evolutionary inference techniques. We provide a software implementation for evolutionary biologists to assess the potential impact of extra base hits in their data in the HyPhy package and in the Datamonkey.org server.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Martin:2021te", + "year": 2021, + "authors": "Martin, Darren P and Weaver, Steven and Tegally, Houryiah and San, Emmanuel James and Shank, Stephen D and Wilkinson, Eduan and Giandhari, Jennifer and Naidoo, Sureshnee and Pillay, Yeshnee and Singh, Lavanya and Lessells, Richard J and {NGS-SA} and {COVID-19 Genomics UK (COG-UK)} and Gupta, Ravindra K and Wertheim, Joel O and Nekturenko, Anton and Murrell, Ben and Harkins, Gordon W and Lemey, Philippe and MacLean, Oscar A and Robertson, David L and de Oliveira, Tulio and Pond, Sergei L Kosakovsky", + "title": "The emergence and ongoing convergent evolution of the N501Y lineages coincides with a major global shift in the SARS-CoV-2 selective landscape", + "journal": "medRxiv", + "doi": "", + "abstract": "The emergence and rapid rise in prevalence of three independent SARS-CoV-2 \"501Y lineages'', B.1.1.7, B.1.351 and P.1, in the last three months of 2020 has prompted renewed concerns about the evolutionarily capacity of SARS-CoV-2 to adapt to both rising population immunity, and public health interventions such as vaccines and social distancing. Viruses giving rise to the different 501Y lineages have, presumably under intense natural selection following a shift in host environment, independently acquired multiple unique and convergent mutations. As a consequence all have gained epidemiological and immunological properties that will likely complicate the control of COVID-19. Here, by examining patterns of mutations that arose in SARS-CoV-2 genomes during the pandemic we find evidence of a major change in the selective forces acting on immunologically important SARS-CoV-2 genes (such as N and S) that likely coincided with the emergence of the 501Y lineages. In addition to involving continuing sequence diversification, we find evidence that a significant portion of the ongoing adaptive evolution of the 501Y lineages also involves further convergence between the lineages. Our findings highlight the importance of monitoring how members of these known 501Y lineages, and others still undiscovered, are convergently evolving similar strategies to ensure their persistence in the face of mounting infection and vaccine induced host immune recognition.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Tegally:2021aa", + "year": 2021, + "authors": "Tegally, Houriiyah and Wilkinson, Eduan and Giovanetti, Marta and Iranzadeh, Arash and Fonseca, Vagner and Giandhari, Jennifer and Doolabh, Deelan and Pillay, Sureshnee and San, Emmanuel James and Msomi, Nokukhanya and Mlisana, Koleka and von Gottberg, Anne and Walaza, Sibongile and Allam, Mushal and Ismail, Arshad and Mohale, Thabo and Glass, Allison J and Engelbrecht, Susan and Van Zyl, Gert and Preiser, Wolfgang and Petruccione, Francesco and Sigal, Alex and Hardie, Diana and Marais, Gert and Hsiao, Nei-Yuan and Korsman, Stephen and Davies, Mary-Ann and Tyers, Lynn and Mudau, Innocent and York, Denis and Maslo, Caroline and Goedhals, Dominique and Abrahams, Shareef and Laguda-Akingba, Oluwakemi and Alisoltani-Dehkordi, Arghavan and Godzik, Adam and Wibmer, Constantinos Kurt and Sewell, Bryan Trevor and Louren{\\c c}o, Jos{\\'e} and Alcantara, Luiz Carlos Junior and Pond, Sergei L Kosakovsky and Weaver, Steven and Martin, Darren and Lessells, Richard J and Bhiman, Jinal N and Williamson, Carolyn and de Oliveira, Tulio", + "title": "Detection of a SARS-CoV-2 variant of concern in South Africa", + "journal": "Nature", + "doi": "", + "abstract": "Continued uncontrolled transmission of SARS-CoV-2 in many parts of the world is creating conditions for substantial evolutionary changes to the virus1,2. Here we describe a newly arisen lineage of SARS-CoV-2 (designated 501Y.V2; also known as B.1.351 or 20H) that is defined by eight mutations in the spike protein, including three substitutions (K417N, E484K and N501Y) at residues in its receptor-binding domain that may have functional importance3-5. This lineage was identified in South Africa after the first wave of the epidemic in a severely affected metropolitan area (Nelson Mandela Bay) that is located on the coast of the Eastern Cape province. This lineage spread rapidly, and became dominant in Eastern Cape, Western Cape and KwaZulu-Natal provinces within weeks. Although the full import of the mutations is yet to be determined, the genomic data-which show rapid expansion and displacement of other lineages in several regions-suggest that this lineage is associated with a selection advantage that most plausibly results from increased transmissibility or immune escape6-8.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Rahman:2021vk", + "year": 2021, + "authors": "Rahman, Shakibur and Pond, Sergei L Kosakovsky and Webb, Andrew and Hey, Jody", + "title": "Weak selection on synonymous codons substantially inflates dN/dS estimates in bacteria", + "journal": "Proc Natl Acad Sci U S A", + "doi": "", + "abstract": "Synonymous codon substitutions are not always selectively neutral as revealed by several types of analyses, including studies of codon usage patterns among genes. We analyzed codon usage in 13 bacterial genomes sampled from across a large order of bacteria, Enterobacterales, and identified presumptively neutral and selected classes of synonymous substitutions. To estimate substitution rates, given a neutral/selected classification of synonymous substitutions, we developed a flexible [Formula: see text] substitution model that allows multiple classes of synonymous substitutions. Under this multiclass synonymous substitution (MSS) model, the denominator of [Formula: see text] includes only the strictly neutral class of synonymous substitutions. On average, the value of [Formula: see text] under the MSS model was 80% of that under the standard codon model in which all synonymous substitutions are assumed to be neutral. The indication is that conventional [Formula: see text] analyses overestimate these values and thus overestimate the frequency of positive diversifying selection and underestimate the strength of purifying selection. To quantify the strength of selection necessary to explain this reduction, we developed a model of selected compensatory codon substitutions. The reduction in synonymous substitution rate, and thus the contribution that selection makes to codon bias variation among genes, can be adequately explained by very weak selection, with a mean product of population size and selection coefficient, [Formula: see text].", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kumar:2021wx", + "year": 2021, + "authors": "Kumar, Sudhir and Tao, Qiqing and Weaver, Steven and Sanderford, Maxwell and Caraballo-Ortiz, Marcos A and Sharma, Sudip and Pond, Sergei L K and Miura, Sayaka", + "title": "An evolutionary portrait of the progenitor SARS-CoV-2 and its dominant offshoots in COVID-19 pandemic", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Global sequencing of hundreds of thousands of genomes of Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, has continued to reveal new genetic variants that are the key to unraveling its early evolutionary history and tracking its global spread over time. Here, we present the heretofore cryptic mutational history and spatiotemporal dynamics of SARS-CoV-2 from an analysis of thousands of high-quality genomes. We report the likely most recent common ancestor of SARS-CoV-2, reconstructed through a novel application and advancement of computational methods initially developed to infer the mutational history of tumor cells in a patient. This progenitor genome differs from genomes of the first coronaviruses sampled in China by three variants, implying that none of the earliest patients represent the index case or gave rise to all the human infections. However, multiple coronavirus infections in China and the USA harbored the progenitor genetic fingerprint in January 2020 and later, suggesting that the progenitor was spreading worldwide months before and after the first reported cases of COVID-19 in China. Mutations of the progenitor and its offshoots have produced many dominant coronavirus strains, which have spread episodically over time. Fingerprinting based on common mutations reveals that the same coronavirus lineage has dominated North America for most of the pandemic in 2020. There have been multiple replacements of predominant coronavirus strains in Europe and Asia and the continued presence of multiple high-frequency strains in Asia and North America. We have developed a continually updating dashboard of global evolution and spatiotemporal trends of SARS-CoV-2 spread (http://sars2evo.datamonkey.org/).", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Faria:2021wv", + "year": 2021, + "authors": "Faria, Nuno R and Mellan, Thomas A and Whittaker, Charles and Claro, Ingra M and Candido, Darlan da S and Mishra, Swapnil and Crispim, Myuki A E and Sales, Flavia C S and Hawryluk, Iwona and McCrone, John T and Hulswit, Ruben J G and Franco, Lucas A M and Ramundo, Mariana S and de Jesus, Jaqueline G and Andrade, Pamela S and Coletti, Thais M and Ferreira, Giulia M and Silva, Camila A M and Manuli, Erika R and Pereira, Rafael H M and Peixoto, Pedro S and Kraemer, Moritz U G and Gaburo, Jr, Nelson and Camilo, Cecilia da C and Hoeltgebaum, Henrique and Souza, William M and Rocha, Esmenia C and de Souza, Leandro M and de Pinho, Mariana C and Araujo, Leonardo J T and Malta, Frederico S V and de Lima, Aline B and Silva, Joice do P and Zauli, Danielle A G and Ferreira, Alessandro C de S and Schnekenberg, Ricardo P and Laydon, Daniel J and Walker, Patrick G T and Schl{\\\"u}ter, Hannah M and Dos Santos, Ana L P and Vidal, Maria S and Del Caro, Valentina S and Filho, Rosinaldo M F and Dos Santos, Helem M and Aguiar, Renato S and Proen{\\c c}a-Modena, Jos{\\'e} L and Nelson, Bruce and Hay, James A and Monod, M{\\'e}lodie and Miscouridou, Xenia and Coupland, Helen and Sonabend, Raphael and Vollmer, Michaela and Gandy, Axel and Prete, Jr, Carlos A and Nascimento, Vitor H and Suchard, Marc A and Bowden, Thomas A and Pond, Sergei L K and Wu, Chieh-Hsi and Ratmann, Oliver and Ferguson, Neil M and Dye, Christopher and Loman, Nick J and Lemey, Philippe and Rambaut, Andrew and Fraiji, Nelson A and Carvalho, Maria do P S S and Pybus, Oliver G and Flaxman, Seth and Bhatt, Samir and Sabino, Ester C", + "title": "Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil", + "journal": "Science", + "doi": "", + "abstract": "Cases of SARS-CoV-2 infection in Manaus, Brazil, resurged in late 2020, despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1, acquired 17 mutations, including a trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.7-2.4-fold more transmissible, and that previous (non-P.1) infection provides 54-79% of the protection against infection with P.1 that it provides against non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness.", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Li:2021up", + "year": 2021, + "authors": "Li, Xingguang and Liu, Haizhou and Rife Magalis, Brittany and Pond, Sergei L Kosakovsky and Volz, Erik M", + "title": "Molecular Evolution of Human Norovirus GII.2 Clusters", + "journal": "Front Microbiol", + "doi": "", + "abstract": "Background: The human norovirus GII.2 outbreak during the 2016-2017 winter season was of unprecedented scale and geographic distribution.\nMethods: We analyzed 519 complete VP1 gene sequences of the human norovirus GII.2 genotype sampled during the 2016-2017 winter season, as well as prior (dating back to 1976) from 7 countries. Phylodynamic analyses of these sequences were performed using maximum likelihood and Bayesian statistical frameworks in order to estimate viral evolutionary and population dynamics associated with the outbreak.\nResults: Our results revealed an increase in the genetic diversity of human norovirus GII.2 during the recent Asian outbreak and diversification was characterized by at least eight distinct clusters. Bayesian estimation of viral population dynamics revealed a highly fluctuating effective population size, increasing in frequency during the past 15 years.\nConclusion: Despite an increasing viral diversity, we found no evidence of an elevated evolutionary rate or significant selection pressure in human norovirus GII.2, indicating viral evolutionary adaptation was not responsible for the volatility of or spread of the virus during this time.", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Tagliamonte:2020th", + "year": 2020, + "authors": "Tagliamonte, Massimiliano S and Abid, Nabil and Borocci, Stefano and Sangiovanni, Elisa and Ostrov, David A and Pond, Sergei L Kosakovsky and Salemi, Marco and Chillemi, Giovanni and Mavian, Carla", + "title": "Multiple Recombination Events and Strong Purifying Selection at the Origin of SARS-CoV-2 Spike Glycoprotein Increased Correlated Dynamic Movements", + "journal": "Int J Mol Sci", + "doi": "", + "abstract": "Our evolutionary and structural analyses revealed that the severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) spike gene is a complex mosaic resulting from several recombination events. Additionally, the fixation of variants has mainly been driven by purifying selection, suggesting the presence of conserved structural features. Our dynamic simulations identified two main long-range covariant dynamic movements of the novel glycoprotein, and showed that, as a result of the evolutionary duality, they are preserved. The first movement involves the receptor binding domain with the N-terminal domain and the C-terminal domain 2 and is maintained across human, bat and pangolin coronaviruses. The second is a complex network of long-range dynamics specific to SARS-CoV-2 involving the novel PRRA and the conserved KR*SF cleavage sites, as well as conserved segments in C-terminal domain 3. These movements, essential for host cell binding, are maintained by hinges conserved across human, bat, and pangolin coronaviruses glycoproteins. The hinges, located around Threonine 333 and Proline 527 within the N-terminal domain and C-terminal domain 2, represent candidate targets for the future development of novel pan-coronavirus inhibitors. In summary, we show that while recombination created a new configuration that increased the covariant dynamic movements of the SARS-CoV-2 glycoprotein, negative selection preserved its inter-domain structure throughout evolution in different hosts and inter-species transmissions.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Little:2021ts", + "year": 2021, + "authors": "Little, Susan J and Chen, Tom and Wang, Rui and Anderson, Christy and Kosakovsky Pond, Sergei and Nakazawa, Masato and Mathews, William C and DeGruttola, Victor and Smith, Davey M", + "title": "Effective HIV Molecular Surveillance Requires Identification of Incident Cases of Infection", + "journal": "Clin Infect Dis", + "doi": "", + "abstract": "BACKGROUND: Ending the HIV epidemic requires knowledge of key drivers of spread of HIV infection.\nMETHODS: Between 1996 and 2018, 1119 newly and previously diagnosed, therapy-na{\\\"\\i}ve persons with HIV (PWH) from San Diego were followed. A genetic distance-based network was inferred using pol sequences, and genetic clusters grew over time through linkage of sequences from newly observed infections. Cox proportional hazards models were used to identify factors associated with the rate of growth. These results were used to predict the impact of a hypothetical intervention targeting PWH with incident infection. Comparison was made to the CDC EHE molecular surveillance strategy, which prioritizes clusters recently linked to all new HIV diagnoses and does not incorporate data on incident infections.\nRESULTS: Overall, 219 genetic linkages to incident infections were identified over a median follow-up of 8.8 years. Incident cluster growth was strongly associated with proportion of PWH in the cluster who themselves had incident infection. (HR 44.09; 95% CI: 17.09, 113.78). The CDC EHE molecular surveillance strategy identified 11 linkages to incident infections a genetic distance threshold of 0.5%, and 24 linkages at 1.5%.\nCONCLUSIONS: Over the past two decades, incident infections drove incident HIV cluster growth in San Diego. The current CDC EHE molecular detection and response strategy would not have identified most transmission events arising from those with incident infection in San Diego. Molecular surveillance that includes detection of incident cases will provide a more effective strategy for EHE.", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Council:2020aa", + "year": 2020, + "authors": "Council, Olivia D and Zhou, Shuntai and McCann, Chase D and Hoffman, Irving and Tegha, Gerald and Kamwendo, Deborah and Matoga, Mitch and Pond, Sergei LK and Cohen, Myron S and Swanstrom, Ronald", + "title": "Deep Sequencing Reveals Compartmentalized HIV-1 in the Semen of Men with and without Sexually Transmitted Infection-Associated Urethritis", + "journal": "J Virol", + "doi": "", + "abstract": "Concurrent sexually transmitted infections (STI) can increase the probability of HIV-1 transmission primarily by increasing the viral load present in semen. In this study, we explored the relationship of HIV-1 in blood and seminal plasma in the presence and absence of urethritis and after treatment of the concurrent STI. Primer ID deep sequencing of the V1/V3 region of the HIV-1 env gene was done for paired blood and semen samples from antiretroviral therapy (ART)-naive men living in Malawi with (n\u2009=\u200919) and without (n\u2009=\u20095) STI-associated urethritis; for a subset of samples, full-length env genes were generated for sequence analysis and to test entry phenotype. Cytokine concentrations in the blood and semen were also measured, and a reduction in the levels of proinflammatory cytokines was observed following STI treatment. We observed no difference in the prevalence of diverse compartmentalized semen-derived lineages in men with or without STI-associated urethritis, and these viral populations were largely stable during STI treatment. Clonal amplification of one or a few viral sequences accounted for nearly 50% of the viral population, indicating a recent bottleneck followed by limited viral replication. We conclude that the male genital tract is a site where virus can be brought in from the blood, where localized sustained replication can occur, and where specific genotypes can be amplified, perhaps initially by cellular proliferation but further by limited viral replication.IMPORTANCE HIV-1 infection is a sexually transmitted infection that coexists with other STI. Here, we examined the impact of a concurrent STI resulting in urethritis on the HIV-1 population within the male genital tract. We found that viral populations remain largely stable even with treatment of the STI. These results show that viral populations within the male genital tract are defined by factors beyond transient inflammation associated with a concurrent STI.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wisotsky:2020ab", + "year": 2020, + "authors": "Wisotsky, Sadie R and Pond, Sergei LK and Shank, Stephen D and Muse, Spencer V", + "title": "Synonymous Site-to-Site Substitution Rate Variation Dramatically Inflates False Positive Rates of Selection Analyses: Ignore at Your Own Peril", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Most molecular evolutionary studies of natural selection maintain the decades-old assumption that synonymous substitution rate variation (SRV) across sites within genes occurs at levels that are either nonexistent or negligible. However, numerous studies challenge this assumption from a biological perspective and show that SRV is comparable in magnitude to that of nonsynonymous substitution rate variation. We evaluated the impact of this assumption on methods for inferring selection at the molecular level by incorporating SRV into an existing method (BUSTED) for detecting signatures of episodic diversifying selection in genes. Using simulated data we found that failing to account for even moderate levels of SRV in selection testing is likely to produce intolerably high false positive rates. To evaluate the effect of the SRV assumption on actual inferences we compared results of tests with and without the assumption in an empirical analysis of over 13,000 Euteleostomi (bony vertebrate) gene alignments from the Selectome database. This exercise reveals that close to 50% of positive results (i.e., evidence for selection) in empirical analyses disappear when SRV is modeled as part of the statistical analysis and are thus candidates for being false positives. The results from this work add to a growing literature establishing that tests of selection are much more sensitive to certain model assumptions than previously believed.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Pollock:2020ab", + "year": 2020, + "authors": "Pollock, David D and Castoe, Todd A and Perry, Blair W and Lytras, Spyros and Wade, Kristen J and Robertson, David L and Holmes, Edward C and Boni, Maciej F and Pond, Sergei LK and Parry, Rhys and Carlton, Elizabeth J and Wood, James L N and Pennings, Pleuni S and Goldstein, Richard A", + "title": "Viral CpG Deficiency Provides No Evidence That Dogs Were Intermediate Hosts for SARS-CoV-2", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Due to the scope and impact of the COVID-19 pandemic there exists a strong desire to understand where the SARS-CoV-2 virus came from and how it jumped species boundaries to humans. Molecular evolutionary analyses can trace viral origins by establishing relatedness and divergence times of viruses and identifying past selective pressures. However, we must uphold rigorous standards of inference and interpretation on this topic because of the ramifications of being wrong. Here, we dispute the conclusions of Xia (2020. Extreme genomic CpG deficiency in SARS-CoV-2 and evasion of host antiviral defense. Mol Biol Evol. doi:10.1093/molbev/masa095) that dogs are a likely intermediate host of a SARS-CoV-2 ancestor. We highlight major flaws in Xia's inference process and his analysis of CpG deficiencies, and conclude that there is no direct evidence for the role of dogs as intermediate hosts. Bats and pangolins currently have the greatest support as ancestral hosts of SARS-CoV-2, with the strong caveat that sampling of wildlife species for coronaviruses has been limited.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kosakovsky-Pond:2020aa", + "year": 2020, + "authors": "Pond, Sergei LK and Wisotsky, Sadie R and Escalante, Ananias and Magalis, Brittany Rife and Weaver, Steven", + "title": "Contrast-FEL - a test for differences in selective pressures at individual sites among clades and sets of branches", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "A number of evolutionary hypotheses can be tested by comparing selective pressures among sets of branches in a phylogenetic tree. When the question of interest is to identify specific sites within genes that may be evolving differently, a common approach is to perform separate analyses on subsets of sequences, and compare parameter estimates in a post hoc fashion. This approach is statistically suboptimal, and not always applicable. Here, we develop a simple extension of a popular fixed effects likelihood method in the context of codon-based evolutionary phylogenetic maximum likelihood testing, Contrast-FEL. It is suitable for identifying individual alignment sites where any among the K \u2265 2 sets of branches in a phylogenetic tree have detectably different \u03c9 ratios, indicative of different selective regimes. Using extensive simulations, we show that Contrast-FEL delivers good power, exceeding 90% for sufficiently large differences, while maintaining tight control over false positive rates, when the model is correctly specified. We conclude by applying Contrast-FEL to data from five previously published studies spanning a diverse range of organisms and focusing on different evolutionary questions.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Mavian:2020ab", + "year": 2020, + "authors": "Mavian, Carla and Pond, Sergei Kosakovsky and Marini, Simone and Magalis, Brittany Rife and Vandamme, Anne-Mieke and Dellicour, Simon and Scarpino, Samuel V and Houldcroft, Charlotte and Villabona-Arenas, Julian and Paisie, Taylor K and Trov{\\~a}o, N{\\'\\i}dia S and Boucher, Christina and Zhang, Yun and Scheuermann, Richard H and Gascuel, Olivier and Lam, Tommy Tsan-Yuk and Suchard, Marc A and Abecasis, Ana and Wilkinson, Eduan and de Oliveira, Tulio and Bento, Ana I and Schmidt, Heiko A and Martin, Darren and Hadfield, James and Faria, Nuno and Grubaugh, Nathan D and Neher, Richard A and Baele, Guy and Lemey, Philippe and Stadler, Tanja and Albert, Jan and Crandall, Keith A and Leitner, Thomas and Stamatakis, Alexandros and Prosperi, Mattia and Salemi, Marco", + "title": "Sampling bias and incorrect rooting make phylogenetic network tracing of SARS-COV-2 infections unreliable", + "journal": "Proc Natl Acad Sci U S A", + "doi": "", + "abstract": "", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Baker:2020aa", + "year": 2020, + "authors": "Baker, Dannon and van den Beek, Marius and Blankenberg, Daniel and Bouvier, Dave and Chilton, John and Coraor, Nate and Coppens, Frederik and Eguinoa, Ignacio and Gladman, Simon and Gr{\\\"u}ning, Bj{\\\"o}rn and Keener, Nicholas and Larivi{\\`e}re, Delphine and Lonie, Andrew and Kosakovsky Pond, Sergei and Maier, Wolfgang and Nekrutenko, Anton and Taylor, James and Weaver, Steven", + "title": "No more business as usual: Agile and effective responses to emerging pathogen threats require open data and open analytics", + "journal": "PLoS Pathog", + "doi": "", + "abstract": "The current state of much of the Wuhan pneumonia virus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) research shows a regrettable lack of data sharing and considerable analytical obfuscation. This impedes global research cooperation, which is essential for tackling public health emergencies and requires unimpeded access to data, analysis tools, and computational infrastructure. Here, we show that community efforts in developing open analytical software tools over the past 10 years, combined with national investments into scientific computational infrastructure, can overcome these deficiencies and provide an accessible platform for tackling global health emergencies in an open and transparent manner. Specifically, we use all SARS-CoV-2 genomic data available in the public domain so far to (1) underscore the importance of access to raw data and (2) demonstrate that existing community efforts in curation and deployment of biomedical software can reliably support rapid, reproducible research during global health crises. All our analyses are fully documented at https://github.com/galaxyproject/SARS-CoV-2.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "RifeMagalis:2020aa", + "year": 2020, + "authors": "RifeMagalis, Brittany and Strickland, Samantha L and Shank, Stephen D and Autissier, Patrick and Schuetz, Alexandra and Sithinamsuwan, Pasiri and Lerdlum, Sukalaya and Fletcher, James L K and de Souza, Mark and Ananworanich, Jintanat and Valcour, Victor and {Search007 Study Group} and Williams, Kenneth C and Pond, Sergei L Kosakovsky and RattoKim, Silvia and Salemi, Marco", + "title": "Phyloanatomic characterization of the distinct T cell and monocyte contributions to the peripheral blood HIV population within the host", + "journal": "Virus Evol", + "doi": "", + "abstract": "Human immunodeficiency virus (HIV) is a rapidly evolving virus, allowing its genetic sequence to act as a fingerprint for epidemiological processes among, as well as within, individual infected hosts. Though primarily infecting the CD4+ T-cell population, HIV can also be found in monocytes, an immune cell population that differs in several aspects from the canonical T-cell viral target. Using single genome viral sequencing and statistical phylogenetic inference, we investigated the viral RNA diversity and relative contribution of each of these immune cell types to the viral population within the peripheral blood. Results provide evidence of an increased prevalence of circulating monocytes harboring virus in individuals with high viral load in the absence of suppressive antiretroviral therapy. Bayesian phyloanatomic analysis of three of these individuals demonstrated a measurable role for these cells, but not the circulating T-cell population, as a source of cell-free virus in the plasma, supporting the hypothesis that these cells can act as an additional conduit of virus spread.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Mannino:2020aa", + "year": 2020, + "authors": "Mannino, Frank and Wisotsky, Sadie and Pond, Sergei L Kosakovsky and Muse, Spencer V", + "title": "Equiprobable discrete models of site-specific substitution rates underestimate the extent of rate variability", + "journal": "PLoS One", + "doi": "", + "abstract": "It is standard practice to model site-to-site variability of substitution rates by discretizing a continuous distribution into a small number, K, of equiprobable rate categories. We demonstrate that the variance of this discretized distribution has an upper bound determined solely by the choice of K and the mean of the distribution. This bound can introduce biases into statistical inference, especially when estimating parameters governing site-to-site variability of substitution rates. Applications to two large collections of sequence alignments demonstrate that this upper bound is often reached in analyses of real data. When parameter estimation is of primary interest, additional rate categories or more flexible modeling methods should be considered.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Tzou:2020aa", + "year": 2020, + "authors": "Tzou, Philip L and Pond, Sergei L Kosakovsky and Avila-Rios, Santiago and Holmes, Susan P and Kantor, Rami and Shafer, Robert W", + "title": "Analysis of unusual and signature APOBEC-mutations in HIV-1 pol next-generation sequences", + "journal": "PLoS One", + "doi": "", + "abstract": "INTRODUCTION: At low mutation-detection thresholds, next generation sequencing (NGS) for HIV-1 genotypic resistance testing is susceptible to artifactual detection of mutations arising from PCR error and APOBEC-mediated G-to-A hypermutation.\nMETHODS: We analyzed published HIV-1 pol Illumina NGS data to characterize the distribution of mutations at eight NGS mutation detection thresholds: 20%, 10%, 5%, 2%, 1%, 0.5%, 0.2%, and 0.1%. At each threshold, we determined proportions of amino acid mutations that were unusual (defined as having a prevalence <0.01% in HIV-1 group M sequences) or signature APOBEC mutations.\nRESULTS: Eight studies, containing 855 samples, in the NCBI Sequence Read Archive were analyzed. As detection thresholds were lowered, there was a progressive increase in the proportion of positions with usual and unusual mutations and in the proportion of all mutations that were unusual. The median proportion of positions with an unusual mutation increased gradually from 0% at the 20% threshold to 0.3% at the 1% threshold and then exponentially to 1.3% (0.5% threshold), 6.9% (0.2% threshold), and 23.2% (0.1% threshold). In two of three studies with available plasma HIV-1 RNA levels, the proportion of positions with unusual mutations was negatively associated with virus levels. Although the complete set of signature APOBEC mutations was much smaller than that of unusual mutations, the former outnumbered the latter in one-sixth of samples at the 0.5%, 1%, and 2% thresholds.\nCONCLUSIONS: The marked increase in the proportion of positions with unusual mutations at thresholds below 1% and in samples with lower virus loads suggests that, at low thresholds, many unusual mutations are artifactual, reflecting PCR error or G-to-A hypermutation. Profiling the numbers of unusual and signature APOBEC pol mutations at different NGS mutation detection thresholds may be useful to avoid selecting a threshold that is too low and poses an unacceptable risk of identifying artifactual mutations.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Miura:2020aa", + "year": 2020, + "authors": "Miura, Sayaka and Tamura, Koichiro and Tao, Qiqing and Huuki, Louise A and Pond, Sergei L Kosakovsky and Priest, Jessica and Deng, Jiamin and Kumar, Sudhir", + "title": "A new method for inferring timetrees from temporally sampled molecular sequences", + "journal": "PLoS Comput Biol", + "doi": "", + "abstract": "Pathogen timetrees are phylogenies scaled to time. They reveal the temporal history of a pathogen spread through the populations as captured in the evolutionary history of strains. These timetrees are inferred by using molecular sequences of pathogenic strains sampled at different times. That is, temporally sampled sequences enable the inference of sequence divergence times. Here, we present a new approach (RelTime with Dated Tips [RTDT]) to estimating pathogen timetrees based on a relative rate framework underlying the RelTime approach that is algebraic in nature and distinct from all other current methods. RTDT does not require many of the priors demanded by Bayesian approaches, and it has light computing requirements. In analyses of an extensive collection of computer-simulated datasets, we found the accuracy of RTDT time estimates and the coverage probabilities of their confidence intervals (CIs) to be excellent. In analyses of empirical datasets, RTDT produced dates that were similar to those reported in the literature. In comparative benchmarking with Bayesian and non-Bayesian methods (LSD, TreeTime, and treedater), we found that no method performed the best in every scenario. So, we provide a brief guideline for users to select the most appropriate method in empirical data analysis. RTDT is implemented for use via a graphical user interface and in high-throughput settings in the newest release of cross-platform MEGA X software, freely available from http://www.megasoftware.net.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wisotsky:2020aa", + "year": 2020, + "authors": "Wisotsky, Sadie R and Pond, Sergei L Kosakovsky and Shank, Stephen D and Muse, Spencer V", + "title": "Synonymous site-to-site substitution rate variation dramatically inflates false positive rates of selection analyses: ignore at your own peril", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Most molecular evolutionary studies of natural selection maintain the decades-old assumption that synonymous substitution rate variation across sites within genes occurs at levels that are either nonexistent or negligible. However, numerous studies challenge this assumption from a biological perspective and show that synonymous substitution rate variation (SRV) is comparable in magnitude to that of nonsynonymous substitution rate variation. We evaluated the impact of this assumption on methods for inferring selection at the molecular level by incorporating SRV into an existing method (BUSTED) for detecting signatures of episodic diversifying selection in genes. Using simulated data we found that failing to account for even moderate levels of SRV in selection testing is likely to produce intolerably high false positive rates. To evaluate the effect of the SRV assumption on actual inferences we compared results of tests with and without the assumption in an empirical analysis of over 13, 000 Euteleostomi (bony vertebrate) gene alignments from the Selectome database. This exercise reveals that close to 50% of positive results (i.e., evidence for selection) in empirical analyses disappear when SRV is modeled as part of the statistical analysis and are thus candidates for being false positives. The results from this work add to a growing literature establishing that tests of selection are much more sensitive to certain model assumptions than previously believed.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Yan:2019aa", + "year": 2019, + "authors": "Yan, Ying and Maurer-Alcal{\\'a}, Xyrus X and Knight, Rob and Pond, Sergei L Kosakovsky and Katz, Laura A", + "title": "Single-Cell Transcriptomics Reveal a Correlation between Genome Architecture and Gene Family Evolution in Ciliates", + "journal": "mBio", + "doi": "", + "abstract": "Ciliates, a eukaryotic clade that is over 1 billion years old, are defined by division of genome function between transcriptionally inactive germline micronuclei and functional somatic macronuclei. To date, most analyses of gene family evolution have been limited to cultivable model lineages (e.g., Tetrahymena, Paramecium, Oxytricha, and Stylonychia). Here, we focus on the uncultivable Karyorelictea and its understudied sister class Heterotrichea, which represent two extremes in genome architecture. Somatic macronuclei within the Karyorelictea are described as nearly diploid, while the Heterotrichea have hyperpolyploid somatic genomes. Previous analyses indicate that genome architecture impacts ciliate gene family evolution as the most diverse and largest gene families are found in lineages with extensively processed somatic genomes (i.e., possessing thousands of gene-sized chromosomes). To further assess ciliate gene family evolution, we analyzed 43 single-cell transcriptomes from 33 ciliate species representing 10 classes. Focusing on conserved eukaryotic genes, we use estimates of transcript diversity as a proxy for the number of paralogs in gene families among four focal clades: Karyorelictea, Heterotrichea, extensive fragmenters (with gene-size somatic chromosomes), and non-extensive fragmenters (with more traditional somatic chromosomes), the latter two within the subphylum Intramacronucleata. Our results show that (i) the Karyorelictea have the lowest average transcript diversity, while Heterotrichea are highest among the four groups; (ii) proteins in Karyorelictea are under the highest functional constraints, and the patterns of selection in ciliates may reflect genome architecture; and (iii) stop codon reassignments vary among members of the Heterotrichea and Spirotrichea but are conserved in other classes.IMPORTANCE To further our understanding of genome evolution in eukaryotes, we assess the relationship between patterns of molecular evolution within gene families and variable genome structures found among ciliates. We combine single-cell transcriptomics with bioinformatic tools, focusing on understudied and uncultivable lineages selected from across the ciliate tree of life. Our analyses show that genome architecture correlates with patterns of protein evolution as lineages with more canonical somatic genomes, such as the class Karyorelictea, have more conserved patterns of molecular evolution compared to other classes. This study showcases the power of single-cell transcriptomics for investigating genome architecture and evolution in uncultivable microbial lineages and provides transcriptomic resources for further research on genome evolution.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Abrahams:2019aa", + "year": 2019, + "authors": "Abrahams, Melissa-Rose and Joseph, Sarah B and Garrett, Nigel and Tyers, Lynn and Moeser, Matthew and Archin, Nancie and Council, Olivia D and Matten, David and Zhou, Shuntai and Doolabh, Deelan and Anthony, Colin and Goonetilleke, Nilu and Karim, Salim Abdool and Margolis, David M and Pond, Sergei Kosakovsky and Williamson, Carolyn and Swanstrom, Ronald", + "title": "The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation", + "journal": "Sci Transl Med", + "doi": "", + "abstract": "Although antiretroviral therapy (ART) is highly effective at suppressing HIV-1 replication, the virus persists as a latent reservoir in resting CD4+ T cells during therapy. This reservoir forms even when ART is initiated early after infection, but the dynamics of its formation are largely unknown. The viral reservoirs of individuals who initiate ART during chronic infection are generally larger and genetically more diverse than those of individuals who initiate therapy during acute infection, consistent with the hypothesis that the reservoir is formed continuously throughout untreated infection. To determine when viruses enter the latent reservoir, we compared sequences of replication-competent viruses from resting peripheral CD4+ T cells from nine HIV-positive women on therapy to viral sequences circulating in blood collected longitudinally before therapy. We found that, on average, 71% of the unique viruses induced from the post-therapy latent reservoir were most genetically similar to viruses replicating just before ART initiation. This proportion is far greater than would be expected if the reservoir formed continuously and was always long lived. We conclude that ART alters the host environment in a way that allows the formation or stabilization of most of the long-lived latent HIV-1 reservoir, which points to new strategies targeted at limiting the formation of the reservoir around the time of therapy initiation.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Avanzato:2019aa", + "year": 2019, + "authors": "Avanzato, Victoria A and Oguntuyo, Kasopefoluwa Y and Escalera-Zamudio, Marina and Gutierrez, Bernardo and Golden, Michael and Pond, Sergei L Kosakovsky and Pryce, Rhys and Walter, Thomas S and Seow, Jeffrey and Doores, Katie J and Pybus, Oliver G and Munster, Vincent J and Lee, Benhur and Bowden, Thomas A", + "title": "A structural basis for antibody-mediated neutralization of Nipah virus reveals a site of vulnerability at the fusion glycoprotein apex", + "journal": "Proc Natl Acad Sci U S A", + "doi": "", + "abstract": "Nipah virus (NiV) is a highly pathogenic paramyxovirus that causes frequent outbreaks of severe neurologic and respiratory disease in humans with high case fatality rates. The 2 glycoproteins displayed on the surface of the virus, NiV-G and NiV-F, mediate host-cell attachment and membrane fusion, respectively, and are targets of the host antibody response. Here, we provide a molecular basis for neutralization of NiV through antibody-mediated targeting of NiV-F. Structural characterization of a neutralizing antibody (nAb) in complex with trimeric prefusion NiV-F reveals an epitope at the membrane-distal domain III (DIII) of the molecule, a region that undergoes substantial refolding during host-cell entry. The epitope of this monoclonal antibody (mAb66) is primarily protein-specific and we observe that glycosylation at the periphery of the interface likely does not inhibit mAb66 binding to NiV-F. Further characterization reveals that a Hendra virus-F-specific nAb (mAb36) and many antibodies in an antihenipavirus-F polyclonal antibody mixture (pAb835) also target this region of the molecule. Integrated with previously reported paramyxovirus F-nAb structures, these data support a model whereby the membrane-distal region of the F protein is targeted by the antibody-mediated immune response across henipaviruses. Notably, our domain-specific sequence analysis reveals no evidence of selective pressure at this region of the molecule, suggestive that functional constraints prevent immune-driven sequence variation. Combined, our data reveal the membrane-distal region of NiV-F as a site of vulnerability on the NiV surface.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kosakovsky-Pond:2019aa", + "year": 2019, + "authors": "Pond, Sergei L Kosakovsky and Poon, Art F Y and Velazquez, Ryan and Weaver, Steven and Hepler, N Lance and Murrell, Ben and Shank, Stephen D and Magalis, Brittany Rife and Bouvier, Dave and Nekrutenko, Anton and Wisotsky, Sadie and Spielman, Stephanie J and Frost, Simon D W and Muse, Spencer V", + "title": "HyPhy 2.5 - a customizable platform for evolutionary hypothesis testing using phylogenies", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "hyphy (HYpothesis testing using PHYlogenies) is a scriptable, open-source package for fitting a broad range of evolutionary models to multiple sequence alignments, and for conducting subsequent parameter estimation and hypothesis testing, primarily in the maximum likelihood statistical framework. It has become a popular choice for characterizing various aspects of the evolutionary process: natural selection, evolutionary rates, recombination, and coevolution. The 2.5 release (available from www.hyphy.org) includes a completely re-engineered computational core and analysis library that introduces new classes of evolutionary models and statistical tests, delivers substantial performance and stability enhancements, improves usability, streamlines end-to-end analysis workflows, makes it easier to develop custom analyses, and is mostly backwards compatible with previous HyPhy releases.", + "category": "METHODS", + "isRecent": false, + "isLegendary": true, + "stats": "Landmark Software" + }, + { + "id": "Spielman:2019aa", + "year": 2019, + "authors": "Spielman, Stephanie J and Weaver, Steven and Shank, Stephen D and Magalis, Brittany Rife and Li, Michael and Pond, Sergei L Kosakovsky", + "title": "Evolution of Viral Genomes: Interplay Between Selection, Recombination, and Other Forces", + "journal": "Methods Mol Biol", + "doi": "", + "abstract": "Natural selection is a fundamental force shaping organismal evolution, as it both maintains function and enables adaptation and innovation. Viruses, with their typically short and largely coding genomes, experience strong and diverse selective forces, sometimes acting on timescales that can be directly measured. These selection pressures emerge from an antagonistic interplay between rapidly changing fitness requirements (immune and antiviral responses from hosts, transmission between hosts, or colonization of new host species) and functional imperatives (the ability to infect hosts or host cells and replicate within hosts). Indeed, computational methods to quantify these evolutionary forces using molecular sequence data were initially, dating back to the 1980s, applied to the study of viral pathogens. This preference largely emerged because the strong selective forces are easiest to detect in viruses, and, of course, viruses have clear biomedical relevance. Recent commoditization of affordable high-throughput sequencing has made it possible to generate truly massive genomic data sets, on which powerful and accurate methods can yield a very detailed depiction of when, where, and (sometimes) how viral pathogens respond to various selective forces.Here, we present recent statistical developments and state-of-the-art methods to identify and characterize these selection pressures from protein-coding sequence alignments and phylogenies. Methods described here can reveal critical information about various evolutionary regimes, including whole-gene selection, lineage-specific selection, and site-specific selection acting upon viral genomes, while accounting for confounding biological processes, such as recombination and variation in mutation rates.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Rhee:2019ab", + "year": 2019, + "authors": "Rhee, Soo-Yon and Clutter, Dana and Fessel, W Jeffrey and Klein, Daniel and Slome, Sally and Pinsky, Benjamin A and Marcus, Julia L and Hurley, Leo and Silverberg, Michael J and Pond, Sergei L Kosakovsky and Shafer, Robert W", + "title": "Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted Human Immunodeficiency Virus Type 1 Drug Resistance in a Large US Clinic Population", + "journal": "Clin Infect Dis", + "doi": "", + "abstract": "Background: There are few large studies of transmitted drug resistance (TDR) prevalence and the drug resistance mutations (DRMs) responsible for TDR in the United States.\nMethods: Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and protease sequences were obtained from 4253 antiretroviral therapy (ART)-naive individuals in a California clinic population from 2003 to 2016. Phylogenetic analyses were performed to study linkages between TDR strains and selection pressure on TDR-associated DRMs.\nResults: From 2003 to 2016, there was a significant increase in overall (odds ratio [OR], 1.05 per year [95% confidence interval {CI}, 1.03-1.08]; P < .001) and nonnucleoside RT inhibitor (NNRTI)-associated TDR (OR, 1.11 per year [95% CI, 1.08-1.15]; P < .001). Between 2012 and 2016, TDR rates to any drug class ranged from 15.7% to 19.2%, and class-specific rates ranged from 10.0% to 12.8% for NNRTIs, 4.1% to 8.1% for nucleoside RT inhibitors (NRTIs), and 3.6% to 5.2% for protease inhibitors. The thymidine analogue mutations, M184V/I and the tenofovir-associated DRMs K65R and K70E/Q/G/N/T accounted for 82.9%, 7.3%, and 1.4% of NRTI-associated TDR, respectively. Thirty-seven percent of TDR strains clustered with other TDR strains sharing the same DRMs.\nConclusions: Although TDR has increased significantly in this large cohort, many TDR strains are unlikely to influence the activity of currently preferred first-line ART regimens. The high proportion of DRMs associated with infrequently used regimens combined with the clustering of TDR strains suggest that some TDR strains are being transmitted between ART-naive individuals.", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Eren:2018aa", + "year": 2018, + "authors": "Eren, Kemal and Weaver, Steven and Ketteringham, Robert and Valentyn, Morn{\\'e} and Laird Smith, Melissa and Kumar, Venkatesh and Mohan, Sanjay and Pond, Sergei L Kosakovsky and Murrell, Ben", + "title": "Full-Length Envelope Analyzer (FLEA): A tool for longitudinal analysis of viral amplicons", + "journal": "PLoS Comput Biol", + "doi": "", + "abstract": "Next generation sequencing of viral populations has advanced our understanding of viral population dynamics, the development of drug resistance, and escape from host immune responses. Many applications require complete gene sequences, which can be impossible to reconstruct from short reads. HIV env, the protein of interest for HIV vaccine studies, is exceptionally challenging for long-read sequencing and analysis due to its length, high substitution rate, and extensive indel variation. While long-read sequencing is attractive in this setting, the analysis of such data is not well handled by existing methods. To address this, we introduce FLEA (Full-Length Envelope Analyzer), which performs end-to-end analysis and visualization of long-read sequencing data. FLEA consists of both a pipeline (optionally run on a high-performance cluster), and a client-side web application that provides interactive results. The pipeline transforms FASTQ reads into high-quality consensus sequences (HQCSs) and uses them to build a codon-aware multiple sequence alignment. The resulting alignment is then used to infer phylogenies, selection pressure, and evolutionary dynamics. The web application provides publication-quality plots and interactive visualizations, including an annotated viral alignment browser, time series plots of evolutionary dynamics, visualizations of gene-wide selective pressures (such as dN/dS) across time and across protein structure, and a phylogenetic tree browser. We demonstrate how FLEA may be used to process Pacific Biosciences HIV env data and describe recent examples of its use. Simulations show how FLEA dramatically reduces the error rate of this sequencing platform, providing an accurate portrait of complex and variable HIV env populations. A public instance of FLEA is hosted at http://flea.datamonkey.org. The Python source code for the FLEA pipeline can be found at https://github.com/veg/flea-pipeline. The client-side application is available at https://github.com/veg/flea-web-app. A live demo of the P018 results can be found at http://flea.murrell.group/view/P018.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Dalai:2018aa", + "year": 2018, + "authors": "Dalai, Sudeb C and Junqueira, Dennis Maletich and Wilkinson, Eduan and Mehra, Renee and Pond, Sergei L Kosakovsky and Levy, Vivian and Israelski, Dennis and de Oliveira, Tulio and Katzenstein, David", + "title": "Combining Phylogenetic and Network Approaches to Identify HIV-1 Transmission Links in San Mateo County, California", + "journal": "Front Microbiol", + "doi": "", + "abstract": "The HIV epidemic in San Mateo County is sustained by multiple overlapping risk groups and is an important hub for HIV transmission in northern California. Limited access to care has led historically to delayed clinical presentation, higher rates of opportunistic infections, and an increased prevalence of antiretroviral drug resistance. The virologic and clinical consequences of treatment within these multiple ethnic and behavioral groups are poorly understood, highlighting the need for efficient surveillance strategies that are able to elucidate transmission networks and drug resistance patterns. We obtained sequence data from a group of 316 HIV-positive individuals in the San Mateo AIDS Program over a 14-year period and integrated epidemiologic, phylogenetic, and network approaches to characterize transmission clusters, risk factors and drug resistance. Drug resistance mutations were identified using the Stanford HIV Drug Resistance Database. A maximum likelihood tree was inferred in RAxML and subjected to clustering analysis in Cluster Picker. Network analysis using pairwise genetic distances was performed in HIV-TRACE. Participants were primarily male (60%), white Hispanics and non-Hispanics (32%) and African American (20.6%). The most frequent behavior risk factor was male-male sex (33.5%), followed by heterosexual (23.4%) and injection drug use (9.5%). Nearly all sequences were subtype B (96%) with subtypes A, C, and CRF01_AE also observed. Sequences from 65% of participants had at least one drug resistance mutation. Clustered transmissions included a higher number of women when compared to non-clustered individuals and were more likely to include heterosexual or people who inject drugs (PWID). Detailed analysis of the largest network (N = 47) suggested that PWID played a central role in overall transmission of HIV-1 as well as bridging men who have sex with men (MSM) transmission with heterosexual/PWID among primarily African American men. Combined phylogenetic and network analysis of HIV sequence data identified several overlapping risk factors in the epidemic, including MSM, heterosexual and PWID transmission with a disproportionate impact on African Americans and a high prevalence of drug resistance.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Rhee:2019aa", + "year": 2019, + "authors": "Rhee, Soo-Yon and Magalis, Brittany R and Hurley, Leo and Silverberg, Michael J and Marcus, Julia L and Slome, Sally and Pond, Sergei L Kosakovsky and Shafer, Robert W", + "title": "National and International Dimensions of Human Immunodeficiency Virus-1 Sequence Clusters in a Northern California Clinical Cohort", + "journal": "Open Forum Infect Dis", + "doi": "", + "abstract": "Background: Recent advances in high-throughput molecular epidemiology are transforming the analysis of viral infections.\nMethods: Human immunodeficiency virus (HIV)-1 pol sequences from a Northern Californian cohort (NCC) of 4553 antiretroviral-naive individuals sampled between 1998 and 2016 were analyzed together with 140 000 previously published global pol sequences. The HIV-TRAnsmission Cluster Engine (HIV-TRACE) was used to infer a transmission network comprising links between NCC and previously published sequences having a genetic distance \u22641.5%.\nResults: Twenty-five percent of NCC sequences were included in 264 clusters linked to a published sequence, and approximately one third of these (8.0% of the total) were linked to 1 or more non-US sequences. The largest cluster, containing 512 NCC sequences (11.2% of the total), comprised the subtype B lineage that traced its origin to the earliest North American sequences. Approximately 5 percent of NCC sequences belonged to a non-B subtype, and these were more likely to cluster with a non-US sequence. Twenty-two NCC sequences belonged to 1 of 4 large clusters containing sequences from rapidly growing regional epidemics: CRF07_BC (East Asia), subtype A6 (former Soviet Union), a Japanese subtype B lineage, and an East/Southeast Asian CRF01_AE lineage. Bayesian phylogenetics suggested that most non-B sequences resulted from separate introductions but that local spread within the largest CRF01_AE cluster occurred twice.\nConclusions: The NCC contains national and international links to previously published sequences including many to the subtype B strain that originated in North America and several to rapidly growing Asian epidemics. Despite their rapid regional growth, the Asian epidemic strains demonstrated limited NCC spread.", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wertheim:2018aa", + "year": 2018, + "authors": "Wertheim, Joel O and Murrell, Ben and Mehta, Sanjay R and Forgione, Lisa A and Pond, Sergei L Kosakovsky and Smith, Davey M and Torian, Lucia V", + "title": "Growth of HIV-1 Molecular Transmission Clusters in New York City", + "journal": "J Infect Dis", + "doi": "", + "abstract": "Background: HIV-1 genetic sequences can be used to infer viral transmission history and dynamics. Throughout the United States, HIV-1 sequences from drug resistance testing are reported to local public health departments.\nMethods: We investigated whether inferred HIV transmission network dynamics can identify individuals and clusters of individuals most likely to give rise to future HIV cases in a surveillance setting. We used HIV-TRACE, a genetic distance-based clustering tool, to infer molecular transmission clusters from HIV-1 pro/RT sequences from 65,736 people in the New York City surveillance registry. Logistic and LASSO regression analyses were used to identify correlates of clustering and cluster growth, respectively. We performed retrospective transmission network analyses to evaluate individual- and cluster-level prioritization schemes for identifying parts of the network most likely to give rise to new cases in the subsequent year.\nResults: Individual-level prioritization schemes predicted network growth better than random targeting. Across the 3,600 inferred molecular transmission clusters, previous growth dynamics were superior predictors of future transmission cluster growth compared to individual-level prediction schemes. Cluster-level prioritization schemes considering previous cluster growth relative to cluster size further improved network growth predictions.\nConclusions: Prevention efforts based on HIV molecular epidemiology may improve public health outcomes in a U.S. surveillance setting.", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Shank:2018aa", + "year": 2018, + "authors": "Shank, Stephen D and Weaver, Steven and Pond, Sergei L Kosakovsky", + "title": "phylotree.js - a JavaScript library for application development and interactive data visualization in phylogenetics", + "journal": "BMC Bioinformatics", + "doi": "", + "abstract": "BACKGROUND: While several JavaScript packages for visualizing phylogenetic trees exist, most are best characterized as frameworks that are designed with a specific set of tasks in mind. Extending such packages to use cases that are not available as features often ends up being difficult. Moreover, existing packages tend to produce standalone widgets that are not designed to serve as middleware, as opposed to flexible tools that can integrate with other components of an application.\nRESULTS: phylotree.js is a library that extends the popular data visualization framework d3.js, and is suitable for building JavaScript applications where users can view and interact with phylogenetic trees. The effects of such interactions can be captured and communicated to other package components, making it possible to engineer complex and responsive applications that include phylogenetic trees. phylotree.js implements several abstractions in addition to features, and comes with a documented application programming interface, thus promoting interoperability and extensibility. Example applications include a tool to visualize and annotate phylogenetic trees, a web application for comparative sequence analysis, a structural viewer that interacts with a large phylogenetic tree, and an interactive tanglegram.\nCONCLUSIONS: phylotree.js is a useful tool and application module for a variety of computational biology software applications. The code is available on Github and is released under the MIT license.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Tzou:2018aa", + "year": 2018, + "authors": "Tzou, Philip L and Rhee, Soo-Yon and Pond, Sergei L Kosakovsky and Manasa, Justen and Shafer, Robert W", + "title": "Selection analyses of paired HIV-1 gag and gp41 sequences obtained before and after antiretroviral therapy", + "journal": "Sci Data", + "doi": "", + "abstract": "Most HIV-1-infected individuals with virological failure on a pharmacologically-boosted protease inhibitor (PI) regimen do not develop PI-resistance protease mutations. One proposed explanation is that HIV-1 gag or gp41 cytoplasmic domain mutations might also reduce PI susceptibility. In a recent study of paired gag and gp41 sequences from individuals with virological failure on a PI regimen, we did not identify PI-selected mutations and concluded that if such mutations existed, larger numbers of paired sequences from multiple studies would be needed for their identification. In this study, we generated site-specific amino acid profiles using gag and gp41 published sequences from 5,338 and 4,242 ART-na{\\\"\\i}ve individuals, respectively, to assist researchers identify unusual mutations arising during therapy and to provide scripts for performing established and novel maximal likelihood estimates of dN/dS substitution rates in paired sequences. The pipelines used to generate the curated sequences, amino acid profiles, and dN/dS analyses will facilitate the application of consistent methods to paired gag and gp41 sequence datasets and expedite the identification of potential sites under PI-selection pressure.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Pacheco:2018qf", + "year": 2018, + "authors": "Pacheco, M Andre{\\'\\i}na and Matta, Nubia E and Valkiunas, Gediminas and Parker, Patricia G and Mello, Beatriz and Stanley, Jr, Craig E and Lentino, Miguel and Garcia-Amado, Maria Alexandra and Cranfield, Michael and Pond, Sergei L Kosakovsky and Escalante, Ananias A", + "title": "Mode and Rate of Evolution of Haemosporidian Mitochondrial Genomes: Timing the Radiation of Avian Parasites", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Haemosporidians are a diverse group of vector-borne parasitic protozoa that includes the agents of human malaria; however, most of the described species are found in birds and reptiles. Although our understanding of these parasites' diversity has expanded by analyses of their mitochondrial genes, there is limited information on these genes' evolutionary rates. Here, 114 mitochondrial genomes (mtDNA) were studied from species belonging to four genera: Leucocytozoon, Haemoproteus, Hepatocystis, and Plasmodium. Contrary to previous assertions, the mtDNA is phylogenetically informative. The inferred phylogeny showed that, like the genus Plasmodium, the Leucocytozoon and Haemoproteus genera are not monophyletic groups. Although sensitive to the assumptions of the molecular dating method used, the estimated times indicate that the diversification of the avian haemosporidian subgenera/genera took place after the Cretaceous-Paleogene boundary following the radiation of modern birds. Furthermore, parasite clade differences in mtDNA substitution rates and strength of negative selection were detected. These differences may affect the biological interpretation of mtDNA gene lineages used as a proxy to species in ecological and parasitological investigations. Given that the mitochondria are critically important in the parasite life cycle stages that take place in the vector and that the transmission of parasites belonging to particular clades has been linked to specific insect families/subfamilies, this study suggests that differences in vectors have affected the mode of evolution of haemosporidian mtDNA genes. The observed patterns also suggest that the radiation of haemosporidian parasites may be the result of community-level evolutionary processes between their vertebrate and invertebrate hosts.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Rife-Magalis:2018ys", + "year": 2018, + "authors": "Rife Magalis, Brittany and Pond, Sergei L Kosakovsky and Summers, Michael F and Salemi, Marco", + "title": "Evaluation of global HIV/SIV envelope gp120 RNA structure and evolution within and among infected hosts", + "journal": "Virus Evol", + "doi": "", + "abstract": "Lentiviral RNA genomes contain structural elements that play critical roles in viral replication. Although structural features of 5'-untranslated regions have been well characterized, attempts to identify important structures in other genomic regions by Selective 2'-Hydroxyl Acylation analyzed by Primer Extension (SHAPE) have led to conflicting structural and mechanistic conclusions. Previous approaches accounted neither for sequence heterogeneity that is ubiquitous in viral populations, nor for selective constraints operating at the protein level. We developed an approach that augments SHAPE with phylogenetic analyses and applied it to investigate structure in coding regions (cRNA) within the HIV and SIV envelope genes. Analysis of single-genome SHAPE data with phylogenetic information from diverse lentiviral sequences argues against the conservation of a putative global gp120 RNA structure but points to the existence of core RNA sub-structures. Our findings establish a framework for considering sequence heterogeneity and protein function in de novo RNA structure inference approaches.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Rhee:2018vn", + "year": 2018, + "authors": "Rhee, Soo-Yon and Clutter, Dana and Fessel, W Jeffrey and Klein, Daniel and Slome, Sally and Pinsky, Benjamin A and Marcus, Julia L and Hurley, Leo and Silverberg, Michael J and Pond, Sergei L Kosakovsky and Shafer, Robert W", + "title": "Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance in a Large U.S. Clinic Population", + "journal": "Clin Infect Dis", + "doi": "", + "abstract": "Background: There are few large studies of transmitted drug resistance (TDR) prevalence and the drug resistance mutations (DRMs) responsible for TDR in the U.S.\nMethods: HIV-1 RT and protease sequences were obtained from 4,253 antiretroviral therapy (ART)-na{\\\"\\i}ve individuals in a California clinic population from 2003-2016. Phylogenetic analyses were performed to study linkages between TDR strains and selection pressure on TDR-associated DRMs.\nResults: From 2003-2016, there was a significant increase in overall (odds ratio [OR]=1.05 per year; 95% CI: 1.03 - 1.08; p<0.001) and nonnucleoside RT inhibitor (NNRTI)-associated TDR (OR=1.11 per year; 95% CI: 1.08 - 1.15; p<0.001). Between 2012 and 2016, TDR rates to any drug class ranged from 15.7%-19.2%, and class-specific rates ranged from 10.0%-12.8% for NNRTIs, 4.1%-8.1% for nucleoside RT inhibitors (NRTIs), and 3.6%-5.2% for protease inhibitors. K103N/S, Y181C, Y188L, and G190A mutations accounted for 88.5% of NNRTI-associated TDR. The thymidine analog mutations, M184V/I, and the tenofovir-associated DRMs K65R and K70E/Q/G/N/T accounted for 82.9%, 7.3%, and 1.4% of NRTI-associated TDR, respectively. The proportions of individuals with low-level resistance or higher to boosted atazanavir and darunavir were 2.2% and 0.3%, respectively. 37% of TDR strains clustered with other TDR strains sharing the same DRMs.\nConclusions: Although TDR has increased significantly in this large cohort, many TDR strains are unlikely to influence the activity of currently preferred first-line ART regimens. The high proportion of DRMs associated with infrequently used regimens combined with the clustering of TDR strains suggest that some TDR strains are being transmitted between ART-na{\\\"\\i}ve individuals.", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Frost:2018kx", + "year": 2018, + "authors": "Frost, Simon D W and Magalis, Brittany Rife and Pond, Sergei L Kosakovsky", + "title": "Neutral Theory and Rapidly Evolving Viral Pathogens", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "The evolution of viral pathogens is shaped by strong selective forces that are exerted during jumps to new hosts, confrontations with host immune responses and antiviral drugs, and numerous other processes. However, while undeniably strong and frequent, adaptive evolution is largely confined to small parts of information-packed viral genomes, and the majority of observed variation is effectively neutral. The predictions and implications of the neutral theory have proven immensely useful in this context, with applications spanning understanding within-host population structure, tracing the origins and spread of viral pathogens, predicting evolutionary dynamics, and modeling the emergence of drug resistance. We highlight the multiple ways in which the neutral theory has had an impact, which has been accelerated in the age of high-throughput, high-resolution genomics.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Spielman:2018uq", + "year": 2018, + "authors": "Spielman, Stephanie J and Pond, Sergei L Kosakovsky", + "title": "Relative evolutionary rates in proteins are largely insensitive to the substitution model", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "The relative evolutionary rates at individual sites in proteins are informative measures of conservation or adaptation. Often used as evolutionarily-aware conservation scores, relative rates reveal key functional or strongly-selected residues. Estimating rates in a phylogenetic context requires specifying a protein substitution model, which is typically a phenomenological model trained on a large empirical dataset. A strong emphasis has traditionally been placed on selecting the \"best-fit\" model, with the implicit understanding that suboptimal or otherwise ill-fitting models might bias inferences. However, the pervasiveness and degree of such bias has not been systematically examined. We investigated how model choice impacts site-wise relative rates in a large set of empirical protein alignments. We compared models designed for use on any general protein, models designed for specific domains of life, and the simple equal-rates Jukes Cantor-style model (JC). As expected, information theoretic measures showed overwhelming evidence that some models fit the data decidedly better than others. By contrast, estimates of site-specific evolutionary rates were impressively insensitive to the substitution model used, revealing an unexpected degree of robustness to potential model misspecification. A deeper examination of the fewer than 5% of sites for which model inferences differed in a meaningful way showed that the JC model could uniquely identify rapidly-evolving sites that models with empirically-derived exchangeabilities failed to detect. We conclude that relative protein rates appear robust to the applied substitution model, and any sensible model of protein evolution, regardless of its fit to the data, should produce broadly consistent evolutionary rates.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kosakovsky-Pond:2018fk", + "year": 2018, + "authors": "Pond, Sergei L Kosakovsky and Weaver, Steven and Leigh Brown, Andrew J and Wertheim, Joel O", + "title": "HIV-TRACE (TRAnsmission Cluster Engine): a Tool for Large Scale Molecular Epidemiology of HIV-1 and Other Rapidly Evolving Pathogens", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "In modern applications of molecular epidemiology, genetic sequence data are routinely used to identify clusters of transmission in rapidly evolving pathogens, most notably HIV-1. Traditional 'shoe-leather' epidemiology infers transmission clusters by tracing chains of partners sharing epidemiological connections (e.g., sexual contact). Here, we present a computational tool for identifying a molecular transmission analog of such clusters: HIV-TRACE (TRAnsmission Cluster Engine). HIV-TRACE implements an approach inspired by traditional epidemiology, by identifying chains of partners whose viral genetic relatedness imply direct or indirect epidemiological connections. Molecular transmission clusters are constructed using codon-aware pairwise alignment to a reference sequence followed by pairwise genetic distance estimation among all sequences. This approach is computationally tractable and is capable of identifying HIV-1 transmission clusters in large surveillance databases comprising tens or hundreds of thousands of sequences in near real time, that is, on the order of minutes to hours. HIV-TRACE is available at www.hivtrace.org and from www.github.com/veg/hivtrace, along with the accompanying result visualization module from www.github.com/veg/hivtrace-viz. Importantly, the approach underlying HIV-TRACE is not limited to the study of HIV-1 and can be applied to study outbreaks and epidemics of other rapidly evolving pathogens.", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": true, + "stats": "Landmark Tool" + }, + { + "id": "Spielman:2018aa", + "year": 2018, + "authors": "Spielman, Stephanie J and Pond, Sergei L Kosakovsky", + "title": "Relative evolutionary rate inference in HyPhy with LEISR", + "journal": "PeerJ", + "doi": "", + "abstract": "We introduce LEISR (Likehood Estimation of Individual Site Rates, pronounced \"laser\"), a tool to infer relative evolutionary rates from protein and nucleotide data, implemented in HyPhy. LEISR is based on the popular Rate4Site (Pupko et al., 2002) approach for inferring relative site-wise evolutionary rates, primarily from protein data. We extend the original method for more general use in several key ways: (i) we increase the support for nucleotide data with additional models, (ii) we allow for datasets of arbitrary size, (iii) we support analysis of site-partitioned datasets to correct for the presence of recombination breakpoints, (iv) we produce rate estimates at all sites rather than at just a subset of sites, and (v) we implemented LEISR as MPI-enabled to support rapid, high-throughput analysis. LEISR is available in HyPhy starting with version 2.3.8, and it is accessible as an option in the HyPhy analysis menu (\"Relative evolutionary rate inference\"), which calls the HyPhy batchfile LEISR.bf.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Weaver:2018aa", + "year": 2018, + "authors": "Weaver, Steven and Shank, Stephen D and Spielman, Stephanie J and Li, Michael and Muse, Spencer V and Pond, Sergei L Kosakovsky", + "title": "Datamonkey 2.0: a modern web application for characterizing selective and other evolutionary processes", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Inference of how evolutionary forces have shaped extant genetic diversity is a cornerstone of modern comparative sequence analysis. Advances in sequence generation and increased statistical sophistication of relevant methods now allow researchers to extract ever more evolutionary signal from the data, albeit at an increased computational cost. Here, we announce the release of Datamonkey 2.0, a completely re-engineered version of the Datamonkey web-server for analyzing evolutionary signatures in sequence data. For this endeavor, we leveraged recent developments in open-source libraries that facilitate interactive, robust, and scalable web application development. Datamonkey 2.0 provides a carefully curated collection of methods for interrogating coding-sequence alignments for imprints of natural selection, packaged as a responsive (i.e. can be viewed on tablet and mobile devices), fully interactive, and API-enabled web application. To complement Datamonkey 2.0, we additionally release HyPhy Vision, an accompanying JavaScript application for visualizing analysis results. HyPhy Vision can also be used separately from Datamonkey 2.0 to visualize locally-executed HyPhy analyses. Together, Datamonkey 2.0 and HyPhy Vision showcase how scientific software development can benefit from general-purpose open-source frameworks. Datamonkey 2.0 is freely and publicly available at http://www.datamonkey. org, and the underlying codebase is available from https://github.com/veg/datamonkey-js.", + "category": "METHODS", + "isRecent": false, + "isLegendary": true, + "stats": "Landmark Platform" + }, + { + "id": "Landais:2017aa", + "year": 2017, + "authors": "Landais, Elise and Murrell, Ben and Briney, Bryan and Murrell, Sasha and Rantalainen, Kimmo and Berndsen, Zachary T and Ramos, Alejandra and Wickramasinghe, Lalinda and Smith, Melissa Laird and Eren, Kemal and de Val, Natalia and Wu, Mengyu and Cappelletti, Audrey and Umotoy, Jeffrey and Lie, Yolanda and Wrin, Terri and Algate, Paul and Chan-Hui, Po-Ying and Karita, Etienne and {IAVI Protocol C Investigators} and {IAVI African HIV Research Network} and Ward, Andrew B and Wilson, Ian A and Burton, Dennis R and Smith, Davey and Pond, Sergei L Kosakovsky and Poignard, Pascal", + "title": "HIV Envelope Glycoform Heterogeneity and Localized Diversity Govern the Initiation and Maturation of a V2 Apex Broadly Neutralizing Antibody Lineage", + "journal": "Immunity", + "doi": "", + "abstract": "Understanding how broadly neutralizing antibodies (bnAbs) to HIV envelope (Env) develop during natural infection can help guide the rational design of an HIV vaccine. Here, we described a bnAb lineage targeting the Env V2 apex and the Ab-Env co-evolution that led to development of neutralization breadth. The lineage Abs bore an anionic heavy chain complementarity-determining region 3 (CDRH3) of 25 amino acids, among the shortest known for this class of Abs, and achieved breadth with only 10% nucleotide somatic hypermutation and no insertions or deletions. The data suggested a role for Env glycoform heterogeneity in the activation of the lineage germline B cell. Finally, we showed that localized diversity at key V2 epitope residues drove bnAb maturation toward breadth, mirroring the Env evolution pattern described for another donor who developed V2-apex targeting bnAbs. Overall, these findings suggest potential strategies for vaccine approaches based on germline-targeting and serial immunogen design.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Lorenzo-Redondo:2017aa", + "year": 2017, + "authors": "Lorenzo-Redondo, Ramon and Fryer, Helen R and Bedford, Trevor and Kim, Eun-Young and Archer, John and Pond, Sergei L Kosakovsky and Chung, Yoon-Seok and Penugonda, Sudhir and Chipman, Jeffrey G and Fletcher, Courtney V and Schacker, Timothy W and Malim, Michael H and Rambaut, Andrew and Haase, Ashley T and McLean, Angela R and Wolinsky, Steven M", + "title": "Lorenzo-Redondo et al. reply", + "journal": "Nature", + "doi": "", + "abstract": "", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Manasa:2017aa", + "year": 2017, + "authors": "Manasa, Justen and Varghese, Vici and Pond, Sergei L Kosakovsky and Rhee, Soo-Yon and Tzou, Philip L and Fessel, W Jeffrey and Jang, Karen S and White, Elizabeth and R{\\\"o}gnvaldsson, Thorsteinn and Katzenstein, David A and Shafer, Robert W", + "title": "Evolution of gag and gp41 in Patients Receiving Ritonavir-Boosted Protease Inhibitors", + "journal": "Sci Rep", + "doi": "", + "abstract": "Several groups have proposed that genotypic determinants in gag and the gp41 cytoplasmic domain (gp41-CD) reduce protease inhibitor (PI) susceptibility without PI-resistance mutations in protease. However, no gag and gp41-CD mutations definitively responsible for reduced PI susceptibility have been identified in individuals with virological failure (VF) while receiving a boosted PI (PI/r)-containing regimen. To identify gag and gp41 mutations under selective PI pressure, we sequenced gag and/or gp41 in 61 individuals with VF on a PI/r (n\u2009=\u200940) or NNRTI (n\u2009=\u200920) containing regimen. We quantified nonsynonymous and synonymous changes in both genes and identified sites exhibiting signal for directional or diversifying selection. We also used published gag and gp41 polymorphism data to highlight mutations displaying a high selection index, defined as changing from a conserved to an uncommon amino acid. Many amino acid mutations developed in gag and in gp41-CD in both the PI- and NNRTI-treated groups. However, in neither gene, were there discernable differences between the two groups in overall numbers of mutations, mutations displaying evidence of diversifying or directional selection, or mutations with a high selection index. If gag and/or gp41 encode PI-resistance mutations, they may not be confined to consistent mutations at a few sites.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Forrester:2017aa", + "year": 2017, + "authors": "Forrester, Naomi L and Wertheim, Joel O and Dugan, Vivian G and Auguste, Albert J and Lin, David and Adams, A Paige and Chen, Rubing and Gorchakov, Rodion and Leal, Grace and Estrada-Franco, Jose G and Pandya, Jyotsna and Halpin, Rebecca A and Hari, Kumar and Jain, Ravi and Stockwell, Timothy B and Das, Suman R and Wentworth, David E and Smith, Martin D and Pond, Sergei L Kosakovsky and Weaver, Scott C", + "title": "Evolution and spread of Venezuelan equine encephalitis complex alphavirus in the Americas", + "journal": "PLoS Negl Trop Dis", + "doi": "", + "abstract": "Venezuelan equine encephalitis (VEE) complex alphaviruses are important re-emerging arboviruses that cause life-threatening disease in equids during epizootics as well as spillover human infections. We conducted a comprehensive analysis of VEE complex alphaviruses by sequencing the genomes of 94 strains and performing phylogenetic analyses of 130 isolates using complete open reading frames for the nonstructural and structural polyproteins. Our analyses confirmed purifying selection as a major mechanism influencing the evolution of these viruses as well as a confounding factor in molecular clock dating of ancestors. Times to most recent common ancestors (tMRCAs) could be robustly estimated only for the more recently diverged subtypes; the tMRCA of the ID/IAB/IC/II and IE clades of VEE virus (VEEV) were estimated at ca. 149-973 years ago. Evolution of the IE subtype has been characterized by a significant evolutionary shift from the rest of the VEEV complex, with an increase in structural protein substitutions that are unique to this group, possibly reflecting adaptation to its unique enzootic mosquito vector Culex (Melanoconion) taeniopus. Our inferred tree topologies suggest that VEEV is maintained primarily in situ, with only occasional spread to neighboring countries, probably reflecting the limited mobility of rodent hosts and mosquito vectors.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Brayne:2017aa", + "year": 2017, + "authors": "Brayne, Adam B and Dearlove, Bethany L and Lester, James S and Pond, Sergei L Kosakovsky and Frost, Simon D W", + "title": "Genotype-Specific Evolution of Hepatitis E Virus", + "journal": "J Virol", + "doi": "", + "abstract": "Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis globally. HEV comprises four genotypes with different geographic distributions and host ranges. We utilize this natural case-control study for investigating the evolution of zoonotic viruses compared to single-host viruses, using 244 near-full-length HEV genomes. Genome-wide estimates of the ratio of nonsynonymous to synonymous evolutionary changes (dN/dS ratio) located a region of overlapping reading frames, which is subject to positive selection in genotypes 3 and 4. The open reading frames (ORFs) involved have functions related to host-pathogen interaction, so genotype-specific evolution of these regions may reflect their fitness. Bayesian inference of evolutionary rates shows that genotypes 3 and 4 have significantly higher rates than genotype 1 across all ORFs. Reconstruction of the phylogenies of zoonotic genotypes demonstrates significant intermingling of isolates between hosts. We speculate that the genotype-specific differences may result from cyclical adaptation to different hosts in genotypes 3 and 4.IMPORTANCE Hepatitis E virus (HEV) is increasingly recognized as a pathogen that affects both the developing and the developed world. While most often clinically mild, HEV can be severe or fatal in certain demographics, such as expectant mothers. Like many other viral pathogens, HEV has been classified into several distinct genotypes. We show that most of the HEV genome is evolutionarily constrained. One locus of positive selection is unusual in that it encodes two distinct protein products. We are the first to detect positive selection in this overlap region. Genotype 1, which infects humans only, appears to be evolving differently from genotypes 3 and 4, which infect multiple species, possibly because genotypes 3 and 4 are unable to achieve the same fitness due to repeated host jumps.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "El-Bannoudi:2017aa", + "year": 2017, + "authors": "El Bannoudi, Hanane and Anquetil, C{\\'e}line and Braunstein, Marc J and Pond, Sergei L Kosakovsky and Silverman, Gregg J", + "title": "Unbiased RACE-Based Massive Parallel Surveys of Human IgA Antibody Repertoires", + "journal": "Methods Mol Biol", + "doi": "", + "abstract": "For investigations of human B-cell receptor (BCR) repertoires, we have developed a protocol for large-scale surveys of human antibody heavy chain (VH) rearrangements. Here we study IgA repertoires, as more IgA antibodies are synthesized in the human body on a daily level than all other isotypes combined. In fact, IgA is secreted at all mucosal surfaces, and it is also secreted in the perspiration that coats our cutaneous surfaces. In these studies we can characterize the IgA clonal diversity of B-cell populations obtained from any donor. To recover representative repertoire libraries, we make our libraries from antibody gene transcript templates (i.e., cDNA), as these are closer reflections of the immune repertoire expressed at the antibody protein level. To avoid biases potentially introduced by upstream oligonucleotide primers that hybridize to variable region framework regions, our approach also uses rapid amplification of cDNA ends (RACE) of antibody transcripts. For exploration of human IgA responses, we have designed a duplexing antisense constant region primer that efficiently amplifies, side-by-side, heavy chain transcripts of both the IgA1 and IgA2 subclasses. By these methods we have begun to define the molecular differences in the IgA1 and IgA2 responses occurring simultaneously in different donors. These methods will be used to investigate the effects of microbial virulence factors on host defenses, during autoimmune responses, and in B-cell malignancies.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wagner:2017aa", + "year": 2017, + "authors": "Wagner, Gabriel A and Landais, Elise and Caballero, Gemma and Phung, Pham and Pond, Sergei L Kosakovsky and Poignard, Pascal and Richman, Douglas D and Little, Susan J and Smith, Davey M", + "title": "Intrasubtype B HIV-1 Superinfection Correlates with Delayed Neutralizing Antibody Response", + "journal": "J Virol", + "doi": "", + "abstract": "Understanding whether the neutralizing antibody (NAb) response impacts HIV-1 superinfection and how superinfection subsequently modulates the NAb response can help clarify correlates of protection from HIV exposures and better delineate pathways of NAb development. We examined associations between the development of NAb and the occurrence of superinfection in a well-characterized, antiretroviral therapy (ART)-naive, primary infection cohort of men who have sex with men. Deep sequencing was applied to blood plasma samples from the cohort to detect cases of superinfection. We compared the NAb activity against autologous and heterologous viruses between 10 participants with intrasubtype B superinfection and 19 monoinfected controls, matched to duration of infection and risk behavior. Three to 6 months after primary infection, individuals who would later become superinfected had significantly weaker NAb activity against tier 1 subtype B viruses (P = 0.003 for SF-162 and P = 0.017 for NL4-3) and marginally against autologous virus (P = 0.054). Lower presuperinfection NAb responses correlated with weaker gp120 binding and lower plasma total IgG titers. Soon after superinfection, the NAb response remained lower, but between 2 and 3 years after primary infection, NAb levels strengthened and reached those of controls. Superinfecting viruses were typically not susceptible to neutralization by presuperinfection plasma. These observations suggest that recently infected individuals with a delayed NAb response against primary infecting and tier 1 subtype B viruses are more susceptible to superinfection.IMPORTANCE Our findings suggest that within the first year after HIV infection, a relatively weak neutralizing antibody response against primary and subtype-specific neutralization-sensitive viruses increases susceptibility to superinfection in the face of repeated exposures. As natural infection progresses, the immune response strengthens significantly in some superinfected individuals. These findings will inform HIV vaccine design by providing testable correlates of protection from initial HIV infection.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Choi:2017aa", + "year": 2017, + "authors": "Choi, Jun Yong and Pond, Sergei L Kosakovsky and Anderson, Christy M and Richman, Douglas D and Smith, Davey M", + "title": "Molecular Features of the V1-V4 Coding Region of Sexually Transmitted Human Immunodeficiency Virus Type 1", + "journal": "J Infect Dis", + "doi": "", + "abstract": "Background.: Investigations into which human immunodeficiency virus type 1 (HIV-1) sequence features may be selected for transmission during sexual exposure have been hampered by the small number of characterized transmission pairs in individual studies.\nMethods.: To boost statistical power to detect differences in glycosylation, length, and electrical charge in the HIV-1 V1-V4 coding region, we reanalyzed all available 2485 env sequences derived from 114 subjects representing 58 transmission pairs from previous studies using mixed-effects linear regression and an approach to approximate the unobserved transmitted virus.\nResults.: The recipient partner had a shorter V1-V4 region and fewer potential N-linked glycosylation sites (PNGS) than sequences from the source partner. We also detected a trend toward more PNGS and lower isoelectric points in transmitted sequences with source partner and the evolutionary tendency to shorten V1-V4 sequences, reduce the number of PNGS, and lower isoelectric points in the recipient following transmission.\nConclusions.: By using all available well-characterized env sequences from transmission pairs via sexual exposure, we were able to identify several important virologic factors that may be important in the development of biomedical preventive interventions.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "doi:10.1093/ve/vew018", + "year": 2016, + "authors": "Laird Smith, Melissa and Murrell, Ben and Eren, Kemal and Ignacio, Caroline and Landais, Elise and Weaver, Steven and Phung, Pham and Ludka, Colleen and Hepler, Lance and Caballero, Gemma and Pollner, Tristan and Guo, Yan and Richman, Douglas and , and Poignard, Pascal and Paxinos, Ellen E. and Pond, Sergei L Kosakovsky. and Smith, Davey M.", + "title": "Rapid Sequencing of Complete env Genes from Primary HIV-1 Samples", + "journal": "Virus Evolution", + "doi": "", + "abstract": "", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Green:2017aa", + "year": 2017, + "authors": "Green, Nella and Hoenigl, Martin and Chaillon, Antoine and Anderson, Christy M and Pond, Sergei L Kosakovsky and Smith, Davey M and Little, Susan J", + "title": "Partner services in adults with acute and early HIV infection", + "journal": "AIDS", + "doi": "", + "abstract": "BACKGROUND: To examine the yield of HIV partner services provided to persons newly diagnosed with acute and early HIV infection (AEH) in San Diego, United States.\nDESIGN: Observational cohort study.\nMETHODS: The study investigated the yield (i.e. number of new HIV and AEH diagnoses, genetically linked partnerships and high-risk uninfected partners) of partner services (confidential contact tracing) for individuals with AEH enrolled in the San Diego Primary Infection Resource Consortium 1996-2014.\nRESULTS: A total of 107 of 574 persons with AEH (19%; i.e. index cases) provided sufficient information to recruit 119 sex partners. Fifty-seven percent of the 119 recruited partners were HIV infected, and 33% of the 119 were newly HIV diagnosed. Among those newly HIV diagnosed, 36% were diagnosed during AEH. There were no significant demographic or behavioral risk differences between HIV-infected and HIV-uninfected recruited partners. Genetic sequences were available for both index cases and partners in 62 partnerships, of which 61% were genetically linked. Partnerships in which both index case and partner enrolled within 30 days were more likely to yield a new HIV diagnosis (P\u200a=\u200a0.01) and to be genetically linked (P\u200a<\u200a0.01).\nCONCLUSION: Partner services for persons with AEH within 30 days of diagnosis represents an effective tool to find HIV-unaware persons, including those with AEH who are at greatest risk of HIV transmission.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wertheim:2017aa", + "year": 2017, + "authors": "Wertheim, Joel O and Pond, Sergei L Kosakovsky and Forgione, Lisa A and Mehta, Sanjay R and Murrell, Ben and Shah, Sharmila and Smith, Davey M and Scheffler, Konrad and Torian, Lucia V", + "title": "Social and Genetic Networks of HIV-1 Transmission in New York City", + "journal": "PLoS Pathog", + "doi": "", + "abstract": "BACKGROUND: Sexually transmitted infections spread across contact networks. Partner elicitation and notification are commonly used public health tools to identify, notify, and offer testing to persons linked in these contact networks. For HIV-1, a rapidly evolving pathogen with low per-contact transmission rates, viral genetic sequences are an additional source of data that can be used to infer or refine transmission networks.\nMETHODS AND FINDINGS: The New York City Department of Health and Mental Hygiene interviews individuals newly diagnosed with HIV and elicits names of sexual and injection drug using partners. By law, the Department of Health also receives HIV sequences when these individuals enter healthcare and their physicians order resistance testing. Our study used both HIV sequence and partner naming data from 1342 HIV-infected persons in New York City between 2006 and 2012 to infer and compare sexual/drug-use named partner and genetic transmission networks. Using these networks, we determined a range of genetic distance thresholds suitable for identifying potential transmission partners. In 48% of cases, named partners were infected with genetically closely related viruses, compatible with but not necessarily representing or implying, direct transmission. Partner pairs linked through the genetic similarity of their HIV sequences were also linked by naming in 53% of cases. Persons who reported high-risk heterosexual contact were more likely to name at least one partner with a genetically similar virus than those reporting their risk as injection drug use or men who have sex with men.\nCONCLUSIONS: We analyzed an unprecedentedly large and detailed partner tracing and HIV sequence dataset and determined an empirically justified range of genetic distance thresholds for identifying potential transmission partners. We conclude that genetic linkage provides more reliable evidence for identifying potential transmission partners than partner naming, highlighting the importance and complementarity of both epidemiological and molecular genetic surveillance for characterizing regional HIV-1 epidemics.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wagner:2016kq", + "year": 2016, + "authors": "Wagner, Gabriel A and Chaillon, Antoine and Liu, Siqi and Franklin, Jr, Donald R and Caballero, Gemma and Pond, Sergei L Kosakovsky and Vaida, Florin and Heaton, Robert K and Letendre, Scott L and Grant, Igor and Richman, Douglas D and Smith, Davey M", + "title": "HIV-associated neurocognitive disorder is associated with HIV-1 dual infection", + "journal": "AIDS", + "doi": "", + "abstract": "OBJECTIVE: Compared to HIV monoinfection, HIV dual infection (DI) has been associated with decreased CD4 T-cell counts and increased viral loads. The same markers are also associated with the development of HIV-associated neurocognitive disorder (HAND), which continues to be a prevalent problem in the era of combination antiretroviral therapy (ART). We sought to determine the relationship between DI and HAND.\nMETHODS: Participants on ART (N\u200a=\u200a38) underwent deep sequencingoffour PCR-amplified HIVcoding regions derived from peripheral blood mononuclear cell (PBMC) DNA samples. Phylogenetic analyses were performedto evaluate whether two distinct viral lineages, i.e. DI, were present in the same individual. All study participants underwent neurocognitive, substance use, and neuromedical assessments at each study visit.\nRESULTS: Of 38 participants, 9 (23.7%) had evidence of DI. Using clinical ratings, global neurocognitive impairment was identified in 21 (55%) participants, and multivariate analysis demonstrated a significant association between DI and impairment;OR (95%CI)\u200a=\u200a18.3 (1.9,414.2), p\u200a=\u200a0.028. Neurocognitive impairment was also associated with lower current (p\u200a=\u200a0.028) and nadir (p\u200a=\u200a0.043) CD4 T-cell counts.\nCONCLUSIONS: Deep sequencing of HIV DNA populations in PBMC identified DI in nearly a quarter ofHIV-infected adultsreceiving ART, and DI was associated with HAND. Dual infection may contribute to the development of HAND, perhaps due to increased viral diversity. Further investigation is needed to determine how DI results in worse neurocognitive performance.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Gianellavew020", + "year": 2016, + "authors": "Gianella, Sara and Pond, Sergei L. Kosakovsky and Oliveira, Michelli F. and Scheffler, Konrad and Strain, Matt C. and De la Torre, Antonio and Letendre, Scott and Smith, Davey M. and Ellis, Ronald J.", + "title": "Compartmentalized HIV rebound in the central nervous system after interruption of antiretroviral therapy", + "journal": "Virus Evolution", + "doi": "", + "abstract": "To design effective eradication strategies, it may be necessary to target HIV reservoirs in anatomic compartments other than blood. This study examined HIV RNA rebound following interruption of antiretroviral therapy (ART) in blood and cerebrospinal fluid (CSF) to determine whether the central nervous system (CNS) might serve as an independent source of resurgent viral replication.Paired blood and CSF samples were collected longitudinally from 14 chronically HIV-infected individuals undergoing ART interruption. HIV env (C2-V3), gag (p24) and pol (reverse transcriptase) were sequenced from cell-free HIV RNA and cell-associated HIV DNA in blood and CSF using the Roche 454 FLX Titanium platform. Comprehensive sequence and phylogenetic analyses were performed to search for evidence of unique or differentially represented viral subpopulations emerging in CSF supernatant as compared with blood plasma.Using a conservative definition of compartmentalization based on four distinct statistical tests, nine participants presented a compartmentalized HIV RNA rebound within the CSF after interruption of ART, even when sampled within 2 weeks from viral rebound. The degree and duration of viral compartmentalization varied considerably between subjects and between time-points within a subject. In 10 cases, we identified viral populations within the CSF supernatant at the first sampled time-point after ART interruption, which were phylogenetically distinct from those present in the paired blood plasma and mostly persisted over time (when longitudinal time-points were available). Our data suggest that an independent source of HIV RNA contributes to viral rebound within the CSF after treatment interruption. The most likely source of compartmentalized HIV RNA is a CNS reservoir that would need to be targeted to achieve complete HIV eradication.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Garcia-Knight:2016aa", + "year": 2016, + "authors": "Garcia-Knight, Miguel A and Slyker, Jennifer and Payne, Barbara Lohman and Pond, Sergei L Kosakovsky and de Silva, Thushan I and Chohan, Bhavna and Khasimwa, Brian and Mbori-Ngacha, Dorothy and John-Stewart, Grace and Rowland-Jones, Sarah L and Esbj{\\\"o}rnsson, Joakim", + "title": "Viral Evolution and Cytotoxic T Cell Restricted Selection in Acute Infant HIV-1 Infection", + "journal": "Sci Rep", + "doi": "", + "abstract": "Antiretroviral therapy-naive HIV-1 infected infants experience poor viral containment and rapid disease progression compared to adults. Viral factors (e.g. transmitted cytotoxic T- lymphocyte (CTL) escape mutations) or infant factors (e.g. reduced CTL functional capacity) may explain this observation. We assessed CTL functionality by analysing selection in CTL-targeted HIV-1 epitopes following perinatal infection. HIV-1 gag, pol and nef sequences were generated from a historical repository of longitudinal specimens from 19 vertically infected infants. Evolutionary rate and selection were estimated for each gene and in CTL-restricted and non-restricted epitopes. Evolutionary rate was higher in nef and gag vs. pol, and lower in infants with non-severe immunosuppression vs. severe immunosuppression across gag and nef. Selection pressure was stronger in infants with non-severe immunosuppression vs. severe immunosuppression across gag. The analysis also showed that infants with non-severe immunosuppression had stronger selection in CTL-restricted vs. non-restricted epitopes in gag and nef. Evidence of stronger CTL selection was absent in infants with severe immunosuppression. These data indicate that infant CTLs can exert selection pressure on gag and nef epitopes in early infection and that stronger selection across CTL epitopes is associated with favourable clinical outcomes. These results have implications for the development of paediatric HIV-1 vaccines.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Landais:2016fv", + "year": 2016, + "authors": "Landais, Elise and Huang, Xiayu and Havenar-Daughton, Colin and Murrell, Ben and Price, Matt A and Wickramasinghe, Lalinda and Ramos, Alejandra and Bian, Charoan B and Simek, Melissa and Allen, Susan and Karita, Etienne and Kilembe, William and Lakhi, Shabir and Inambao, Mubiana and Kamali, Anatoli and Sanders, Eduard J and Anzala, Omu and Edward, Vinodh and Bekker, Linda-Gail and Tang, Jianming and Gilmour, Jill and Pond, Sergei L Kosakovsky and Phung, Pham and Wrin, Terri and Crotty, Shane and Godzik, Adam and Poignard, Pascal", + "title": "Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort", + "journal": "PLoS Pathog", + "doi": "", + "abstract": "Broadly neutralizing antibodies (bnAbs) are thought to be a critical component of a protective HIV vaccine. However, designing vaccines immunogens able to elicit bnAbs has proven unsuccessful to date. Understanding the correlates and immunological mechanisms leading to the development of bnAb responses during natural HIV infection is thus critical to the design of a protective vaccine. The IAVI Protocol C program investigates a large longitudinal cohort of primary HIV-1 infection in Eastern and South Africa. Development of neutralization was evaluated in 439 donors using a 6 cross-clade pseudo-virus panel predictive of neutralization breadth on larger panels. About 15% of individuals developed bnAb responses, essentially between year 2 and year 4 of infection. Statistical analyses revealed no influence of gender, age or geographical origin on the development of neutralization breadth. However, cross-clade neutralization strongly correlated with high viral load as well as with low CD4 T cell counts, subtype-C infection and HLA-A*03(-) genotype. A correlation with high overall plasma IgG levels and anti-Env IgG binding titers was also found. The latter appeared not associated with higher affinity, suggesting a greater diversity of the anti-Env responses in broad neutralizers. Broadly neutralizing activity targeting glycan-dependent epitopes, largely the N332-glycan epitope region, was detected in nearly half of the broad neutralizers while CD4bs and gp41-MPER bnAb responses were only detected in very few individuals. Together the findings suggest that both viral and host factors are critical for the development of bnAbs and that the HIV Env N332-glycan supersite may be a favorable target for vaccine design.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Lorenzo-Redondo:2016zl", + "year": 2016, + "authors": "Lorenzo-Redondo, Ramon and Fryer, Helen R and Bedford, Trevor and Kim, Eun-Young and Archer, John and Pond, Sergei L Kosakovsky and Chung, Yoon-Seok and Penugonda, Sudhir and Chipman, Jeffrey G and Fletcher, Courtney V and Schacker, Timothy W and Malim, Michael H and Rambaut, Andrew and Haase, Ashley T and McLean, Angela R and Wolinsky, Steven M", + "title": "Persistent HIV-1 replication maintains the tissue reservoir during therapy", + "journal": "Nature", + "doi": "", + "abstract": "Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Tully:2016rz", + "year": 2016, + "authors": "Tully, Damien C and Ogilvie, Colin B and Batorsky, Rebecca E and Bean, David J and Power, Karen A and Ghebremichael, Musie and Bedard, Hunter E and Gladden, Adrianne D and Seese, Aaron M and Amero, Molly A and Lane, Kimberly and McGrath, Graham and Bazner, Suzane B and Tinsley, Jake and Lennon, Niall J and Henn, Matthew R and Brumme, Zabrina L and Norris, Philip J and Rosenberg, Eric S and Mayer, Kenneth H and Jessen, Heiko and Pond, Sergei L Kosakovsky and Walker, Bruce D and Altfeld, Marcus and Carlson, Jonathan M and Allen, Todd M", + "title": "Differences in the Selection Bottleneck between Modes of Sexual Transmission Influence the Genetic Composition of the HIV-1 Founder Virus", + "journal": "PLoS Pathog", + "doi": "", + "abstract": "Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome. Analysis of 74 acute and early HIV-1 infected subjects revealed that 83% of men who have sex with men (MSM) exhibit a single founder virus, levels similar to those previously observed in heterosexual (HSX) transmission. In a metadata analysis of a total of 354 subjects, including HSX, MSM and injecting drug users (IDU), we also observed no significant differences in the frequency of single founder virus infections between HSX and MSM transmissions. However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants. Moreover, specific genetic \"signatures\" within MSM and HSX founder viruses were identified, with single polymorphisms within gp41 enriched among HSX viruses while more complex patterns, including clustered polymorphisms surrounding the CD4 binding site, were enriched in MSM viruses. While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition. This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Mehta:2016ty", + "year": 2016, + "authors": "Mehta, Sanjay R and Murrell, Ben and Anderson, Christy M and Pond, Sergei L Kosakovsky and Wertheim, Joel O and Young, Jason A and Freitas, Lorri and Richman, Douglas D and Mathews, W Chris and Scheffler, Konrad and Little, Susan J and Smith, Davey M", + "title": "Using HIV Sequence and Epidemiologic Data to Assess the Effect of Self-referral Testing for Acute HIV Infection on Incident Diagnoses in San Diego, California", + "journal": "Clin Infect Dis", + "doi": "", + "abstract": "BACKGROUND: \u2003Because recently infected individuals disproportionately contribute to the spread of human immunodeficiency virus (HIV), we evaluated the impact of a primary HIV screening program (the Early Test) implemented in San Diego.\nMETHODS: \u2003The Early Test program used combined nucleic acid and serology testing to screen for primary infection targeting local high-risk individuals. Epidemiologic, HIV sequence, and geographic data were obtained from the San Diego County Department of Public Health and the Early Test program. Poisson regression analysis was performed to determine whether the Early Test program was temporally and geographically associated with changes in incident HIV diagnoses. Transmission chains were inferred by phylogenetic analysis of sequence data.\nRESULTS: \u2003Over time, a decrease in incident HIV diagnoses was observed proportional to the number primary HIV infections diagnosed in each San Diego region (P < .001). Molecular network analyses also showed that transmission chains were more likely to terminate in regions where the program was marketed (P = .002). Although, individuals in these zip codes had infection diagnosed earlier (P = .08), they were not treated earlier (P = .83).\nCONCLUSIONS: \u2003These findings suggests that early HIV diagnoses by this primary infection screening program probably contributed to the observed decrease in new HIV diagnoses in San Diego, and they support the expansion and evaluation of similar programs.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "MacLeod:2016qv", + "year": 2016, + "authors": "MacLeod, Daniel T and Choi, Nancy M and Briney, Bryan and Garces, Fernando and Ver, Lorena S and Landais, Elise and Murrell, Ben and Wrin, Terri and Kilembe, William and Liang, Chi-Hui and Ramos, Alejandra and Bian, Chaoran B and Wickramasinghe, Lalinda and Kong, Leopold and Eren, Kemal and Wu, Chung-Yi and Wong, Chi-Huey and {IAVI Protocol C Investigators \\& The IAVI African HIV Research Network} and Pond, Sergei L Kosakovsky and Wilson, Ian A and Burton, Dennis R and Poignard, Pascal", + "title": "Early Antibody Lineage Diversification and Independent Limb Maturation Lead to Broad HIV-1 Neutralization Targeting the Env High-Mannose Patch", + "journal": "Immunity", + "doi": "", + "abstract": "The high-mannose patch on HIV Env is a preferred target for broadly neutralizing antibodies (bnAbs), but to date, no vaccination regimen has elicited bnAbs against this region. Here, we present the development of a bnAb lineage targeting the high-mannose patch in an HIV-1 subtype-C-infected donor from sub-Saharan Africa. The Abs first acquired autologous neutralization, then gradually matured to achieve breadth. One Ab neutralized >47% of HIV-1 strains with only \u223c11% somatic hypermutation and no insertions or deletions. By sequencing autologous env, we determined key residues that triggered the lineage and participated in Ab-Env coevolution. Next-generation sequencing of the Ab repertoire showed an early expansive diversification of the lineage followed by independent maturation of individual limbs, several of them developing notable breadth and potency. Overall, the findings are encouraging from a vaccine standpoint and suggest immunization strategies mimicking the evolution of the entire high-mannose patch and promoting maturation of multiple diverse Ab pathways.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Oliveira:2015aa", + "year": 2015, + "authors": "de Oliveira, Michelli Faria and Gianella, Sara and Letendre, Scott and Scheffler, Konrad and Pond, Sergei L Kosakovsky and Smith, Davey M and Strain, Matt and Ellis, Ronald J", + "title": "Comparative Analysis of Cell-Associated HIV DNA Levels in Cerebrospinal Fluid and Peripheral Blood by Droplet Digital PCR", + "journal": "PLoS One", + "doi": "", + "abstract": "BACKGROUND: Measurement of HIV DNA-bearing cells in cerebrospinal fluid (CSF) is challenging because few cells are present. We present a novel application of the sensitive droplet digital (dd)PCR in this context.\nMETHODS: We analyzed CSF cell pellets and paired peripheral blood mononuclear cells (PBMC) from 28 subjects, 19 of whom had undetectable HIV RNA (<48 copies/mL) in both compartments. We extracted DNA from PBMC using silica-based columns and used direct lysis on CSF cells. HIV DNA and the host housekeeping gene (RPP30) were measured in CSF and PBMC by (dd)PCR. We compared HIV DNA levels in virally-suppressed and-unsuppressed subgroups and calculated correlations between HIV DNA and RNA levels in both compartments using non-parametric tests.\nRESULTS: HIV DNA was detected in 18/28 (64%) CSF cell pellets, including 10/19 (53%) samples with undetectable HIV RNA. HIV DNA levels in CSF cell pellets were not correlated with RPP30 (p = 0.3), but correlated positively with HIV RNA in CSF (p = 0.04) and HIV DNA in PBMC (p = 0.03). Cellular HIV DNA in CSF was detected in comparable levels in HIV RNA-suppressed and unsuppressed subjects (p = 0.14). In contrast, HIV DNA levels in PBMC were significantly lower in HIV RNA-suppressed than in unsuppressed subjects (p = 0.014). Among subjects with detectable HIV DNA in both compartments, HIV DNA levels in CSF were significantly higher than in PBMC (p<0.001).\nCONCLUSIONS: Despite low mononuclear cell numbers in CSF, HIV DNA was detected in most virally suppressed individuals. In contrast to PBMC, suppressive ART was not associated with lower HIV DNA levels in CSF cells, compared to no ART, perhaps due to poorer ART penetration, slower decay of HIV DNA, or enrichment of HIV DNA-bearing mononuclear cells into the CSF, compared to blood. Future studies should determine what fraction of HIV DNA is replication-competent in CSF leukocytes, compared to PBMC.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "lapp20072006", + "year": 2007, + "authors": "Lapp, Hilmar and Bala, Sendu and Balhoff, James P and Bouck, Amy and Goto, Naohisa and Holder, Mark and Holland, Richard and Holloway, Alisha and Katayama, Toshiaki and Lewis, Paul O and others", + "title": "The 2006 NESCent phyloinformatics hackathon: a field report", + "journal": "Evolutionary Bioinformatics Online", + "doi": "", + "abstract": "", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "landais2014development", + "year": 2014, + "authors": "Landais, Elise and Briney, Bryan S and Pond, Sergei L Kosakovsky and MacLeod, Daniel T and Lie, Yolanda and Algate, Paul and Burton, Dennis R and Wrin, Terri and Chan-Hui, Po-Ying and Poignard, Pascal", + "title": "Development of a V1/V2-targeting Quaternary-specific Broadly Neutralizing Lineage", + "journal": "AIDS Res Hum Retroviruses", + "doi": "", + "abstract": "", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Volz:2014wj", + "year": 2014, + "authors": "Volz, Erik and Pond, Sergei L Kosakovsky", + "title": "Phylodynamic analysis of ebola virus in the 2014 Sierra Leone epidemic", + "journal": "PLoS Curr", + "doi": "", + "abstract": "BACKGROUND: The Ebola virus (EBOV) epidemic in Western Africa is the largest in recorded history and control efforts have so far failed to stem the rapid growth in the number of infections. Mathematical models serve a key role in estimating epidemic growth rates and the reproduction number (R0) from surveillance data and, recently, molecular sequence data. Phylodynamic analysis of existing EBOV time-stamped sequence data may provide independent estimates of the unobserved number of infections, reveal recent epidemiological history, and provide insight into selective pressures acting upon viral genes.\nMETHODS: We fit a series mathematical models of infectious disease dynamics to phylogenies estimated from 78 whole EBOV genomes collected from distinct patients in May and June of 2014 in Sierra Leone, and perform evolutionary analysis on these genomes combined with closely related EBOV genomes from previous outbreaks. Two analyses are conducted with values of the latent period that have been used in recent modelling efforts. We also examined the EBOV sequences for evidence of possible episodic adaptive molecular evolution during the 2014 outbreak.\nRESULTS: We find evidence for adaptive evolution affecting L and GP protein coding regions of the EBOV genome, which is unlikely to bias molecular clock and phylodynamic analyses. We estimate R0=2.40 (95% HPD:1.54-3.87 ) if the mean latent period is 5.3 days, and R0=3.81, (95% HPD:2.47-6.3) if the mean latent period is 12.7 days. The estimated coefficient of variation (CV) of the number of transmissions per infected host is very high, and a large proportion of infections yield no transmissions.\nCONCLUSIONS: Estimates of R0 are sensitive to the unknown latent infectious period which can not be reliably estimated from genetic data alone. EBOV phylogenies show significant evidence for superspreading and extreme variance in the number of transmissions per infected individual during the early epidemic in Sierra Leone.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Frost:2015wb", + "year": 2015, + "authors": "Frost, Simon D W and Murrell, Ben and Hossain, A S Md Mukarram and Silverman, Gregg J and Pond, Sergei L Kosakovsky", + "title": "Assigning and visualizing germline genes in antibody repertoires", + "journal": "Philos Trans R Soc Lond B Biol Sci", + "doi": "", + "abstract": "Identifying the germline genes involved in immunoglobulin rearrangements is an essential first step in the analysis of antibody repertoires. Based on our prior work in analysing diverse recombinant viruses, we present IgSCUEAL (Immunoglobulin Subtype Classification Using Evolutionary ALgorithms), a phylogenetic approach to assign V and J regions of immunoglobulin sequences to their corresponding germline alleles, with D regions assigned using a simple pairwise alignment algorithm. We also develop an interactive web application for viewing the results, allowing the user to explore the frequency distribution of sequence assignments and CDR3 region length statistics, which is useful for summarizing repertoires, as well as a detailed viewer of rearrangements and region alignments for individual query sequences. We demonstrate the accuracy and utility of our method compared with sequence similarity-based approaches and other non-phylogenetic model-based approaches, using both simulated data and a set of evaluation datasets of human immunoglobulin heavy chain sequences. IgSCUEAL demonstrates the highest accuracy of V and J assignment amongst existing approaches, even when the reassorted sequence is highly mutated, and can successfully cluster sequences on the basis of shared V/J germline alleles.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Murrell:2015ct", + "year": 2015, + "authors": "Murrell, Ben and Weaver, Steven and Smith, Martin D and Wertheim, Joel O and Murrell, Sasha and Aylward, Anthony and Eren, Kemal and Pollner, Tristan and Martin, Darren P and Smith, Davey M and Scheffler, Konrad and Pond, Sergei L Kosakovsky", + "title": "Gene-wide identification of episodic selection", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "We present BUSTED, a new approach to identifying gene-wide evidence of episodic positive selection, where the non-synonymous substitution rate is transiently greater than the synonymous rate. BUSTED can be used either on an entire phylogeny (without requiring an a priori hypothesis regarding which branches are under positive selection) or on a pre-specified subset of foreground lineages (if a suitable a priori hypothesis is available). Selection is modeled as varying stochastically over branches and sites, and we propose a computationally inexpensive evidence metric for identifying sites subject to episodic positive selection on any foreground branches. We compare BUSTED with existing models on simulated and empirical data. An implementation is available on www.datamonkey.org/busted, with a widget allowing the interactive specification of foreground branches.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Smith:2015oa", + "year": 2015, + "authors": "Smith, Martin D and Wertheim, Joel O and Weaver, Steven and Murrell, Ben and Scheffler, Konrad and Pond, Sergei L Kosakovsky", + "title": "Less is more: an adaptive branch-site random effects model for efficient detection of episodic diversifying selection", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Over the past two decades, comparative sequence analysis using codon-substitution models has been honed into a powerful and popular approach for detecting signatures of natural selection from molecular data. A substantial body of work has focused on developing a class of \"branch-site\" models which permit selective pressures on sequences, quantified by the \u03c9 ratio, to vary among both codon sites and individual branches in the phylogeny. We develop and present a method in this class, adaptive branch-site random effects likelihood (aBSREL), whose key innovation is variable parametric complexity chosen with an information theoretic criterion. By applying models of different complexity to different branches in the phylogeny, aBSREL delivers statistical performance matching or exceeding best-in-class existing approaches, while running an order of magnitude faster. Based on simulated data analysis, we offer guidelines for what extent and strength of diversifying positive selection can be detected reliably and suggest that there is a natural limit on the optimal parametric complexity for \"branch-site\" models. An aBSREL analysis of 8,893 Euteleostomes gene alignments demonstrates that over 80% of branches in typical gene phylogenies can be adequately modeled with a single \u03c9 ratio model, that is, current models are unnecessarily complicated. However, there are a relatively small number of key branches, whose identities are derived from the data using a model selection procedure, for which it is essential to accurately model evolutionary complexity.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Edlefsen:2015ya", + "year": 2015, + "authors": "Edlefsen, Paul T and Rolland, Morgane and Hertz, Tomer and Tovanabutra, Sodsai and Gartland, Andrew J and deCamp, Allan C and Magaret, Craig A and Ahmed, Hasan and Gottardo, Raphael and Juraska, Michal and McCoy, Connor and Larsen, Brendan B and Sanders-Buell, Eric and Carrico, Chris and Menis, Sergey and Bose, Meera and {RV144 Sequencing Team} and Arroyo, Miguel A and O'Connell, Robert J and Nitayaphan, Sorachai and Pitisuttithum, Punnee and Kaewkungwal, Jaranit and Rerks-Ngarm, Supachai and Robb, Merlin L and Kirys, Tatsiana and Georgiev, Ivelin S and Kwong, Peter D and Scheffler, Konrad and Pond, Sergei L Kosakovsky and Carlson, Jonathan M and Michael, Nelson L and Schief, William R and Mullins, James I and Kim, Jerome H and Gilbert, Peter B", + "title": "Comprehensive sieve analysis of breakthrough HIV-1 sequences in the RV144 vaccine efficacy trial", + "journal": "PLoS Comput Biol", + "doi": "", + "abstract": "The RV144 clinical trial showed the partial efficacy of a vaccine regimen with an estimated vaccine efficacy (VE) of 31% for protecting low-risk Thai volunteers against acquisition of HIV-1. The impact of vaccine-induced immune responses can be investigated through sieve analysis of HIV-1 breakthrough infections (infected vaccine and placebo recipients). A V1/V2-targeted comparison of the genomes of HIV-1 breakthrough viruses identified two V2 amino acid sites that differed between the vaccine and placebo groups. Here we extended the V1/V2 analysis to the entire HIV-1 genome using an array of methods based on individual sites, k-mers and genes/proteins. We identified 56 amino acid sites or \"signatures\" and 119 k-mers that differed between the vaccine and placebo groups. Of those, 19 sites and 38 k-mers were located in the regions comprising the RV144 vaccine (Env-gp120, Gag, and Pro). The nine signature sites in Env-gp120 were significantly enriched for known antibody-associated sites (p = 0.0021). In particular, site 317 in the third variable loop (V3) overlapped with a hotspot of antibody recognition, and sites 369 and 424 were linked to CD4 binding site neutralization. The identified signature sites significantly covaried with other sites across the genome (mean = 32.1) more than did non-signature sites (mean = 0.9) (p < 0.0001), suggesting functional and/or structural relevance of the signature sites. Since signature sites were not preferentially restricted to the vaccine immunogens and because most of the associations were insignificant following correction for multiple testing, we predict that few of the genetic differences are strongly linked to the RV144 vaccine-induced immune pressure. In addition to presenting results of the first complete-genome analysis of the breakthrough infections in the RV144 trial, this work describes a set of statistical methods and tools applicable to analysis of breakthrough infection genomes in general vaccine efficacy trials for diverse pathogens.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Fisher:2015xz", + "year": 2015, + "authors": "Fisher, Randall G and Smith, Davey M and Murrell, Ben and Slabbert, Ruhan and Kirby, Bronwyn M and Edson, Clair and Cotton, Mark F and Haubrich, Richard H and Pond, Sergei L Kosakovsky and Van Zyl, Gert U", + "title": "Next generation sequencing improves detection of drug resistance mutations in infants after PMTCT failure", + "journal": "J Clin Virol", + "doi": "", + "abstract": "BACKGROUND: Next generation sequencing (NGS) allows the detection of minor variant HIV drug resistance mutations (DRMs). However data from new NGS platforms after Prevention-of-Mother-to-Child-Transmission (PMTCT) regimen failure are limited.\nOBJECTIVE: To compare major and minor variant HIV DRMs with Illumina MiSeq and Life Technologies Ion Personal Genome Machine (PGM) in infants infected despite a PMTCT regimen.\nSTUDY DESIGN: We conducted a cross-sectional study of NGS for detecting DRMs in infants infected despite a zidovudine (AZT) and Nevirapine (NVP) regimen, before initiation of combination antiretroviral therapy. Sequencing was performed on PCR products from plasma samples on PGM and MiSeq platforms. Bioinformatic analyses were undertaken using a codon-aware version of the Smith-Waterman mapping algorithm and a mixture multinomial error filtering statistical model.\nRESULTS: Of 15 infants, tested at a median age of 3.4 months after birth, 2 (13%) had non-nucleoside reverse transcriptase inhibitor (NNRTI) DRMs (K103N and Y181C) by bulk sequencing, whereas PGM detected 4 (26%) and MiSeq 5 (30%). NGS enabled the detection of additional minor variant DRMs in the infant with K103N. Coverage and instrument quality scores were higher with MiSeq, increasing the confidence of minor variant calls.\nCONCLUSIONS: NGS followed by bioinformatic analyses detected multiple minor variant DRMs in HIV-1 RT among infants where PMTCT failed. The high coverage of MiSeq and high read quality improved the confidence of identified DRMs and may make this platform ideal for minor variant detection.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wertheim:2015fb", + "year": 2015, + "authors": "Wertheim, Joel O and Murrell, Ben and Smith, Martin D and Pond, Sergei L Kosakovsky and Scheffler, Konrad", + "title": "RELAX: detecting relaxed selection in a phylogenetic framework", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Relaxation of selective strength, manifested as a reduction in the efficiency or intensity of natural selection, can drive evolutionary innovation and presage lineage extinction or loss of function. Mechanisms through which selection can be relaxed range from the removal of an existing selective constraint to a reduction in effective population size. Standard methods for estimating the strength and extent of purifying or positive selection from molecular sequence data are not suitable for detecting relaxed selection, because they lack power and can mistake an increase in the intensity of positive selection for relaxation of both purifying and positive selection. Here, we present a general hypothesis testing framework (RELAX) for detecting relaxed selection in a codon-based phylogenetic framework. Given two subsets of branches in a phylogeny, RELAX can determine whether selective strength was relaxed or intensified in one of these subsets relative to the other. We establish the validity of our test via simulations and show that it can distinguish between increased positive selection and a relaxation of selective strength. We also demonstrate the power of RELAX in a variety of biological scenarios where relaxation of selection has been hypothesized or demonstrated previously. We find that obligate and facultative \u03b3-proteobacteria endosymbionts of insects are under relaxed selection compared with their free-living relatives and obligate endosymbionts are under relaxed selection compared with facultative endosymbionts. Selective strength is also relaxed in asexual Daphnia pulex lineages, compared with sexual lineages. Endogenous, nonfunctional, bornavirus-like elements are found to be under relaxed selection compared with exogenous Borna viruses. Finally, selection on the short-wavelength sensitive, SWS1, opsin genes in echolocating and nonecholocating bats is relaxed only in lineages in which this gene underwent pseudogenization; however, selection on the functional medium/long-wavelength sensitive opsin, M/LWS1, is found to be relaxed in all echolocating bats compared with nonecholocating bats.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Carter:2015jb", + "year": 2015, + "authors": "Carter, Christoph C and Wagner, Gabriel A and Hightower, George K and Caballero, Gemma and Phung, Pham and Richman, Douglas D and Pond, Sergei L Kosakovsky and Smith, Davey M", + "title": "HIV-1 neutralizing antibody response and viral genetic diversity characterized with next generation sequencing", + "journal": "Virology", + "doi": "", + "abstract": "To better understand the dynamics of HIV-specific neutralizing antibody (NAb), we examined associations between viral genetic diversity and the NAb response against a multi-subtype panel of heterologous viruses in a well-characterized, therapy-na{\\\"\\i}ve primary infection cohort. Using next generation sequencing (NGS), we computed sequence-based measures of diversity within HIV-1 env, gag and pol, and compared them to NAb breadth and potency as calculated by a neutralization score. Contemporaneous env diversity and the neutralization score were positively correlated (p=0.0033), as were the neutralization score and estimated duration of infection (EDI) (p=0.0038), and env diversity and EDI (p=0.0005). Neither early env diversity nor baseline viral load correlated with future NAb breadth and potency (p>0.05). Taken together, it is unlikely that neutralizing capability in our cohort was conditioned on viral diversity, but rather that env evolution was driven by the level of NAb selective pressure.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Minoarivelo:2014kr", + "year": 2014, + "authors": "Minoarivelo, H O and Hui, C and Terblanche, J S and Pond, S L Kosakovsky and Scheffler, K", + "title": "Detecting phylogenetic signal in mutualistic interaction networks using a Markov process model", + "journal": "Oikos", + "doi": "", + "abstract": "Ecological interaction networks, such as those describing the mutualistic interactions between plants and their pollinators or between plants and their frugivores, exhibit non-random structural properties that cannot be explained by simple models of network formation. One factor affecting the formation and eventual structure of such a network is its evolutionary history. We argue that this, in many cases, is closely linked to the evolutionary histories of the species involved in the interactions. Indeed, empirical studies of interaction networks along with the phylogenies of the interacting species have demonstrated significant associations between phylogeny and network structure. To date, however, no generative model explaining the way in which the evolution of individual species affects the evolution of interaction networks has been proposed. We present a model describing the evolution of pairwise interactions as a branching Markov process, drawing on phylogenetic models of molecular evolution. Using knowledge of the phylogenies of the interacting species, our model yielded a significantly better fit to 21% of a set of plant - pollinator and plant - frugivore mutualistic networks. This highlights the importance, in a substantial minority of cases, of inheritance of interaction patterns without excluding the potential role of ecological novelties in forming the current network architecture. We suggest that our model can be used as a null model for controlling evolutionary signals when evaluating the role of other factors in shaping the emergence of ecological networks.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Hepler:2014xi", + "year": 2014, + "authors": "Hepler, N Lance and Scheffler, Konrad and Weaver, Steven and Murrell, Ben and Richman, Douglas D and Burton, Dennis R and Poignard, Pascal and Smith, Davey M and Pond, Sergei L Kosakovsky", + "title": "IDEPI: rapid prediction of HIV-1 antibody epitopes and other phenotypic features from sequence data using a flexible machine learning platform", + "journal": "PLoS Comput Biol", + "doi": "", + "abstract": "Since its identification in 1983, HIV-1 has been the focus of a research effort unprecedented in scope and difficulty, whose ultimate goals--a cure and a vaccine--remain elusive. One of the fundamental challenges in accomplishing these goals is the tremendous genetic variability of the virus, with some genes differing at as many as 40% of nucleotide positions among circulating strains. Because of this, the genetic bases of many viral phenotypes, most notably the susceptibility to neutralization by a particular antibody, are difficult to identify computationally. Drawing upon open-source general-purpose machine learning algorithms and libraries, we have developed a software package IDEPI (IDentify EPItopes) for learning genotype-to-phenotype predictive models from sequences with known phenotypes. IDEPI can apply learned models to classify sequences of unknown phenotypes, and also identify specific sequence features which contribute to a particular phenotype. We demonstrate that IDEPI achieves performance similar to or better than that of previously published approaches on four well-studied problems: finding the epitopes of broadly neutralizing antibodies (bNab), determining coreceptor tropism of the virus, identifying compartment-specific genetic signatures of the virus, and deducing drug-resistance associated mutations. The cross-platform Python source code (released under the GPL 3.0 license), documentation, issue tracking, and a pre-configured virtual machine for IDEPI can be found at https://github.com/veg/idepi.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Nayak:2015ri", + "year": 2015, + "authors": "Nayak, Aparajita and Pattabiraman, Nagarajan and Fadra, Numrah and Goldman, Radoslav and Pond, Sergei L Kosakovsky and Mazumder, Raja", + "title": "Structure-function analysis of hepatitis C virus envelope glycoproteins E1 and E2", + "journal": "J Biomol Struct Dyn", + "doi": "", + "abstract": "Hepatitis C virus (HCV) is the leading cause of chronic liver disease in humans. The envelope proteins of HCV are potential candidates for vaccine development. The absence of three-dimensional (3D) structures for the functional domain of HCV envelope proteins [E1.E2] monomer complex has hindered overall understanding of the virus infection, and also structure-based drug design initiatives. In this study, we report a 3D model containing both E1 and E2 proteins of HCV using the recently published structure of the core domain of HCV E2 and the functional part of E1, and investigate immunogenic implications of the model. HCV [E1.E2] molecule is modeled by using aa205-319 of E1 to aa421-716 of E2. Published experimental data were used to further refine the [E1.E2] model. Based on the model, we predict 77 exposed residues and several antigenic sites within the [E1.E2] that could serve as vaccine epitopes. This study identifies eight peptides which have antigenic propensity and have two or more sequentially exposed amino acids and 12 singular sites are under negative selection pressure that can serve as vaccine or therapeutic targets. Our special interest is 285FLVGQLFTFSPRRHW299 which has five negatively selected sites (L286, V287, G288, T292, and G303) with three of them sequential and four amino acids exposed (F285, L286, T292, and R296). This peptide in the E1 protein maps to dengue envelope vaccine target identified previously by our group. Our model provides for the first time an overall view of both the HCV envelope proteins thereby allowing researchers explore structure-based drug design approaches.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wertheim:2014mq", + "year": 2014, + "authors": "Wertheim, Joel O and Smith, Martin D and Smith, Davey M and Scheffler, Konrad and Pond, Sergei L Kosakovsky", + "title": "Evolutionary origins of human herpes simplex viruses 1 and 2", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Herpesviruses have been infecting and codiverging with their vertebrate hosts for hundreds of millions of years. The primate simplex viruses exemplify this pattern of virus-host codivergence, at a minimum, as far back as the most recent common ancestor of New World monkeys, Old World monkeys, and apes. Humans are the only primate species known to be infected with two distinct herpes simplex viruses: HSV-1 and HSV-2. Human herpes simplex viruses are ubiquitous, with over two-thirds of the human population infected by at least one virus. Here, we investigated whether the additional human simplex virus is the result of ancient viral lineage duplication or cross-species transmission. We found that standard phylogenetic models of nucleotide substitution are inadequate for distinguishing among these competing hypotheses; the extent of synonymous substitutions causes a substantial underestimation of the lengths of some of the branches in the phylogeny, consistent with observations in other viruses (e.g., avian influenza, Ebola, and coronaviruses). To more accurately estimate ancient viral divergence times, we applied a branch-site random effects likelihood model of molecular evolution that allows the strength of natural selection to vary across both the viral phylogeny and the gene alignment. This selection-informed model favored a scenario in which HSV-1 is the result of ancient codivergence and HSV-2 arose from a cross-species transmission event from the ancestor of modern chimpanzees to an extinct Homo precursor of modern humans, around 1.6 Ma. These results provide a new framework for understanding human herpes simplex virus evolution and demonstrate the importance of using selection-informed models of sequence evolution when investigating viral origin hypotheses.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Little:2014pz", + "year": 2014, + "authors": "Little, Susan J and Pond, Sergei L Kosakovsky and Anderson, Christy M and Young, Jason A and Wertheim, Joel O and Mehta, Sanjay R and May, Susanne and Smith, Davey M", + "title": "Using HIV networks to inform real time prevention interventions", + "journal": "PLoS One", + "doi": "", + "abstract": "OBJECTIVE: To reconstruct the local HIV-1 transmission network from 1996 to 2011 and use network data to evaluate and guide efforts to interrupt transmission.\nDESIGN: HIV-1 pol sequence data were analyzed to infer the local transmission network.\nMETHODS: We analyzed HIV-1 pol sequence data to infer a partial local transmission network among 478 recently HIV-1 infected persons and 170 of their sexual and social contacts in San Diego, California. A transmission network score (TNS) was developed to estimate the risk of HIV transmission from a newly diagnosed individual to a new partner and target prevention interventions.\nRESULTS: HIV-1 pol sequences from 339 individuals (52.3%) were highly similar to sequences from at least one other participant (i.e., clustered). A high TNS (top 25%) was significantly correlated with baseline risk behaviors (number of unique sexual partners and insertive unprotected anal intercourse (p = 0.014 and p = 0.0455, respectively) and predicted risk of transmission (p<0.0001). Retrospective analysis of antiretroviral therapy (ART) use, and simulations of ART targeted to individuals with the highest TNS, showed significantly reduced network level HIV transmission (p<0.05).\nCONCLUSIONS: Sequence data from an HIV-1 screening program focused on recently infected persons and their social and sexual contacts enabled the characterization of a highly connected transmission network. The network-based risk score (TNS) was highly correlated with transmission risk behaviors and outcomes, and can be used identify and target effective prevention interventions, like ART, to those at a greater risk for HIV-1 transmission.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Scheffler:2014wm", + "year": 2014, + "authors": "Scheffler, Konrad and Murrell, Ben and Pond, Sergei L Kosakovsky", + "title": "On the validity of evolutionary models with site-specific parameters", + "journal": "PLoS One", + "doi": "", + "abstract": "Evolutionary models that make use of site-specific parameters have recently been criticized on the grounds that parameter estimates obtained under such models can be unreliable and lack theoretical guarantees of convergence. We present a simulation study providing empirical evidence that a simple version of the models in question does exhibit sensible convergence behavior and that additional taxa, despite not being independent of each other, lead to improved parameter estimates. Although it would be desirable to have theoretical guarantees of this, we argue that such guarantees would not be sufficient to justify the use of these models in practice. Instead, we emphasize the importance of taking the variance of parameter estimates into account rather than blindly trusting point estimates - this is standardly done by using the models to construct statistical hypothesis tests, which are then validated empirically via simulation studies.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Benndorf:2014sh", + "year": 2014, + "authors": "Benndorf, Rainer and Martin, Jody L and Pond, Sergei L Kosakovsky and Wertheim, Joel O", + "title": "Neuropathy- and myopathy-associated mutations in human small heat shock proteins: Characteristics and evolutionary history of the mutation sites", + "journal": "Mutat Res Rev Mutat Res", + "doi": "", + "abstract": "Mutations in four of the ten human small heat shock proteins (sHSP) are associated with various forms of motor neuropathies and myopathies. In HspB1, HspB3, and HspB8 all known mutations cause motor neuropathies, whereas in HspB5 they cause myopathies. Several features are common to the majority of these mutations: (i) they are missense mutations, (ii) most associated disease phenotypes exhibit a dominant inheritance pattern and late disease onset, (iii) in the primary protein sequences, the sites of most mutations are located in the conserved \u03b1-crystallin domain and the variable C-terminal extensions, and (iv) most human mutation sites are highly conserved among the vertebrate orthologs and have been historically exposed to significant purifying selection. In contrast, a minor fraction of these mutations deviate from these rules: they are (i) frame shifting, nonsense, or elongation mutations, (ii) associated with recessive or early onset disease phenotypes, (iii) positioned in the N-terminal domain of the proteins, and (iv) less conserved among the vertebrates and were historically not subject to a strong selective pressure. In several vertebrate sHSPs (including primate sHSPs), homologous sites differ from the human sequence and occasionally even encode the same amino acid residues that cause the disease in humans. Apparently, a number of these mutations sites are not crucial for the protein function in single species or entire taxa, and single species even seem to have adopted mechanisms that compensate for potentially adverse effects of 'mutant-like' sHSPs. The disease-associated dominant sHSP missense mutations have a number of cellular consequences that are consistent with gain-of-function mechanisms of genetic dominance: dominant-negative effects, the formation of cytotoxic amyloid protein oligomers and precipitates, disruption of cytoskeletal networks, and increased downstream enzymatic activities. Future therapeutic concepts should aim for reducing these adverse effects of mutant sHSPs in patients. Indeed, initial experimental results are encouraging.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wagner:2014lp", + "year": 2014, + "authors": "Wagner, Gabriel A and Pacold, Mary E and Pond, Sergei L Kosakovsky and Caballero, Gemma and Chaillon, Antoine and Rudolph, Abby E and Morris, Sheldon R and Little, Susan J and Richman, Douglas D and Smith, Davey M", + "title": "Incidence and prevalence of intrasubtype HIV-1 dual infection in at-risk men in the United States", + "journal": "J Infect Dis", + "doi": "", + "abstract": "BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) dual infection (DI) has been associated with decreased CD4 T-cell counts and increased viral loads; however, the frequency of intrasubtype DI is poorly understood. We used ultradeep sequencing (UDS) to estimate the frequency of DI in a primary infection cohort of predominantly men who have sex with men (MSM).\nMETHODS: \u2003HIV-1 genomes from longitudinal blood samples of recently infected, therapy-naive participants were interrogated with UDS. DI was confirmed when maximum sequence divergence was excessive and supported by phylogenetic analysis. Coinfection was defined as DI at baseline; superinfection was monoinfection at baseline and DI at a later time point.\nRESULTS: \u2003Of 118 participants, 7 were coinfected and 10 acquired superinfection. Superinfection incidence rate was 4.96 per 100 person-years (95% confidence interval [CI], 2.67-9.22); 6 occurred in the first year and 4 in the second. Overall cumulative prevalence of intrasubtype B DI was 14.4% (95% CI, 8.6%-22.1%). Primary HIV-1 incidence was 4.37 per 100 person-years (95% CI, 3.56-5.36).\nCONCLUSIONS: \u2003Intrasubtype DI was frequent and comparable to primary infection rates among MSM in San Diego; however, superinfection rates declined over time. DI is likely an important component of the HIV epidemic dynamics, and development of stronger immune responses to the initial infection may protect from superinfection.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wertheim:2014jh", + "year": 2014, + "authors": "Wertheim, Joel O and Leigh Brown, Andrew J and Hepler, N Lance and Mehta, Sanjay R and Richman, Douglas D and Smith, Davey M and Pond, Sergei L Kosakovsky", + "title": "The global transmission network of HIV-1", + "journal": "J Infect Dis", + "doi": "", + "abstract": "Human immunodeficiency virus type 1 (HIV-1) is pandemic, but its contemporary global transmission network has not been characterized. A better understanding of the properties and dynamics of this network is essential for surveillance, prevention, and eventual eradication of HIV. Here, we apply a simple and computationally efficient network-based approach to all publicly available HIV polymerase sequences in the global database, revealing a contemporary picture of the spread of HIV-1 within and between countries. This approach automatically recovered well-characterized transmission clusters and extended other clusters thought to be contained within a single country across international borders. In addition, previously undescribed transmission clusters were discovered. Together, these clusters represent all known modes of HIV transmission. The extent of international linkage revealed by our comprehensive approach demonstrates the need to consider the global diversity of HIV, even when describing local epidemics. Finally, the speed of this method allows for near-real-time surveillance of the pandemic's progression.", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Chaillon:2013ta", + "year": 2013, + "authors": "Chaillon, Antoine and Wagner, Gabriel A and Hepler, N Lance and Little, Susan J and Pond, Sergei L Kosakovsky and Caballero, Gemma and Pacold, Mary E and Phung, Pham and Wrin, Terri and Richman, Douglas D and Wertheim, Joel O and Smith, Davey M", + "title": "Dynamics of viral evolution and neutralizing antibody response after HIV-1 superinfection", + "journal": "J Virol", + "doi": "", + "abstract": "Investigating the incidence and prevalence of HIV-1 superinfection is challenging due to the complex dynamics of two infecting strains. The superinfecting strain can replace the initial strain, be transiently expressed, or persist along with the initial strain in distinct or in recombined forms. Various selective pressures influence these alternative scenarios in different HIV-1 coding regions. We hypothesized that the potency of the neutralizing antibody (NAb) response to autologous viruses would modulate viral dynamics in env following superinfection in a limited set of superinfection cases. HIV-1 env pyrosequencing data were generated from blood plasma collected from 7 individuals with evidence of superinfection. Viral variants within each patient were screened for recombination, and viral dynamics were evaluated using nucleotide diversity. NAb responses to autologous viruses were evaluated before and after superinfection. In 4 individuals, the superinfecting strain replaced the original strain. In 2 individuals, both initial and superinfecting strains continued to cocirculate. In the final individual, the surviving lineage was the product of interstrain recombination. NAb responses to autologous viruses that were detected within the first 2 years of HIV-1 infection were weak or absent for 6 of the 7 recently infected individuals at the time of and shortly following superinfection. These 6 individuals had detectable on-going viral replication of distinct superinfecting virus in the env coding region. In the remaining case, there was an early and strong autologous NAb response, which was associated with extensive recombination in env between initial and superinfecting strains. This extensive recombination made superinfection more difficult to identify and may explain why the detection of superinfection has typically been associated with low autologous NAb titers.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Hightower:2013zh", + "year": 2013, + "authors": "Hightower, George K and May, Susanne J and Perez-Santiago, Josue and Pacold, Mary E and Wagner, Gabriel A and Little, Susan J and Richman, Douglas D and Mehta, Sanjay R and Smith, Davey M and Pond, Sergei L Kosakovsky", + "title": "HIV-1 clade B pol evolution following primary infection", + "journal": "PLoS One", + "doi": "", + "abstract": "OBJECTIVE: Characterize intra-individual HIV-1 subtype B pol evolution in antiretroviral naive individuals.\nDESIGN: Longitudinal cohort study of individuals enrolled during primary infection.\nMETHODS: Eligible individuals were antiretroviral na{\\\"\\i}ve participants enrolled in the cohort from December 1997-December 2005 and having at least two blood samples available with the first one collected within a year of their estimated date of infection. Population-based pol sequences were generated from collected blood samples and analyzed for genetic divergence over time in respect to dual infection status, HLA, CD4 count and viral load.\nRESULTS: 93 participants were observed for a median of 1.8 years (Mean = 2.2 years, SD =1.9 years). All participants classified as mono-infected had less than 0.7% divergence between any two of their pol sequences using the Tamura-Nei model (TN93), while individuals with dual infection had up to 7.0% divergence. The global substitution rates (substitutions/nucleotide/year) for mono and dually infected individuals were significantly different (p<0.001); however, substitution rates were not associated with HLA haplotype, CD4 or viral load.\nCONCLUSIONS: Even after a maximum of almost 9 years of follow-up, all mono-infected participants had less than 1% divergence between baseline and longitudinal sequences, while participants with dual infection had 10 times greater divergence. These data support the use of HIV-1 pol sequence data to evaluate transmission events, networks and HIV-1 dual infection.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Murray:2013bu", + "year": 2013, + "authors": "Murray, Gemma G R and Pond, Sergei L Kosakovsky and Obbard, Darren J", + "title": "Suppressors of RNAi from plant viruses are subject to episodic positive selection", + "journal": "Proc Biol Sci", + "doi": "", + "abstract": "Viral suppressors of RNAi (VSRs) are proteins that actively inhibit the antiviral RNA interference (RNAi) immune response, providing an immune evasion route for viruses. It has been hypothesized that VSRs are engaged in a molecular 'arms race' with RNAi pathway genes. Two lines of evidence support this. First, VSRs from plant viruses display high sequence diversity, and are frequently gained and lost over evolutionary time scales. Second, Drosophila antiviral RNAi genes show high rates of adaptive evolution. Here, we investigate whether VSRs diversify faster than other genes and, if so, whether this is a result of positive selection, as might be expected in an arms race. By analysis of 12 plant RNA viruses, we show that the relative rate of protein evolution is higher for VSRs than for other genes, but that this is not attributable to pervasive positive selection. We argue that, because evolutionary time scales are extremely different for viruses and eukaryotes, it is improbable that viral adaptation (as measured by the ratio of non-synonymous to synonymous change) will be dominated by one-to-one coevolution with eukaryotes. Instead, for plant virus VSRs, we find strong evidence of episodic selection--diversifying selection that acts on a subset of lineages--which might be attributable to frequent shifts between different host genotypes or species.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wagner:2013xh", + "year": 2013, + "authors": "Wagner, Gabriel A and Pacold, Mary E and Vigil, Edgar and Caballero, Gemma and Morris, Sheldon R and Pond, Sergei L Kosakovsky and Little, Susan J and Richman, Douglas D and Gianella, Sara and Smith, Davey M", + "title": "Using ultradeep pyrosequencing to study HIV-1 coreceptor usage in primary and dual infection", + "journal": "J Infect Dis", + "doi": "", + "abstract": "HIV-1 dual infection (DI) and CXCR4 (X4) coreceptor usage are associated with accelerated disease progression but frequency and dynamics of coreceptor usage during DI is unknown. Ultradeep sequencing was used to interrogate for DI and infer coreceptor usage in longitudinal blood samples of 102 subjects. At baseline, X4 usage was high (23 subjects harbored X4 variants) and was not associated with infection duration or DI. Coreceptor usage changed over time in 12 of 47 participants, and X4 usage emerged in 4 of 41 monoinfections vs 2 of 5 superinfections (P = .12), suggesting a weak statistical trend toward occurrence of superinfection and acquiring X4 usage.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wertheim:2013wa", + "year": 2013, + "authors": "Wertheim, Joel O and Chu, Daniel K W and Peiris, Joseph S M and Pond, Sergei L Kosakovsky and Poon, Leo L M", + "title": "A case for the ancient origin of coronaviruses", + "journal": "J Virol", + "doi": "", + "abstract": "Coronaviruses are found in a diverse array of bat and bird species, which are believed to act as natural hosts. Molecular clock dating analyses of coronaviruses suggest that the most recent common ancestor of these viruses existed around 10,000 years ago. This relatively young age is in sharp contrast to the ancient evolutionary history of their putative natural hosts, which began diversifying tens of millions of years ago. Here, we attempted to resolve this discrepancy by applying more realistic evolutionary models that have previously revealed the ancient evolutionary history of other RNA viruses. By explicitly modeling variation in the strength of natural selection over time and thereby improving the modeling of substitution saturation, we found that the time to the most recent ancestor common for all coronaviruses is likely far greater (millions of years) than the previously inferred range.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Hoffenberg:2013dl", + "year": 2013, + "authors": "Hoffenberg, Simon and Powell, Rebecca and Carpov, Alexei and Wagner, Denise and Wilson, Aaron and Pond, Sergei L Kosakovsky and Lindsay, Ross and Arendt, Heather and Destefano, Joanne and Phogat, Sanjay and Poignard, Pascal and Fling, Steven P and Simek, Melissa and Labranche, Celia and Montefiori, David and Wrin, Terri and Phung, Pham and Burton, Dennis and Koff, Wayne and King, C Richter and Parks, Christopher L and Caulfield, Michael J", + "title": "Identification of an HIV-1 clade A envelope that exhibits broad antigenicity and neutralization sensitivity and elicits antibodies targeting three distinct epitopes", + "journal": "J Virol", + "doi": "", + "abstract": "Broadly neutralizing antibodies (bNAbs) PG9 and PG16 were isolated from an International AIDS Vaccine Initiative (IAVI) Protocol G subject infected with human immunodeficiency virus type 1 (HIV-1) clade A. Both antibodies are highly potent and neutralize greater than 70% of viruses tested. We sought to begin immunogen design based on viral sequences from this patient; however, pseudoviruses prepared with 19 envelope sequences from this subject were resistant to neutralization by PG9 and PG16. Therefore, we used a bioinformatics approach to identify closely related viruses that were potentially sensitive to PG9 and PG16. A most-recent common ancestor (MRCA) sequence for the viral envelope (Env) was determined and aligned with 99 subtype A gp160 sequences from the Los Alamos HIV database. Virus BG505.W6M.ENV.C2 (BG505) was found to have the highest degree of homology (73%) to the MRCA sequence. Pseudoviruses prepared with this Env were sensitive to neutralization with a broad panel of bNAbs, including PG9 and PG16. When expressed by 293T cells as soluble gp120, the BG505 monomer bound well to both PG9 and PG16. We further showed that a point mutation (L111A) enabled more efficient production of a stable gp120 monomer that preserves the major neutralization epitopes. Finally, we showed that an adjuvanted formulation of this gp120 protein elicited neutralizing antibodies in rabbits (following a gp120 DNA vaccine prime) and that the antisera competed with bNAbs from 3 classes of nonoverlapping epitopes. Thus, the BG505 Env protein warrants further investigation as an HIV vaccine candidate, as a stand-alone protein, or as a component of a vaccine vector.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Murrell:2013pt", + "year": 2013, + "authors": "Murrell, Ben and Moola, Sasha and Mabona, Amandla and Weighill, Thomas and Sheward, Daniel and Pond, Sergei L Kosakovsky and Scheffler, Konrad", + "title": "FUBAR: a fast, unconstrained bayesian approximation for inferring selection", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Model-based analyses of natural selection often categorize sites into a relatively small number of site classes. Forcing each site to belong to one of these classes places unrealistic constraints on the distribution of selection parameters, which can result in misleading inference due to model misspecification. We present an approximate hierarchical Bayesian method using a Markov chain Monte Carlo (MCMC) routine that ensures robustness against model misspecification by averaging over a large number of predefined site classes. This leaves the distribution of selection parameters essentially unconstrained, and also allows sites experiencing positive and purifying selection to be identified orders of magnitude faster than by existing methods. We demonstrate that popular random effects likelihood methods can produce misleading results when sites assigned to the same site class experience different levels of positive or purifying selection--an unavoidable scenario when using a small number of site classes. Our Fast Unconstrained Bayesian AppRoximation (FUBAR) is unaffected by this problem, while achieving higher power than existing unconstrained (fixed effects likelihood) methods. The speed advantage of FUBAR allows us to analyze larger data sets than other methods: We illustrate this on a large influenza hemagglutinin data set (3,142 sequences). FUBAR is available as a batch file within the latest HyPhy distribution (http://www.hyphy.org), as well as on the Datamonkey web server (http://www.datamonkey.org/).", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wertheim:2013oy", + "year": 2013, + "authors": "Wertheim, Joel O and Scheffler, Konrad and Choi, Jun Yong and Smith, Davey M and Pond, Sergei L Kosakovsky", + "title": "Phylogenetic relatedness of HIV-1 donor and recipient populations", + "journal": "J Infect Dis", + "doi": "", + "abstract": "", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Lemey:2012ez", + "year": 2012, + "authors": "Lemey, Philippe and Minin, Vladimir N and Bielejec, Filip and Pond, Sergei L Kosakovsky and Suchard, Marc A", + "title": "A counting renaissance: combining stochastic mapping and empirical Bayes to quickly detect amino acid sites under positive selection", + "journal": "Bioinformatics", + "doi": "", + "abstract": "MOTIVATION: Statistical methods for comparing relative rates of synonymous and non-synonymous substitutions maintain a central role in detecting positive selection. To identify selection, researchers often estimate the ratio of these relative rates (dN/dS) at individual alignment sites. Fitting a codon substitution model that captures heterogeneity in dN/dS across sites provides a reliable way to perform such estimation, but it remains computationally prohibitive for massive datasets. By using crude estimates of the numbers of synonymous and non-synonymous substitutions at each site, counting approaches scale well to large datasets, but they fail to account for ancestral state reconstruction uncertainty and to provide site-specific dN/dS estimates.\nRESULTS: We propose a hybrid solution that borrows the computational strength of counting methods, but augments these methods with empirical Bayes modeling to produce a relatively fast and reliable method capable of estimating site-specific dN/dS values in large datasets. Importantly, our hybrid approach, set in a Bayesian framework, integrates over the posterior distribution of phylogenies and ancestral reconstructions to quantify uncertainty about site-specific dN/dS estimates. Simulations demonstrate that this method competes well with more-principled statistical procedures and, in some cases, even outperforms them. We illustrate the utility of our method using human immunodeficiency virus, feline panleukopenia and canine parvovirus evolution examples.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Gianella:2012iw", + "year": 2012, + "authors": "Gianella, Sara and Mehta, Sanjay R and Young, Jason A and Vargas, Milenka V and Little, Susan J and Richman, Douglas D and Pond, Sergei L Kosakovsky and Smith, Davey M", + "title": "Sexual transmission of predicted CXCR4-tropic HIV-1 likely originating from the source partner's seminal cells", + "journal": "Virology", + "doi": "", + "abstract": "We present a case of sexual transmission of HIV-1 predicted to have CXCR4-tropism during male-to-male sexual exposure. Phylogenetic analyses exclude cell-free virus in the seminal plasma of the source partner and possibly point to the seminal cells as the origin of the transmission event.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Hightower:2012km", + "year": 2012, + "authors": "Hightower, George K and Wong, Joseph K and Letendre, Scott L and Umlauf, Anya A and Ellis, Ronald J and Ignacio, Caroline C and Heaton, Robert K and Collier, Ann C and Marra, Christina M and Clifford, David B and Gelman, Benjamin B and McArthur, Justin C and Morgello, Susan and Simpson, David M and McCutchan, J A and Grant, Igor and Little, Susan J and Richman, Douglas D and Pond, Sergei L Kosakovsky and Smith, Davey M and {CHARTER Study Group}", + "title": "Higher HIV-1 genetic diversity is associated with AIDS and neuropsychological impairment", + "journal": "Virology", + "doi": "", + "abstract": "Standard methods used to estimate HIV-1 population diversity are often resource intensive (e.g., single genome amplification, clonal amplification and pyrosequencing) and not well suited for large study cohorts. Additional approaches are needed to address the relationships between intraindividual HIV-1 genetic diversity and 2 disease. With a small cohort of individuals, we validated three methods for measuring diversity: Shannon entropy and average pairwise distance (APD) using single genome sequences, and counts of mixed bases (i.e. ambiguous nucleotides) from population based sequences. In a large cohort, we then used the mixed base approach to determine associations between measure HIV-1 diversity and HIV associated disease. Normalized counts of mixed bases correlated with Shannon Entropy at both the nucleotide (rho=0.72, p=0.002) and amino acid level (rho=0.59, p=0.015), and APD (rho=0.75, p=0.001). Among participants who underwent neuropsychological and clinical assessments (n=187), increased HIV-1 population diversity was associated with both a diagnosis of AIDS and neuropsychological impairment.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Gianella:2012gs", + "year": 2012, + "authors": "Gianella, Sara and Mehta, Sanjay R and Strain, Matthew C and Young, Jason A and Vargas, Milenka V and Little, Susan J and Richman, Douglas D and Pond, Sergei L Kosakovsky and Smith, Davey M", + "title": "Impact of seminal cytomegalovirus replication on HIV-1 dynamics between blood and semen", + "journal": "J Med Virol", + "doi": "", + "abstract": "The genital tract of individuals infected with human immunodeficiency virus type 1 (HIV-1) is an anatomic compartment that supports local HIV-1 and cytomegalovirus (CMV) replication. This study investigated the association of seminal CMV replication with changes in HIV-1 clonal expansion, evolution and phylogenetic compartmentalization between blood and semen. Fourteen paired blood and semen samples were analyzed from four untreated subjects. Clonal sequences (n\u2009=\u2009607) were generated from extracted HIV-1 RNA (env C2-V3 region), and HIV-1 and CMV levels were measured in the seminal plasma by real-time PCR. Sequence alignments were evaluated for: (i) viral compartmentalization between semen and blood samples using Slatkin-Maddison and F(ST) methods, (ii) different nucleotide substitution rates in semen and blood, and (iii) association between proportions of clonal HIV-1 sequences in each compartment and seminal CMV levels. Half of the semen samples had detectable CMV DNA, with at least one CMV positive sample for each patient. Seminal CMV DNA levels correlated positively with seminal HIV-1 RNA levels (Spearman P\u2009=\u20090.05). A trend towards an association between compartmentalization of HIV-1 sequences sampled from blood and semen and presence of seminal CMV was observed (Cochran Q test P\u2009=\u20090.12). Evolutionary rates between semen and blood HIV-1 populations did not differ significantly, and there was no significant association between seminal CMV DNA levels and the frequency of non-unique clonal HIV-1 sequences in the semen. In conclusion, the effects of CMV replication on HIV-1 viral and immunologic dynamics within the male genital tract are not significant enough to perturb evolution or disrupt compartmentalization in the genital tract.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Murrell:2012ov", + "year": 2012, + "authors": "Murrell, Ben and Wertheim, Joel O and Moola, Sasha and Weighill, Thomas and Scheffler, Konrad and Pond, Sergei L Kosakovsky", + "title": "Detecting individual sites subject to episodic diversifying selection", + "journal": "PLoS Genet", + "doi": "", + "abstract": "The imprint of natural selection on protein coding genes is often difficult to identify because selection is frequently transient or episodic, i.e. it affects only a subset of lineages. Existing computational techniques, which are designed to identify sites subject to pervasive selection, may fail to recognize sites where selection is episodic: a large proportion of positively selected sites. We present a mixed effects model of evolution (MEME) that is capable of identifying instances of both episodic and pervasive positive selection at the level of an individual site. Using empirical and simulated data, we demonstrate the superior performance of MEME over older models under a broad range of scenarios. We find that episodic selection is widespread and conclude that the number of sites experiencing positive selection may have been vastly underestimated.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": true, + "stats": "Landmark Method" + }, + { + "id": "Aldous:2012qz", + "year": 2012, + "authors": "Aldous, Jeannette L and Pond, Sergei L Kosakovsky and Poon, Art and Jain, Sonia and Qin, Huifang and Kahn, James S and Kitahata, Mari and Rodriguez, Benigno and Dennis, Ann M and Boswell, Stephen L and Haubrich, Richard and Smith, Davey M", + "title": "Characterizing HIV transmission networks across the United States", + "journal": "Clin Infect Dis", + "doi": "", + "abstract": "BACKGROUND: Clinically, human immunodeficiency virus type 1 (HIV-1) pol sequences are used to evaluate for drug resistance. These data can also be used to evaluate transmission networks and help describe factors associated with transmission risk.\nMETHODS: HIV-1 pol sequences from participants at 5 sites in the CFAR Network of Integrated Clinical Systems (CNICS) cohort from 2000-2009 were analyzed for genetic relatedness. Only the first available sequence per participant was included. Inferred transmission networks (\"clusters\") were defined as \u22652 sequences with \u22641.5% genetic distance. Clusters including \u22653 patients (\"networks\") were evaluated for clinical and demographic associations.\nRESULTS: Of 3697 sequences, 24% fell into inferred clusters: 155 clusters of 2 individuals (\"dyads\"), 54 clusters that included 3-14 individuals (\"networks\"), and 1 large cluster that included 336 individuals across all study sites. In multivariable analyses, factors associated with being in a cluster included not using antiretroviral (ARV) drugs at time of sampling (P < .001), sequence collected after 2004 (P < .001), CD4 cell count >350 cells/mL (P < .01), and viral load 10,000-100,000 copies/mL (P < .001) or >100,000 copies/mL (P < .001). In networks, women were more likely to cluster with other women (P < .001), and African Americans with other African Americans (P < .001).\nCONCLUSIONS: Molecular epidemiology can be applied to study HIV transmission networks in geographically and demographically diverse cohorts. Clustering was associated with lack of ARV use and higher viral load, implying transmission may be interrupted by earlier diagnosis and treatment. Observed female and African American networks reinforce the importance of diagnosis and prevention efforts targeted by sex and race.", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Gronwall:2012gd", + "year": 2012, + "authors": "Gronwall, Caroline and Pond, Sergei L Kosakovsky and Young, Jason A and Silverman, Gregg J", + "title": "In vivo VL-targeted microbial superantigen induced global shifts in the B cell repertoire", + "journal": "J Immunol", + "doi": "", + "abstract": "To subvert host defenses, some microbial pathogens produce proteins that interact with conserved motifs in V regions of B cell Ag receptor shared by large sets of lymphocytes, which define the properties of a superantigen. Because the clonal composition of the lymphocyte pool is a major determinant of immune responsiveness, this study was undertaken to examine the in vivo effect on the host immune system of exposure to a B cell superantigen, protein L (PpL), a product of the common commensal bacterial species, Finegoldia magna, which is one of the most common pathogenic species among Gram-positive anaerobic cocci. Libraries of V\u03ba L chain transcripts were generated from the spleens of control and PpL-exposed mice, and the expressed V\u03ba rearrangements were characterized by high-throughput sequencing. A total of 120,855 sequencing reads could be assigned to a germline V\u03ba gene, with all 20 known V\u03ba subgroups represented. In control mice, we found a recurrent and consistent hierarchy of V\u03ba gene usage, as well as patterns of preferential V\u03ba-J\u03ba pairing. PpL exposure induced significant targeted global shifts in repertoire with reduction of V\u03ba that contain the superantigen binding motif in all exposed mice. We found significant targeted reductions in the expression of clonotypes encoded by 14 specific V\u03ba genes with the predicted PpL binding motif. These rigorous surveys document the capacity of a microbial protein to modulate the composition of the expressed lymphocyte repertoire, which also has broad potential implications for host-microbiome and host-pathogen relationships.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Murrell:2012ix", + "year": 2012, + "authors": "Murrell, Ben and de Oliveira, Tulio and Seebregts, Chris and Pond, Sergei L Kosakovsky and Scheffler, Konrad and {Southern African Treatment and Resistance Network-SATuRN Consortium}", + "title": "Modeling HIV-1 drug resistance as episodic directional selection", + "journal": "PLoS Comput Biol", + "doi": "", + "abstract": "The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS) which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Fisher:2012rp", + "year": 2012, + "authors": "Fisher, Randall and van Zyl, Gert U and Travers, Simon A A and Pond, Sergei L Kosakovsky and Engelbrech, Susan and Murrell, Ben and Scheffler, Konrad and Smith, Davey", + "title": "Deep sequencing reveals minor protease resistance mutations in patients failing a protease inhibitor regimen", + "journal": "J Virol", + "doi": "", + "abstract": "Standard genotypic antiretroviral resistance testing, performed by bulk sequencing, does not readily detect variants that comprise <20% of the circulating HIV-1 RNA population. Nevertheless, it is valuable in selecting an antiretroviral regimen after antiretroviral failure. In patients with poor adherence, resistant variants may not reach this threshold. Therefore, deep sequencing would be potentially valuable for detecting minority resistant variants. We compared bulk sequencing and deep sequencing to detect HIV-1 drug resistance at the time of a second-line protease inhibitor (PI)-based antiretroviral regimen failure. Eligibility criteria were virologic failure (HIV-1 RNA load of >500 copies/ml) of a first-line nonnucleoside reverse transcriptase inhibitor-based regimen, with at least the M184V mutation (lamivudine resistance), and second-line failure of a lopinavir/ritonavir (LPV/r)-based regimen. An amplicon-sequencing approach on the Roche 454 system was used. Six patients with viral loads of >90,000 copies/ml and one patient with a viral load of 520 copies/ml were included. Mutations not detectable by bulk sequencing during first- and second-line failure were detected by deep sequencing during second-line failure. Low-frequency variants (>0.5% of the sequence population) harboring major protease inhibitor resistance mutations were found in 5 of 7 patients despite poor adherence to the LPV/r-based regimen. In patients with intermittent adherence to a boosted PI regimen, deep sequencing may detect minority PI-resistant variants, which likely represent early events in resistance selection. In patients with poor or intermittent adherence, there may be low evolutionary impetus for such variants to reach fixation, explaining the low prevalence of PI resistance.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Mehta:2012dd", + "year": 2012, + "authors": "Mehta, Sanjay R and Pond, Sergei L Kosakovsky and Young, Jason A and Richman, Douglas and Little, Susan and Smith, Davey M", + "title": "Associations between phylogenetic clustering and HLA profile among HIV-infected individuals in San Diego, California", + "journal": "J Infect Dis", + "doi": "", + "abstract": "BACKGROUND: Specific sequence changes of human immunodeficiency virus type 1 (HIV-1) in the presence of specific HLA molecules may alter the composition and processing of viral peptides, leading to immune escape. Persistence of these mutations after transmission may leave the genetic fingerprint of the transmitter's HLA profile. Here, we evaluated the associations between HLA profiles and the phylogenetic relationships of HIV sequences sampled from a cohort of recently infected individuals in San Diego, California.\nMETHODS: We identified transmission clusters within the study cohort, using phylogenetic analysis of sampled HIV pol genotypes at a genetic distance of <1.5%. We then evaluated the association of specific HLA alleles, HLA homozygosity, HLA concordance, race and ethnicity, and mutational patterns within the clustering and nonclustering groups.\nRESULTS: From 350 cohort participants, we identified 162 clustering individuals and 188 nonclustering individuals. We identified trends for enrichment of particular alleles within individual clusters and evidence of viral escape within those clusters. We also found that discordance of HLA alleles was significantly associated with clustering individuals.\nCONCLUSIONS: Some transmission clusters demonstrate HLA enrichment, and viruses in these HLA-associated clusters often show evidence of escape to enriched alleles. Interestingly, HLA discordance was associated with clustering in our predominantly MSM population.", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Pond:2012zp", + "year": 2012, + "authors": "Pond, Sergei L Kosakovsky and Murrell, Ben and Poon, Art F Y", + "title": "Evolution of viral genomes: interplay between selection, recombination, and other forces", + "journal": "Methods Mol Biol", + "doi": "", + "abstract": "RNA viruses evolve very rapidly, often recombine, and are subject to strong host (immune response) and anthropogenic (antiretroviral drugs) selective forces. Given their compact and extensively sequenced genomes, comparative analysis of RNA viral data can provide important insights into the molecular mechanisms of adaptation, pathogenicity, immune evasion, and drug resistance. In this chapter, we present an example-based overview of recent advances in evolutionary models and statistical approaches that enable screening viral alignments for evidence of adaptive change in the presence of recombination, detecting bursts of directional adaptive evolution associated with the phenotypic changes, and detecting of coevolving sites in viral genes.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wertheim:2011lc", + "year": 2011, + "authors": "Wertheim, Joel O and Pond, Sergei L Kosakovsky and Little, Susan J and De Gruttola, Victor", + "title": "Using HIV transmission networks to investigate community effects in HIV prevention trials", + "journal": "PLoS One", + "doi": "", + "abstract": "Effective population screening of HIV and prevention of HIV transmission are only part of the global fight against AIDS. Community-level effects, for example those aimed at thwarting future transmission, are potential outcomes of treatment and may be important in stemming the epidemic. However, current clinical trial designs are incapable of detecting a reduction in future transmission due to treatment. We took advantage of the fact that HIV is an evolving pathogen whose transmission network can be reconstructed using genetic sequence information to address this shortcoming. Here, we use an HIV transmission network inferred from recently infected men who have sex with men (MSM) in San Diego, California. We developed and tested a network-based statistic for measuring treatment effects using simulated clinical trials on our inferred transmission network. We explored the statistical power of this network-based statistic against conventional efficacy measures and find that when future transmission is reduced, the potential for increased statistical power can be realized. Furthermore, our simulations demonstrate that the network statistic is able to detect community-level effects (e.g., reduction in onward transmission) of HIV treatment in a clinical trial setting. This study demonstrates the potential utility of a network-based statistical metric when investigating HIV treatment options as a method to reduce onward transmission in a clinical trial setting.", + "category": "SURVEILLANCE", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Farrer:2011rw", + "year": 2011, + "authors": "Farrer, Rhys A and Weinert, Lucy A and Bielby, Jon and Garner, Trenton W J and Balloux, Francois and Clare, Frances and Bosch, Jaime and Cunningham, Andrew A and Weldon, Che and du Preez, Louis H and Anderson, Lucy and Pond, Sergei L Kosakovsky and Shahar-Golan, Revital and Henk, Daniel A and Fisher, Matthew C", + "title": "Multiple emergences of genetically diverse amphibian-infecting chytrids include a globalized hypervirulent recombinant lineage", + "journal": "Proc Natl Acad Sci U S A", + "doi": "", + "abstract": "Batrachochytrium dendrobatidis (Bd) is a globally ubiquitous fungal infection that has emerged to become a primary driver of amphibian biodiversity loss. Despite widespread effort to understand the emergence of this panzootic, the origins of the infection, its patterns of global spread, and principle mode of evolution remain largely unknown. Using comparative population genomics, we discovered three deeply diverged lineages of Bd associated with amphibians. Two of these lineages were found in multiple continents and are associated with known introductions by the amphibian trade. We found that isolates belonging to one clade, the global panzootic lineage (BdGPL) have emerged across at least five continents during the 20th century and are associated with the onset of epizootics in North America, Central America, the Caribbean, Australia, and Europe. The two newly identified divergent lineages, Cape lineage (BdCAPE) and Swiss lineage (BdCH), were found to differ in morphological traits when compared against one another and BdGPL, and we show that BdGPL is hypervirulent. BdGPL uniquely bears the hallmarks of genomic recombination, manifested as extensive intergenomic phylogenetic conflict and patchily distributed heterozygosity. We postulate that contact between previously genetically isolated allopatric populations of Bd may have allowed recombination to occur, resulting in the generation, spread, and invasion of the hypervirulent BdGPL leading to contemporary disease-driven losses in amphibian biodiversity.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wertheim:2012nq", + "year": 2012, + "authors": "Wertheim, Joel O and Fourment, Mathieu and Pond, Sergei L Kosakovsky", + "title": "Inconsistencies in estimating the age of HIV-1 subtypes due to heterotachy", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Rate heterogeneity among lineages is a common feature of molecular evolution, and it has long impeded our ability to accurately estimate the age of evolutionary divergence events. The development of relaxed molecular clocks, which model variable substitution rates among lineages, was intended to rectify this problem. Major subtypes of pandemic HIV-1 group M are thought to exemplify closely related lineages with different substitution rates. Here, we report that inferring the time of most recent common ancestor of all these subtypes in a single phylogeny under a single (relaxed) molecular clock produces significantly different dates for many of the subtypes than does analysis of each subtype on its own. We explore various methods to ameliorate this problem. We conclude that current molecular dating methods are inadequate for dealing with this type of substitution rate variation in HIV-1. Through simulation, we show that heterotachy causes root ages to be overestimated.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Pacold:2012wq", + "year": 2012, + "authors": "Pacold, Mary E and Pond, Sergei L Kosakovsky and Wagner, Gabriel A and Delport, Wayne and Bourque, Daniel L and Richman, Douglas D and Little, Susan J and Smith, Davey M", + "title": "Clinical, virologic, and immunologic correlates of HIV-1 intraclade B dual infection among men who have sex with men", + "journal": "AIDS", + "doi": "", + "abstract": "OBJECTIVE: To investigate the susceptibilities to and consequences of HIV-1 dual infection.\nDESIGN: We compared clinical, virologic, and immunologic factors between participants who were dually infected with HIV-1 subtype B and monoinfected controls who were matched by ongoing HIV risk factor.\nMETHODS: The viral load and CD4 progressions of dually and singly infected participant groups were compared with linear mixed-effects models, and individual dynamics before and after superinfection were assessed with a structural change test (Chow test). Recombination breakpoint analysis (GARD), HLA frequency analysis, and cytotoxic T-lymphocyte (CTL) epitope mapping were also performed (HIV LANL Database).\nRESULTS: The viral loads of dually infected participants increased more over 3 years of follow-up than the viral loads of monoinfected controls, whereas CD4 progressions of the two groups did not differ. Viral escape from CTL responses following superinfection was observed in two participants whose superinfecting strain completely replaced the initial strain. This pattern was not seen among participants whose superinfecting virus persisted in a recombinant form with the initial virus or was only detected transiently. Several HLA types were over-represented in dually infected participants as compared to monoinfected controls.\nCONCLUSIONS: These results identify potential factors for dual infection susceptibility and further define its clinical consequences.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kumar:2012ec", + "year": 2012, + "authors": "Kumar, Sudhir and Filipski, Alan J and Battistuzzi, Fabia U and Pond, Sergei L Kosakovsky and Tamura, Koichiro", + "title": "Statistics and truth in phylogenomics", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Phylogenomics refers to the inference of historical relationships among species using genome-scale sequence data and to the use of phylogenetic analysis to infer protein function in multigene families. With rapidly decreasing sequencing costs, phylogenomics is becoming synonymous with evolutionary analysis of genome-scale and taxonomically densely sampled data sets. In phylogenetic inference applications, this translates into very large data sets that yield evolutionary and functional inferences with extremely small variances and high statistical confidence (P value). However, reports of highly significant P values are increasing even for contrasting phylogenetic hypotheses depending on the evolutionary model and inference method used, making it difficult to establish true relationships. We argue that the assessment of the robustness of results to biological factors, that may systematically mislead (bias) the outcomes of statistical estimation, will be a key to avoiding incorrect phylogenomic inferences. In fact, there is a need for increased emphasis on the magnitude of differences (effect sizes) in addition to the P values of the statistical test of the null hypothesis. On the other hand, the amount of sequence data available will likely always remain inadequate for some phylogenomic applications, for example, those involving episodic positive selection at individual codon positions and in specific lineages. Again, a focus on effect size and biological relevance, rather than the P value, may be warranted. Here, we present a theoretical overview and discuss practical aspects of the interplay between effect sizes, bias, and P values as it relates to the statistical inference of evolutionary truth in phylogenomics.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Goto:2011yj", + "year": 2011, + "authors": "Goto, Hiroki and Ryder, Oliver A and Fisher, Allison R and Schultz, Bryant and Pond, Sergei L Kosakovsky and Nekrutenko, Anton and Makova, Kateryna D", + "title": "A massively parallel sequencing approach uncovers ancient origins and high genetic variability of endangered Przewalski's horses", + "journal": "Genome Biol Evol", + "doi": "", + "abstract": "The endangered Przewalski's horse is the closest relative of the domestic horse and is the only true wild horse species surviving today. The question of whether Przewalski's horse is the direct progenitor of domestic horse has been hotly debated. Studies of DNA diversity within Przewalski's horses have been sparse but are urgently needed to ensure their successful reintroduction to the wild. In an attempt to resolve the controversy surrounding the phylogenetic position and genetic diversity of Przewalski's horses, we used massively parallel sequencing technology to decipher the complete mitochondrial and partial nuclear genomes for all four surviving maternal lineages of Przewalski's horses. Unlike single-nucleotide polymorphism (SNP) typing usually affected by ascertainment bias, the present method is expected to be largely unbiased. Three mitochondrial haplotypes were discovered-two similar ones, haplotypes I/II, and one substantially divergent from the other two, haplotype III. Haplotypes I/II versus III did not cluster together on a phylogenetic tree, rejecting the monophyly of Przewalski's horse maternal lineages, and were estimated to split 0.117-0.186 Ma, significantly preceding horse domestication. In the phylogeny based on autosomal sequences, Przewalski's horses formed a monophyletic clade, separate from the Thoroughbred domestic horse lineage. Our results suggest that Przewalski's horses have ancient origins and are not the direct progenitors of domestic horses. The analysis of the vast amount of sequence data presented here suggests that Przewalski's and domestic horse lineages diverged at least 0.117 Ma but since then have retained ancestral genetic polymorphism and/or experienced gene flow.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Wertheim:2011yi", + "year": 2011, + "authors": "Wertheim, Joel O and Pond, Sergei L Kosakovsky", + "title": "Purifying selection can obscure the ancient age of viral lineages", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Statistical methods for molecular dating of viral origins have been used extensively to infer the time of most common recent ancestor for many rapidly evolving pathogens. However, there are a number of cases, in which epidemiological, historical, or genomic evidence suggests much older viral origins than those obtained via molecular dating. We demonstrate how pervasive purifying selection can mask the ancient origins of recently sampled pathogens, in part due to the inability of nucleotide-based substitution models to properly account for complex patterns of spatial and temporal variability in selective pressures. We use codon-based substitution models to infer the length of branches in viral phylogenies; these models produce estimates that are often considerably longer than those obtained with traditional nucleotide-based substitution models. Correcting the apparent underestimation of branch lengths suggests substantially older origins for measles, Ebola, and avian influenza viruses. This work helps to reconcile some of the inconsistencies between molecular dating and other types of evidence concerning the age of viral lineages.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kosakovsky-Pond:2011bf", + "year": 2011, + "authors": "Pond, Sergei L Kosakovsky and Murrell, Ben and Fourment, Mathieu and Frost, Simon D W and Delport, Wayne and Scheffler, Konrad", + "title": "A random effects branch-site model for detecting episodic diversifying selection", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Adaptive evolution frequently occurs in episodic bursts, localized to a few sites in a gene, and to a small number of lineages in a phylogenetic tree. A popular class of \"branch-site\" evolutionary models provides a statistical framework to search for evidence of such episodic selection. For computational tractability, current branch-site models unrealistically assume that all branches in the tree can be partitioned a priori into two rigid classes--\"foreground\" branches that are allowed to undergo diversifying selective bursts and \"background\" branches that are negatively selected or neutral. We demonstrate that this assumption leads to unacceptably high rates of false positives or false negatives when the evolutionary process along background branches strongly deviates from modeling assumptions. To address this problem, we extend Felsenstein's pruning algorithm to allow efficient likelihood computations for models in which variation over branches (and not just sites) is described in the random effects likelihood framework. This enables us to model the process at every branch-site combination as a mixture of three Markov substitution models--our model treats the selective class of every branch at a particular site as an unobserved state that is chosen independently of that at any other branch. When benchmarked on a previously published set of simulated sequences, our method consistently matched or outperformed existing branch-site tests in terms of power and error rates. Using three empirical data sets, previously analyzed for episodic selection, we discuss how modeling assumptions can influence inference in practical situations.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Gianella:2011jy", + "year": 2011, + "authors": "Gianella, Sara and Delport, Wayne and Pacold, Mary E and Young, Jason A and Choi, Jun Yong and Little, Susan J and Richman, Douglas D and Pond, Sergei L Kosakovsky and Smith, Davey M", + "title": "Detection of minority resistance during early HIV-1 infection: natural variation and spurious detection rather than transmission and evolution of multiple viral variants", + "journal": "J Virol", + "doi": "", + "abstract": "Reports of a high frequency of the transmission of minority viral populations with drug-resistant mutations (DRM) are inconsistent with evidence that HIV-1 infections usually arise from mono- or oligoclonal transmission. We performed ultradeep sequencing (UDS) of partial HIV-1 gag, pol, and env genes from 32 recently infected individuals. We then evaluated overall and per-site diversity levels, selective pressure, sequence reproducibility, and presence of DRM and accessory mutations (AM). To differentiate biologically meaningful mutations from those caused by methodological errors, we obtained multinomial confidence intervals (CI) for the proportion of DRM at each site and fitted a binomial mixture model to determine background error rates for each sample. We then examined the association between detected minority DRM and the virologic failure of first-line antiretroviral therapy (ART). Similar to other studies, we observed increased detection of DRM at low frequencies (average, 0.56%; 95% CI, 0.43 to 0.69; expected UDS error, 0.21 $\\pm$ 0.08% mutations/site). For 8 duplicate runs, there was variability in the proportions of minority DRM. There was no indication of increased diversity or selection at DRM sites compared to other sites and no association between minority DRM and AM. There was no correlation between detected minority DRM and clinical failure of first-line ART. It is unlikely that minority viral variants harboring DRM are transmitted and maintained in the recipient host. The majority of low-frequency DRM detected using UDS are likely errors inherent to UDS methodology or a consequence of error-prone HIV-1 replication.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Smith:2010km", + "year": 2010, + "authors": "Smith, Davey and Delport, Wayne and Butler, David and Little, Susan and Richman, Douglas and Pond, Sergei L Kosakovsky", + "title": "Response to Comment on \"The Origins of Sexually Transmitted HIV Among Men Who Have Sex with Men\"", + "journal": "Sci Transl Med", + "doi": "", + "abstract": "In this investigation, we evaluated explanations for the unusual degree of genetic diversity in HIV populations within the sampled seminal cell and plasma compartments observed in our previous study. These analyses included clonal sequencing of HIV DNA in peripheral blood mononuclear cells, ultradeep sequencing of HIV RNA in blood plasma, human leukocyte antigen (HLA) haplotyping of previously used samples, and a BLAST screen against both a local and public repository of HIV-1 sequences, and the investigations to determine whether these observations were secondary to contamination or artifact were unsuccessful. As there are very few HIV sequences from seminal cell tissues and transmission pairs described in the literature, future studies that evaluate more transmission pairs with sampling from multiple anatomic compartments and at multiple time points will most likely be required to resolve this controversy.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Mehta:2011jf", + "year": 2011, + "authors": "Mehta, Sanjay R and Wertheim, Joel O and Delport, Wayne and Ene, Luminita and Tardei, Gratiela and Duiculescu, Dan and Pond, Sergei L Kosakovsky and Smith, Davey M", + "title": "Using phylogeography to characterize the origins of the HIV-1 subtype F epidemic in Romania", + "journal": "Infect Genet Evol", + "doi": "", + "abstract": "BACKGROUND: During the late 1980s and early 1990s, an estimated 10,000 Romanian children were infected with HIV-1 subtype F nosocomially through contaminated needles and blood transfusions. However, the geographic source and origins of this epidemic remain unclear.\nMETHODS: Here we used phylogenetic inference and \"relaxed\" molecular clock dating analysis to further characterize the Romanian HIV-1 subtype F epidemic.\nRESULTS: These analyses revealed a major lineage of Romanian HIV sequences consisting nearly entirely of virus sampled from adolescents and children and a distinct cluster that included a much higher ratio of adult sequences. Divergence time estimates inferred the time of most recent common ancestor of subtype F1 sequences to be 1973 (1966-1980) and for all Angolan sequences to 1975 (1968-1980). The most common ancestor of the Romanian sequences was dated to 1978 (1972-1983) with pediatric and adolescent sequences interspersed throughout the lineage. The phylogenetic structure of the entire subtype F epidemic suggests that multiple introductions of subtype F into Romania occurred either from the Angolan epidemic or from more distant ancestors. Since the historical records note that the Romanian pediatric epidemic did not begin until the late 1980s, the inferred time of most recent common ancestor of the Romanian lineage of 1978 suggests that there were multiple introductions of subtype F occurred into the pediatric population from HIV already circulating in Romania.\nCONCLUSIONS: Analysis of the subtype F HIV-1 epidemic in an historical context allows for a deeper appreciation of how the HIV pandemic has been influenced by socio-political events.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Price:2011qw", + "year": 2011, + "authors": "Price, Matt A and Wallis, Carole L and Lakhi, Shabir and Karita, Etienne and Kamali, Anatoli and Anzala, Omu and Sanders, Eduard J and Bekker, Linda-Gail and Twesigye, Rogers and Hunter, Eric and Kaleebu, Pontiano and Kayitenkore, Kayitesi and Allen, Susan and Ruzagira, Eugene and Mwangome, Mary and Mutua, Gaudensia and Amornkul, Pauli N and Stevens, Gwynn and Pond, Sergei L K and Schaefer, Malinda and Papathanasopoulos, Mary A and Stevens, Wendy and Gilmour, Jill and {IAVI Early Infection Cohort Study Group}", + "title": "Transmitted HIV type 1 drug resistance among individuals with recent HIV infection in East and Southern Africa", + "journal": "AIDS Res Hum Retroviruses", + "doi": "", + "abstract": "To characterize WHO-defined transmitted HIV drug resistance mutation (TDRM) data from recently HIV-infected African volunteers, we sequenced HIV (pol) and evaluated for TDRM the earliest available specimens from ARV-naive volunteers diagnosed within 1 year of their estimated date of infection at eight research centers in sub-Saharan Africa. TDRMs were detected in 19/408 (5%) volunteers. The prevalence of TDRMs varied by research center, from 5/26 (19%) in Entebbe, 6/78 (8%) in Kigali, 2/49 (4%) in Kilifi, to 3/106 (3%) in Lusaka. One of five volunteers from Cape Town (20%) had TDRMs. Despite small numbers, our data suggest an increase in DRMs by year of infection in Zambia (p\u2009=\u20090.004). The prevalence observed in Entebbe was high across the entire study. ARV history data from 12 (63%) HIV-infected sexual partners were available; 3 reported ARV use prior to transmission. Among four partners with sequence data available, transmission linkage was confirmed and two had the same TDRMs as the newly infected volunteer (both K103N). As ARV therapy continues to increase in availability throughout Africa, monitoring incident virus strains for the presence of TDRMs should be a priority. Early HIV infection cohorts provide an excellent and important platform to monitor the development of TDRMs to inform treatment guidelines, drug choices, and strategies for secondary prevention of TDRM transmission.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Mehta:2010lt", + "year": 2010, + "authors": "Mehta, Sanjay R and Delport, Wayne and Brouwer, Kimberly C and Espitia, Stephen and Patterson, Thomas and Pond, Sergei L Kosakovsky and Strathdee, Steffanie A and Smith, Davey M", + "title": "The relatedness of HIV epidemics in the United States-Mexico border region", + "journal": "AIDS Res Hum Retroviruses", + "doi": "", + "abstract": "Phylogeography can improve the understanding of local and worldwide HIV epidemics, including the migration of subepidemics across national borders. We analyzed HIV-1 sequences sampled from Mexico and San Diego, California to determine the relatedness of these epidemics. We sampled the HIV epidemics in (1) Mexico by downloading all publicly available HIV-1 pol sequences from antiretroviral-naive individuals in GenBank (n = 100) and generating similar sequences from cohorts of injection drug users and female sex workers in Tijuana, Mexico (n = 27) and (2) in San Diego, California by pol sequencing well-characterized primary (n = 395) and chronic (n = 267) HIV infection cohorts. Estimates of population structure (F(ST)), genetic distance cluster analysis, and a cladistic measure of migration events (Slatkin-Maddison test) were used to assess the relatedness of the epidemics. Both a test of population differentiation (F(ST)\u2009=\u20090.06; p < 0.01) and a cladistic estimate of migration events (84 migrations, p < 0.01) indicated that the Tijuana and San Diego epidemics were not freely mixing. A conservative cluster analysis identified 72 clusters (two or more sequences), with two clusters containing both Mexican and San Diego sequences (permutation p < 0.01). Analysis of this very large dataset of HIV-1 sequences suggested that the HIV-1 epidemics in San Diego, California and Tijuana, Mexico are distinct. Larger epidemiological studies are needed to quantify the magnitude and associations of cross-border mixing.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Pacold:2010vz", + "year": 2010, + "authors": "Pacold, Mary and Smith, Davey and Little, Susan and Cheng, Pok Man and Jordan, Parris and Ignacio, Caroline and Richman, Douglas and Pond, Sergei L Kosakovsky", + "title": "Comparison of methods to detect HIV dual infection", + "journal": "AIDS Res Hum Retroviruses", + "doi": "", + "abstract": "Current methods to detect intraclade HIV dual infection are poorly suited for determining its prevalence in large cohorts. To investigate the potential of ultra-deep sequencing to screen for dual infection, we compared it to bulk sequence-based synonymous mixture index and the current standard of single genome sequencing. The synonymous mixture index identified samples likely to harbor dual infection, while ultra-deep sequencing captured more intra-host viral diversity than single genome sequencing at approximately 40% of the cost and 20% of the laboratory and analysis time. The synonymous mixture index and ultra-deep sequencing are promising methods for rapid and cost-effective systematic identification of HIV dual infection.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Delport:2010kq", + "year": 2010, + "authors": "Delport, Wayne and Scheffler, Konrad and Botha, Gordon and Gravenor, Mike B and Muse, Spencer V and Pond, Sergei L Kosakovsky", + "title": "CodonTest: modeling amino acid substitution preferences in coding sequences", + "journal": "PLoS Comput Biol", + "doi": "", + "abstract": "Codon models of evolution have facilitated the interpretation of selective forces operating on genomes. These models, however, assume a single rate of non-synonymous substitution irrespective of the nature of amino acids being exchanged. Recent developments have shown that models which allow for amino acid pairs to have independent rates of substitution offer improved fit over single rate models. However, these approaches have been limited by the necessity for large alignments in their estimation. An alternative approach is to assume that substitution rates between amino acid pairs can be subdivided into rate classes, dependent on the information content of the alignment. However, given the combinatorially large number of such models, an efficient model search strategy is needed. Here we develop a Genetic Algorithm (GA) method for the estimation of such models. A GA is used to assign amino acid substitution pairs to a series of rate classes, where is estimated from the alignment. Other parameters of the phylogenetic Markov model, including substitution rates, character frequencies and branch lengths are estimated using standard maximum likelihood optimization procedures. We apply the GA to empirical alignments and show improved model fit over existing models of codon evolution. Our results suggest that current models are poor approximations of protein evolution and thus gene and organism specific multi-rate models that incorporate amino acid substitution biases are preferred. We further anticipate that the clustering of amino acid substitution rates into classes will be biologically informative, such that genes with similar functions exhibit similar clustering, and hence this clustering will be useful for the evolutionary fingerprinting of genes.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kosakovsky-Pond:2010tp", + "year": 2010, + "authors": "Pond, Sergei L Kosakovsky and Delport, Wayne and Muse, Spencer V and Scheffler, Konrad", + "title": "Correcting the bias of empirical frequency parameter estimators in codon models", + "journal": "PLoS One", + "doi": "", + "abstract": "Markov models of codon substitution are powerful inferential tools for studying biological processes such as natural selection and preferences in amino acid substitution. The equilibrium character distributions of these models are almost always estimated using nucleotide frequencies observed in a sequence alignment, primarily as a matter of historical convention. In this note, we demonstrate that a popular class of such estimators are biased, and that this bias has an adverse effect on goodness of fit and estimates of substitution rates. We propose a \"corrected\" empirical estimator that begins with observed nucleotide counts, but accounts for the nucleotide composition of stop codons. We show via simulation that the corrected estimates outperform the de facto standard estimates not just by providing better estimates of the frequencies themselves, but also by leading to improved estimation of other parameters in the evolutionary models. On a curated collection of sequence alignments, our estimators show a significant improvement in goodness of fit compared to the approach. Maximum likelihood estimation of the frequency parameters appears to be warranted in many cases, albeit at a greater computational cost. Our results demonstrate that there is little justification, either statistical or computational, for continued use of the -style estimators.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Delport:2010vo", + "year": 2010, + "authors": "Delport, Wayne and Poon, Art F Y and Frost, Simon D W and Pond, Sergei L Kosakovsky", + "title": "Datamonkey 2010: a suite of phylogenetic analysis tools for evolutionary biology", + "journal": "Bioinformatics", + "doi": "", + "abstract": "Datamonkey is a popular web-based suite of phylogenetic analysis tools for use in evolutionary biology. Since the original release in 2005, we have expanded the analysis options to include recently developed algorithmic methods for recombination detection, evolutionary fingerprinting of genes, codon model selection, co-evolution between sites, identification of sites, which rapidly escape host-immune pressure and HIV-1 subtype assignment. The traditional selection tools have also been augmented to include recent developments in the field. Here, we summarize the analyses options currently available on Datamonkey, and provide guidelines for their use in evolutionary biology. Availability and documentation: http://www.datamonkey.org.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Delport:2010lp", + "year": 2010, + "authors": "Delport, Wayne and Scheffler, Konrad and Gravenor, Mike B and Muse, Spencer V and Pond, Sergei L Kosakovsky", + "title": "Benchmarking multi-rate codon models", + "journal": "PLoS One", + "doi": "", + "abstract": "The single rate codon model of non-synonymous substitution is ubiquitous in phylogenetic modeling. Indeed, the use of a non-synonymous to synonymous substitution rate ratio parameter has facilitated the interpretation of selection pressure on genomes. Although the single rate model has achieved wide acceptance, we argue that the assumption of a single rate of non-synonymous substitution is biologically unreasonable, given observed differences in substitution rates evident from empirical amino acid models. Some have attempted to incorporate amino acid substitution biases into models of codon evolution and have shown improved model performance versus the single rate model. Here, we show that the single rate model of non-synonymous substitution is easily outperformed by a model with multiple non-synonymous rate classes, yet in which amino acid substitution pairs are assigned randomly to these classes. We argue that, since the single rate model is so easy to improve upon, new codon models should not be validated entirely on the basis of improved model fit over this model. Rather, we should strive to both improve on the single rate model and to approximate the general time-reversible model of codon substitution, with as few parameters as possible, so as to reduce model over-fitting. We hint at how this can be achieved with a Genetic Algorithm approach in which rate classes are assigned on the basis of sequence information content.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Deng:2010hc", + "year": 2010, + "authors": "Deng, Wenjie and Maust, Brandon S and Nickle, David C and Learn, Gerald H and Liu, Yi and Heath, Laura and Pond, Sergei L Kosakovsky and Mullins, James I", + "title": "DIVEIN: a web server to analyze phylogenies, sequence divergence, diversity, and informative sites", + "journal": "Biotechniques", + "doi": "", + "abstract": "DIVEIN is a web interface that performs automated phylogenetic and other analyses of nucleotide and amino acid sequences. Starting with a set of aligned sequences, DIVEIN estimates evolutionary parameters and phylogenetic trees while allowing the user to choose from a variety of evolutionary models; it then reconstructs the consensus (CON), most recent common ancestor (MRCA), and center of tree (COT) sequences. DIVEIN also provides tools for further analyses, including condensing sequence alignments to show only informative sites or private mutations; computing phylogenetic or pairwise divergence from any user-specified sequence (CON, MRCA, COT, or existing sequence from the alignment); computing and outputting all genetic distances in column format; calculating summary statistics of diversity and divergence from pairwise distances; and graphically representing the inferred tree and plots of divergence, diversity, and distance distribution histograms. DIVEIN is available at http://indra.mullins.microbiol.washington.edu/DIVEIN.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Siebenga:2010kc", + "year": 2010, + "authors": "Siebenga, J Joukje and Lemey, Philippe and Pond, Sergei L Kosakovsky and Rambaut, Andrew and Vennema, Harry and Koopmans, Marion", + "title": "Phylodynamic reconstruction reveals norovirus GII.4 epidemic expansions and their molecular determinants", + "journal": "PLoS Pathog", + "doi": "", + "abstract": "Noroviruses are the most common cause of viral gastroenteritis. An increase in the number of globally reported norovirus outbreaks was seen the past decade, especially for outbreaks caused by successive genogroup II genotype 4 (GII.4) variants. Whether this observed increase was due to an upswing in the number of infections, or to a surveillance artifact caused by heightened awareness and concomitant improved reporting, remained unclear. Therefore, we set out to study the population structure and changes thereof of GII.4 strains detected through systematic outbreak surveillance since the early 1990s. We collected 1383 partial polymerase and 194 full capsid GII.4 sequences. A Bayesian MCMC coalescent analysis revealed an increase in the number of GII.4 infections during the last decade. The GII.4 strains included in our analyses evolved at a rate of 4.3-9.0x10(-3) mutations per site per year, and share a most recent common ancestor in the early 1980s. Determinants of adaptation in the capsid protein were studied using different maximum likelihood approaches to identify sites subject to diversifying or directional selection and sites that co-evolved. While a number of the computationally determined adaptively evolving sites were on the surface of the capsid and possible subject to immune selection, we also detected sites that were subject to constrained or compensatory evolution due to secondary RNA structures, relevant in virus-replication. We highlight codons that may prove useful in identifying emerging novel variants, and, using these, indicate that the novel 2008 variant is more likely to cause a future epidemic than the 2007 variant. While norovirus infections are generally mild and self-limiting, more severe outcomes of infection frequently occur in elderly and immunocompromized people, and no treatment is available. The observed pattern of continually emerging novel variants of GII.4, causing elevated numbers of infections, is therefore a cause for concern.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Butler:2010yu", + "year": 2010, + "authors": "Butler, David M and Delport, Wayne and Pond, Sergei L Kosakovsky and Lakdawala, Malcolm K and Cheng, Pok Man and Little, Susan J and Richman, Douglas D and Smith, Davey M", + "title": "The origins of sexually transmitted HIV among men who have sex with men", + "journal": "Sci Transl Med", + "doi": "", + "abstract": "Although it is known that most HIV-1 infections worldwide result from exposure to virus in semen, it has not yet been established whether transmitted strains originate as RNA virions in seminal plasma or as integrated proviral DNA in infected seminal leukocytes. We present phylogenetic evidence that among six transmitting pairs of men who have sex with men, blood plasma virus in the recipient is consistently more closely related to the seminal plasma virus in the source. All sequences were subtype B, and the env C2V3 of transmitted variants tended to have higher mean isoelectric points, contain potential N-linked glycosylation sites, and favor CCR5 co-receptor usage. A statistically robust phylogenetically corrected analysis did not detect genetic signatures reliably associated with transmission, but further investigation of larger samples of transmitting pairs holds promise for determining which structural and genetic features of viral genomes are associated with transmission.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Manosuthi:2010fd", + "year": 2010, + "authors": "Manosuthi, Weerawat and Butler, David M and Perez-Santiago, Josue and Poon, Art Fy and Pillai, Satish K and Mehta, Sanjay R and Pacold, Mary E and Richman, Douglas D and Pond, Sergei L Kosakovsky and Smith, Davey M", + "title": "Protease polymorphisms in HIV-1 subtype CRF01_AE represent selection by antiretroviral therapy and host immune pressure", + "journal": "AIDS", + "doi": "", + "abstract": "BACKGROUND: Most of our knowledge about how antiretrovirals and host immune responses influence the HIV-1 protease gene is derived from studies of subtype B virus. We investigated the effect of protease resistance-associated mutations (PRAMs) and population-based HLA haplotype frequencies on polymorphisms found in CRF01_AE pro.\nMETHODS: We used all CRF01_AE protease sequences retrieved from the LANL database and obtained regional HLA frequencies from the dbMHC database. Polymorphisms and major PRAMs in the sequences were identified using the Stanford Resistance Database, and we performed phylogenetic and selection analyses using HyPhy. HLA binding affinities were estimated using the Immune Epitope Database and Analysis.\nRESULTS: Overall, 99% of CRF01_AE sequences had at least 1 polymorphism and 10% had at least 1 major PRAM. Three polymorphisms (L10 V, K20RMI and I62 V) were associated with the presence of a major PRAM (P < 0.05). Compared to the subtype B consensus, six additional polymorphisms (I13 V, E35D, M36I, R41K, H69K, L89M) were identified in the CRF01_AE consensus; all but L89M were located within epitopes recognized by HLA class I alleles. Of the predominant HLA haplotypes in the Asian regions of CRF01_AE origin, 80% were positively associated with the observed polymorphisms, and estimated HLA binding affinity was estimated to decrease 19-40 fold with the observed polymorphisms at positions 35, 36 and 41.\nCONCLUSION: Polymorphisms in CRF01_AE protease gene were common, and polymorphisms at residues 10, 20 and 62 most likely represent selection by use of protease inhibitors, whereas R41K and H69K were more likely attributable to recognition of epitopes by the HLA haplotypes of the host population.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kosakovsky-Pond:2009qm", + "year": 2009, + "authors": "Pond, Sergei L Kosakovsky and Posada, David and Stawiski, Eric and Chappey, Colombe and Poon, Art F Y and Hughes, Gareth and Fearnhill, Esther and Gravenor, Mike B and Leigh Brown, Andrew J and Frost, Simon D W", + "title": "An evolutionary model-based algorithm for accurate phylogenetic breakpoint mapping and subtype prediction in HIV-1", + "journal": "PLoS Comput Biol", + "doi": "", + "abstract": "Genetically diverse pathogens (such as Human Immunodeficiency virus type 1, HIV-1) are frequently stratified into phylogenetically or immunologically defined subtypes for classification purposes. Computational identification of such subtypes is helpful in surveillance, epidemiological analysis and detection of novel variants, e.g., circulating recombinant forms in HIV-1. A number of conceptually and technically different techniques have been proposed for determining the subtype of a query sequence, but there is not a universally optimal approach. We present a model-based phylogenetic method for automatically subtyping an HIV-1 (or other viral or bacterial) sequence, mapping the location of breakpoints and assigning parental sequences in recombinant strains as well as computing confidence levels for the inferred quantities. Our Subtype Classification Using Evolutionary ALgorithms (SCUEAL) procedure is shown to perform very well in a variety of simulation scenarios, runs in parallel when multiple sequences are being screened, and matches or exceeds the performance of existing approaches on typical empirical cases. We applied SCUEAL to all available polymerase (pol) sequences from two large databases, the Stanford Drug Resistance database and the UK HIV Drug Resistance Database. Comparing with subtypes which had previously been assigned revealed that a minor but substantial (approximately 5%) fraction of pure subtype sequences may in fact be within- or inter-subtype recombinants. A free implementation of SCUEAL is provided as a module for the HyPhy package and the Datamonkey web server. Our method is especially useful when an accurate automatic classification of an unknown strain is desired, and is positioned to complement and extend faster but less accurate methods. Given the increasingly frequent use of HIV subtype information in studies focusing on the effect of subtype on treatment, clinical outcome, pathogenicity and vaccine design, the importance of accurate, robust and extensible subtyping procedures is clear.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Poon:2010lg", + "year": 2010, + "authors": "Poon, Art F Y and Swenson, Luke C and Dong, Winnie W Y and Deng, Wenjie and Pond, Sergei L Kosakovsky and Brumme, Zabrina L and Mullins, James I and Richman, Douglas D and Harrigan, P Richard and Frost, Simon D W", + "title": "Phylogenetic analysis of population-based and deep sequencing data to identify coevolving sites in the nef gene of HIV-1", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Rapidly evolving viruses such as HIV-1 display extensive sequence variation in response to host-specific selection, while simultaneously maintaining functions that are critical to replication and infectivity. This apparent conflict between diversifying and purifying selection may be resolved by an abundance of epistatic interactions such that the same functional requirements can be met by highly divergent sequences. We investigate this hypothesis by conducting an extensive characterization of sequence variation in the HIV-1 nef gene that encodes a highly variable multifunctional protein. Population-based sequences were obtained from 686 patients enrolled in the HOMER cohort in British Columbia, Canada, from which the distribution of nonsynonymous substitutions in the phylogeny was reconstructed by maximum likelihood. We used a phylogenetic comparative method on these data to identify putative epistatic interactions between residues. Two interactions (Y120/Q125 and N157/S169) were chosen to further investigate within-host evolution using HIV-1 RNA extractions from plasma samples from eight patients. Clonal sequencing confirmed strong linkage between polymorphisms at these sites in every case. We used massively parallel pyrosequencing (MPP) to reconstruct within-host evolution in these patients. Experimental error associated with MPP was quantified by performing replicates at two different stages of the protocol, which were pooled prior to analysis to reduce this source of variation. Phylogenetic reconstruction from these data revealed correlated substitutions at Y120/Q125 or N157/S169 repeated across multiple lineages in every host, indicating convergent within-host evolution shaped by epistatic interactions.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Pond:2010li", + "year": 2010, + "authors": "Pond, Sergei L Kosakovsky and Scheffler, Konrad and Gravenor, Michael B and Poon, Art F Y and Frost, Simon D W", + "title": "Evolutionary fingerprinting of genes", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Over time, natural selection molds every gene into a unique mosaic of sites evolving rapidly or resisting change-an \"evolutionary fingerprint\" of the gene. Aspects of this evolutionary fingerprint, such as the site-specific ratio of nonsynonymous to synonymous substitution rates (dN/dS), are commonly used to identify genetic features of potential biological interest; however, no framework exists for comparing evolutionary fingerprints between genes. We hypothesize that protein-coding genes with similar protein structure and/or function tend to have similar evolutionary fingerprints and that comparing evolutionary fingerprints can be useful for discovering similarities between genes in a way that is analogous to, but independent of, discovery of similarity via sequence-based comparison tools such as Blast. To test this hypothesis, we develop a novel model of coding sequence evolution that uses a general bivariate discrete parameterization of the evolutionary rates. We show that this approach provides a better fit to the data using a smaller number of parameters than existing models. Next, we use the model to represent evolutionary fingerprints as probability distributions and present a methodology for comparing these distributions in a way that is robust against variations in data set size and divergence. Finally, using sequences of three rapidly evolving RNA viruses (HIV-1, hepatitis C virus, and influenza A virus), we demonstrate that genes within the same functional group tend to have similar evolutionary fingerprints. Our framework provides a sound statistical foundation for efficient inference and comparison of evolutionary rate patterns in arbitrary collections of gene alignments, clustering homologous and nonhomologous genes, and investigation of biological and functional correlates of evolutionary rates.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kosakovsky-Pond:2009mk", + "year": 2009, + "authors": "Pond, Sergei L Kosakovsky and Wadhawan, Samir and Chiaromonte, Francesca and Ananda, Guruprasad and Chung, Wen-Yu and Taylor, James and Nekrutenko, Anton and {Galaxy Team}", + "title": "Windshield splatter analysis with the Galaxy metagenomic pipeline", + "journal": "Genome Res", + "doi": "", + "abstract": "How many species inhabit our immediate surroundings? A straightforward collection technique suitable for answering this question is known to anyone who has ever driven a car at highway speeds. The windshield of a moving vehicle is subjected to numerous insect strikes and can be used as a collection device for representative sampling. Unfortunately the analysis of biological material collected in that manner, as with most metagenomic studies, proves to be rather demanding due to the large number of required tools and considerable computational infrastructure. In this study, we use organic matter collected by a moving vehicle to design and test a comprehensive pipeline for phylogenetic profiling of metagenomic samples that includes all steps from processing and quality control of data generated by next-generation sequencing technologies to statistical analyses and data visualization. To the best of our knowledge, this is also the first publication that features a live online supplement providing access to exact analyses and workflows used in the article.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Volz:2009lf", + "year": 2009, + "authors": "Volz, Erik M and Pond, Sergei L Kosakovsky and Ward, Melissa J and Leigh Brown, Andrew J and Frost, Simon D W", + "title": "Phylodynamics of infectious disease epidemics", + "journal": "Genetics", + "doi": "", + "abstract": "We present a formalism for unifying the inference of population size from genetic sequences and mathematical models of infectious disease in populations. Virus phylogenies have been used in many recent studies to infer properties of epidemics. These approaches rely on coalescent models that may not be appropriate for infectious diseases. We account for phylogenetic patterns of viruses in susceptible-infected (SI), susceptible-infected-susceptible (SIS), and susceptible-infected-recovered (SIR) models of infectious disease, and our approach may be a viable alternative to demographic models used to reconstruct epidemic dynamics. The method allows epidemiological parameters, such as the reproductive number, to be estimated directly from viral sequence data. We also describe patterns of phylogenetic clustering that are often construed as arising from a short chain of transmissions. Our model reproduces the moments of the distribution of phylogenetic cluster sizes and may therefore serve as a null hypothesis for cluster sizes under simple epidemiological models. We examine a small cross-sectional sample of human immunodeficiency (HIV)-1 sequences collected in the United States and compare our results to standard estimates of effective population size. Estimated prevalence is consistent with estimates of effective population size and the known history of the HIV epidemic. While our model accurately estimates prevalence during exponential growth, we find that periods of decline are harder to identify.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Poon:2009zk", + "year": 2009, + "authors": "Poon, Art F Y and Brouwer, Kimberly C and Strathdee, Steffanie A and Firestone-Cruz, Michelle and Lozada, Remedios M and Pond, Sergei L Kosakovsky and Heckathorn, Douglas D and Frost, Simon D W", + "title": "Parsing social network survey data from hidden populations using stochastic context-free grammars", + "journal": "PLoS One", + "doi": "", + "abstract": "BACKGROUND: Human populations are structured by social networks, in which individuals tend to form relationships based on shared attributes. Certain attributes that are ambiguous, stigmatized or illegal can create a OhiddenO population, so-called because its members are difficult to identify. Many hidden populations are also at an elevated risk of exposure to infectious diseases. Consequently, public health agencies are presently adopting modern survey techniques that traverse social networks in hidden populations by soliciting individuals to recruit their peers, e.g., respondent-driven sampling (RDS). The concomitant accumulation of network-based epidemiological data, however, is rapidly outpacing the development of computational methods for analysis. Moreover, current analytical models rely on unrealistic assumptions, e.g., that the traversal of social networks can be modeled by a Markov chain rather than a branching process.\nMETHODOLOGY/PRINCIPAL FINDINGS: Here, we develop a new methodology based on stochastic context-free grammars (SCFGs), which are well-suited to modeling tree-like structure of the RDS recruitment process. We apply this methodology to an RDS case study of injection drug users (IDUs) in Tijuana, Mexico, a hidden population at high risk of blood-borne and sexually-transmitted infections (i.e., HIV, hepatitis C virus, syphilis). Survey data were encoded as text strings that were parsed using our custom implementation of the inside-outside algorithm in a publicly-available software package (HyPhy), which uses either expectation maximization or direct optimization methods and permits constraints on model parameters for hypothesis testing. We identified significant latent variability in the recruitment process that violates assumptions of Markov chain-based methods for RDS analysis: firstly, IDUs tended to emulate the recruitment behavior of their own recruiter; and secondly, the recruitment of like peers (homophily) was dependent on the number of recruits.\nCONCLUSIONS: SCFGs provide a rich probabilistic language that can articulate complex latent structure in survey data derived from the traversal of social networks. Such structure that has no representation in Markov chain-based models can interfere with the estimation of the composition of hidden populations if left unaccounted for, raising critical implications for the prevention and control of infectious disease epidemics.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Lycett:2009tg", + "year": 2009, + "authors": "Lycett, S J and Ward, M J and Lewis, F I and Poon, A F Y and Kosakovsky Pond, S L and Brown, A J Leigh", + "title": "Detection of mammalian virulence determinants in highly pathogenic avian influenza H5N1 viruses: multivariate analysis of published data", + "journal": "J Virol", + "doi": "", + "abstract": "Highly pathogenic avian influenza (HPAI) virus H5N1 infects water and land fowl and can infect and cause mortality in mammals, including humans. However, HPAI H5N1 strains are not equally virulent in mammals, and some strains have been shown to cause only mild symptoms in experimental infections. Since most experimental studies of the basis of virulence in mammals have been small in scale, we undertook a meta-analysis of available experimental studies and used Bayesian graphical models (BGM) to increase the power of inference. We applied text-mining techniques to identify 27 individual studies that experimentally determined pathogenicity in HPAI H5N1 strains comprising 69 complete genome sequences. Amino acid sequence data in all 11 genes were coded as binary data for the presence or absence of mutations related to virulence in mammals or nonconsensus residues. Sites previously implicated as virulence determinants were examined for association with virulence in mammals in this data set, and the sites with the most significant association were selected for further BGM analysis. The analyses show that virulence in mammals is a complex genetic trait directly influenced by mutations in polymerase basic 1 (PB1) and PB2, nonstructural 1 (NS1), and hemagglutinin (HA) genes. Several intra- and intersegment correlations were also found, and we postulate that there may be two separate virulence mechanisms involving particular combinations of polymerase and NS1 mutations or of NS1 and HA mutations.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Lu:2009yg", + "year": 2009, + "authors": "Lu, Qing and Zhang, Xing-Quan and Pond, Sergei L Kosakovsky and Reed, Sharon and Schooley, Robert T and Liu, Yu-Tsueng", + "title": "Detection in 2009 of the swine origin influenza A (H1N1) virus by a subtyping microarray", + "journal": "J Clin Microbiol", + "doi": "", + "abstract": "", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Poon:2009dt", + "year": 2009, + "authors": "Poon, Art F Y and Frost, Simon D W and Pond, Sergei L Kosakovsky", + "title": "Detecting signatures of selection from DNA sequences using Datamonkey", + "journal": "Methods Mol Biol", + "doi": "", + "abstract": "Natural selection is a fundamental process affecting all evolving populations. In the simplest case, positive selection increases the frequency of alleles that confer a fitness advantage relative to the rest of the population, or increases its genetic diversity, and negative selection removes those alleles that are deleterious. Codon-based models of molecular evolution are able to infer signatures of selection from alignments of homologous sequences by estimating the relative rates of synonymous (dS) and non-synonymous substitutions (dN). Datamonkey (http://www.datamonkey.org) provides a user-friendly web interface to a wide collection of state-of-the-art statistical techniques for estimating dS and dN and identifying codons and lineages under selection, even in the presence of recombinant sequences.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kosakovsky-Pond:2009tn", + "year": 2009, + "authors": "Pond, Sergei L Kosakovsky and Smith, Davey M", + "title": "Are all subtypes created equal? The effectiveness of antiretroviral therapy against non-subtype B HIV-1", + "journal": "Clin Infect Dis", + "doi": "", + "abstract": "", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Smith:2009hc", + "year": 2009, + "authors": "Smith, Davey M and May, Susanne J and Tweeten, Samantha and Drumright, Lydia and Pacold, Mary E and Pond, Sergei L Kosakovsky and Pesano, Rick L and Lie, Yolanda S and Richman, Douglas D and Frost, Simon D W and Woelk, Christopher H and Little, Susan J", + "title": "A public health model for the molecular surveillance of HIV transmission in San Diego, California", + "journal": "AIDS", + "doi": "", + "abstract": "BACKGROUND: Current public health efforts often use molecular technologies to identify and contain communicable disease networks, but not for HIV. Here, we investigate how molecular epidemiology can be used to identify highly related HIV networks within a population and how voluntary contact tracing of sexual partners can be used to selectively target these networks.\nMETHODS: We evaluated the use of HIV-1 pol sequences obtained from participants of a community-recruited cohort (n = 268) and a primary infection research cohort (n = 369) to define highly related transmission clusters and the use of contact tracing to link other individuals (n = 36) within these clusters. The presence of transmitted drug resistance was interpreted from the pol sequences (Calibrated Population Resistance v3.0).\nRESULTS: Phylogenetic clustering was conservatively defined when the genetic distance between any two pol sequences was less than 1%, which identified 34 distinct transmission clusters within the combined community-recruited and primary infection research cohorts containing 160 individuals. Although sequences from the epidemiologically linked partners represented approximately 5% of the total sequences, they clustered with 60% of the sequences that clustered from the combined cohorts (odds ratio 21.7; P < or = 0.01). Major resistance to at least one class of antiretroviral medication was found in 19% of clustering sequences.\nCONCLUSION: Phylogenetic methods can be used to identify individuals who are within highly related transmission groups, and contact tracing of epidemiologically linked partners of recently infected individuals can be used to link into previously defined transmission groups. These methods could be used to implement selectively targeted prevention interventions.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Cachay:2007vp", + "year": 2007, + "authors": "Cachay, Edward R and Moini, Niousha and Pond, Sergei L Kosakovsky and Pesano, Rick and Lie, Yolanda S and Aiem, Heidi and Butler, David M and Letendre, Scott and Mathews, Wm Christopher and Smith, Davey M", + "title": "Active methamphetamine use is associated with transmitted drug resistance to non-nucleoside reverse transcriptase inhibitors in individuals with HIV infection of unknown duration", + "journal": "Open AIDS J", + "doi": "", + "abstract": "BACKGROUND: Frequent methamphetamine use among recently HIV infected individuals is associated with transmitted drug resistance (TDR) to non-nucleoside reverse transcriptase inhibitors (NNRTI); however, the reversion time of TDR to drug susceptible HIV may exceed 3 years. We assessed whether recreational substance use is associated with detectable TDR among individuals newly diagnosed with HIV infection of unknown duration.\nDESIGN: Cross-sectional analysis.\nMETHODS: Subjects were enrolled at the University California, San Diego Early Intervention Program. Demographic, clinical and substance use data were collected using structured interviews. Genotypic resistance testing was performed using GeneSeq, Monogram Biosciences. We analyzed the association between substance use and TDR using bivariate analyses and the corresponding transmission networks using phylogenetic models.\nRESULTS: Between April 2004 and July 2006, 115 individuals with genotype data were enrolled. The prevalence of alcohol, marijuana and methamphetamine use were 98%, 71% and 64% respectively. Only active methamphetamine use in the 30 days prior to HIV diagnosis was independently associated with TDR to NNRTI (OR: 6.6; p=0.002).\nCONCLUSION: Despite not knowing the duration of their HIV infection, individuals reporting active methamphetamine use in the 30 days prior to HIV diagnosis are at an increased risk of having HIV strains that are resistant to NNRTI.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Lam:2008fd", + "year": 2008, + "authors": "Lam, Tommy Tsan-Yuk and Hon, Chung-Chau and Pybus, Oliver G and Pond, Sergei L Kosakovsky and Wong, Raymond Tze-Yeung and Yip, Chi-Wai and Zeng, Fanya and Leung, Frederick Chi-Ching", + "title": "Evolutionary and transmission dynamics of reassortant H5N1 influenza virus in Indonesia", + "journal": "PLoS Pathog", + "doi": "", + "abstract": "H5N1 highly pathogenic avian influenza (HPAI) viruses have seriously affected the Asian poultry industry since their recurrence in 2003. The viruses pose a threat of emergence of a global pandemic influenza through point mutation or reassortment leading to a strain that can effectively transmit among humans. In this study, we present phylogenetic evidences for the interlineage reassortment among H5N1 HPAI viruses isolated from humans, cats, and birds in Indonesia, and identify the potential genetic parents of the reassorted genome segments. Parsimony analyses of viral phylogeography suggest that the reassortant viruses may have originated from greater Jakarta and surroundings, and subsequently spread to other regions in the West Java province. In addition, Bayesian methods were used to elucidate the genetic diversity dynamics of the reassortant strain and one of its genetic parents, which revealed a more rapid initial growth of genetic diversity in the reassortant viruses relative to their genetic parent. These results demonstrate that interlineage exchange of genetic information may play a pivotal role in determining viral genetic diversity in a focal population. Moreover, our study also revealed significantly stronger diversifying selection on the M1 and PB2 genes in the lineages preceding and subsequent to the emergence of the reassortant viruses, respectively. We discuss how the corresponding mutations might drive the adaptation and onward transmission of the newly formed reassortant viruses.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Poon:2008fb", + "year": 2008, + "authors": "Poon, Art F Y and Lewis, Fraser I and Frost, Simon D W and Pond, Sergei L Kosakovsky", + "title": "Spidermonkey: rapid detection of co-evolving sites using Bayesian graphical models", + "journal": "Bioinformatics", + "doi": "", + "abstract": "UNLABELLED: Spidermonkey is a new component of the Datamonkey suite of phylogenetic tools that provides methods for detecting coevolving sites from a multiple alignment of homologous nucleotide or amino acid sequences. It reconstructs the substitution history of the alignment by maximum likelihood-based phylogenetic methods, and then analyzes the joint distribution of substitution events using Bayesian graphical models to identify significant associations among sites.\nAVAILABILITY: Spidermonkey is publicly available both as a web application at http://www.data-monkey.org and as a stand-alone component of the phylogenetic software package HyPhy, which is freely distributed on the web (http://www.hyphy.org) as precompiled binaries and open source.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Duan:2008rp", + "year": 2008, + "authors": "Duan, Junhui and Mu, Jianbing and Thera, Mahamadou Ali and Joy, Deirdre and Pond, Sergei L Kosakovsky and Diemert, David and Long, Carole and Zhou, Hong and Miura, Kazutoyo and Ouattara, Amed and Dolo, Amagana and Doumbo, Ogobara and Su, Xin-Zhuan and Miller, Louis", + "title": "Population structure of the genes encoding the polymorphic Plasmodium falciparum apical membrane antigen 1: implications for vaccine design", + "journal": "Proc Natl Acad Sci U S A", + "doi": "", + "abstract": "Immunization with the highly polymorphic Plasmodium falciparum apical membrane antigen 1 (PfAMA1) induces protection in animals but primarily against parasites that express the same or similar alleles. One strategy to overcome the obstacle of polymorphism is to combine PfAMA1 proteins representing major haplotypes into one vaccine. To determine the minimum number of haplotypes that would confer broad protection, we sequenced the coding region of PfAMA1 from 97 clones from around the world and 61 isolates from Mali, identifying 150 haplotypes for domains 1 to 3 that included previous sequences. A clustering algorithm grouped the 150 haplotypes into six populations that were independent of geographic location. Each of the six populations contained haplotypes predominantly of that population (predominant haplotypes) and haplotypes that were a mixture of haplotypes represented in other populations (admixed haplotypes). To determine the biological relevance of the populations identified through the clustering algorithm, antibodies induced against one predominant haplotype of population 1 (3D7) and one admixed haplotype of population 5 (FVO) were tested for their ability to block parasite invasion of erythrocytes. Parasites expressing PfAMA1s belonging to population 1 were efficiently inhibited by 3D7-specific antibodies, whereas parasites expressing PfAMA1s belonging to other populations were not. For FVO-specific antibodies, we observed growth inhibition against itself as well as isolates belonging to populations 3 and 6. Our data suggests that the inclusion of PfAMA1 sequences from each of the six populations may result in a vaccine that induces protective immunity against a broad range of malaria parasites.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kosakovsky-Pond:2008zl", + "year": 2008, + "authors": "Pond, Sergei L Kosakovsky and Poon, Art F Y and Leigh Brown, Andrew J and Frost, Simon D W", + "title": "A maximum likelihood method for detecting directional evolution in protein sequences and its application to influenza A virus", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "We develop a model-based phylogenetic maximum likelihood test for evidence of preferential substitution toward a given residue at individual positions of a protein alignment--directional evolution of protein sequences (DEPS). DEPS can identify both the target residue and sites evolving toward it, help detect selective sweeps and frequency-dependent selection--scenarios that confound most existing tests for selection, and achieve good power and accuracy on simulated data. We applied DEPS to alignments representing different genomic regions of influenza A virus (IAV), sampled from avian hosts (H5N1 serotype) and human hosts (H3N2 serotype), and identified multiple directionally evolving sites in 5/8 genomic segments of H5N1 and H3N2 IAV. We propose a simple descriptive classification of directionally evolving sites into 5 groups based on the temporal distribution of residue frequencies and document known functional correlates, such as immune escape or host adaptation.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Nickle:2008kv", + "year": 2008, + "authors": "Nickle, David C and Jojic, Nebojsa and Heckerman, David and Jojic, Vladimir and Kirovski, Darko and Rolland, Morgane and Pond, Sergei L Kosakovsky and Mullins, James I", + "title": "Comparison of immunogen designs that optimize peptide coverage: reply to Fischer et al", + "journal": "PLoS Comput Biol", + "doi": "", + "abstract": "", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kosakovsky-Pond:2008sh", + "year": 2008, + "authors": "Kosakovsky Pond, S L and Poon, A F Y and Zarate, S and Smith, D M and Little, S J and Pillai, S K and Ellis, R J and Wong, J K and Leigh Brown, A J and Richman, D D and Frost, S D W", + "title": "Estimating selection pressures on HIV-1 using phylogenetic likelihood models", + "journal": "Stat Med", + "doi": "", + "abstract": "Human immunodeficiency virus (HIV-1) can rapidly evolve due to selection pressures exerted by HIV-specific immune responses, antiviral agents, and to allow the virus to establish infection in different compartments in the body. Statistical models applied to HIV-1 sequence data can help to elucidate the nature of these selection pressures through comparisons of non-synonymous (or amino acid changing) and synonymous (or amino acid preserving) substitution rates. These models also need to take into account the non-independence of sequences due to their shared evolutionary history. We review how we have developed these methods and have applied them to characterize the evolution of HIV-1 in vivo. To illustrate our methods, we present an analysis of compartment-specific evolution of HIV-1 env in blood and cerebrospinal fluid and of site-to-site variation in the gag gene of subtype C HIV-1.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Little:2008wy", + "year": 2008, + "authors": "Little, Susan J and Frost, Simon D W and Wong, Joseph K and Smith, Davey M and Pond, Sergei L Kosakovsky and Ignacio, Caroline C and Parkin, Neil T and Petropoulos, Christos J and Richman, Douglas D", + "title": "Persistence of transmitted drug resistance among subjects with primary human immunodeficiency virus infection", + "journal": "J Virol", + "doi": "", + "abstract": "Following interruption of antiretroviral therapy among individuals with acquired drug resistance, preexisting drug-sensitive virus emerges relatively rapidly. In contrast, wild-type virus is not archived in individuals infected with drug-resistant human immunodeficiency virus (HIV) and thus cannot emerge rapidly in the absence of selective drug pressure. Fourteen recently HIV-infected patients with transmitted drug-resistant virus were followed for a median of 2.1 years after the estimated date of infection (EDI) without receiving antiretroviral therapy. HIV drug resistance and pol replication capacity (RC) in longitudinal plasma samples were assayed. Resistance mutations were characterized as pure populations or mixtures. The mean time to first detection of a mixture of wild-type and drug-resistant viruses was 96 weeks (1.8 years) (95% confidence interval, 48 to 192 weeks) after the EDI. The median time to loss of detectable drug resistance using population-based assays ranged from 4.1 years (conservative estimate) to longer than the lifetime of the individual (less conservative estimate). The transmission of drug-resistant virus was not associated with virus with reduced RC. Sexual transmission of HIV selects for highly fit drug-resistant variants that persist for years. The prolonged persistence of transmitted drug resistance strongly supports the routine use of HIV resistance genotyping for all newly diagnosed individuals.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Gorbach:2008ws", + "year": 2008, + "authors": "Gorbach, Pamina M and Drumright, Lydia N and Javanbakht, Marjan and Pond, Sergei L and Woelk, Christopher H and Daar, Eric S and Little, Susan J", + "title": "Antiretroviral drug resistance and risk behavior among recently HIV-infected men who have sex with men", + "journal": "J Acquir Immune Defic Syndr", + "doi": "", + "abstract": "OBJECTIVES: Examine associations among behaviors including substance use during sexual encounters, and transmitted HIV drug resistance in recently HIV-infected men who have sex with men (MSM).\nMETHODS: Between 2002 and 2006, 117 recently HIV-infected MSM completed questionnaires regarding their 3 most recent sexual partners. Serum samples were tested for the presence of genotypic and phenotypic HIV drug resistance. Logistic regression analysis was used to assess the association of substance use, behaviors, and resistance to at least 1 class of HIV drugs.\nRESULTS: The mean age of participants was 35 years; 71% identified as white and 19% as Hispanic. Sixty (51%) reported substance use during sexual activity in the past 12 months. A total of 12.5% of 112 had genotypic drug resistance to at least 1 class of antiretroviral medications, and 14% of 117 had phenotypic drug resistance. Substances used during sexual activity associated with phenotypic drug resistance in multivariate models included any substance use (adjusted odds ratio [aOR] = 4.21, 95% confidence interval [CI]: 1.13 to 15.68), polysubstance use (aOR = 5.64, 95% CI: 1.62 to 19.60), methamphetamine (aOR = 4.00, 95% CI: 1.19 to 13.38), 3,4-methylenedioxy-N-methylamphetamine (MDMA)/Ecstasy (aOR = 7.16, 95% CI: 1.40 to 36.59), and gamma-hydroxyl butyrate (GHB) (aOR = 6.98, 95% CI: 1.82 to 26.80). The genotype analysis was similar.\nCONCLUSIONS: Among these recently HIV-infected MSM, methamphetamine use during sexual activity and use of other substances, such as MDMA and GHB, was associated with acquired drug-resistant virus. No other behaviors associated with acquisition of drug-resistant HIV.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Poon:2007ht", + "year": 2007, + "authors": "Poon, Art F Y and Lewis, Fraser I and Pond, Sergei L Kosakovsky and Frost, Simon D W", + "title": "An evolutionary-network model reveals stratified interactions in the V3 loop of the HIV-1 envelope", + "journal": "PLoS Comput Biol", + "doi": "", + "abstract": "The third variable loop (V3) of the human immunodeficiency virus type 1 (HIV-1) envelope is a principal determinant of antibody neutralization and progression to AIDS. Although it is undoubtedly an important target for vaccine research, extensive genetic variation in V3 remains an obstacle to the development of an effective vaccine. Comparative methods that exploit the abundance of sequence data can detect interactions between residues of rapidly evolving proteins such as the HIV-1 envelope, revealing biological constraints on their variability. However, previous studies have relied implicitly on two biologically unrealistic assumptions: (1) that founder effects in the evolutionary history of the sequences can be ignored, and; (2) that statistical associations between residues occur exclusively in pairs. We show that comparative methods that neglect the evolutionary history of extant sequences are susceptible to a high rate of false positives (20%-40%). Therefore, we propose a new method to detect interactions that relaxes both of these assumptions. First, we reconstruct the evolutionary history of extant sequences by maximum likelihood, shifting focus from extant sequence variation to the underlying substitution events. Second, we analyze the joint distribution of substitution events among positions in the sequence as a Bayesian graphical model, in which each branch in the phylogeny is a unit of observation. We perform extensive validation of our models using both simulations and a control case of known interactions in HIV-1 protease, and apply this method to detect interactions within V3 from a sample of 1,154 HIV-1 envelope sequences. Our method greatly reduces the number of false positives due to founder effects, while capturing several higher-order interactions among V3 residues. By mapping these interactions to a structural model of the V3 loop, we find that the loop is stratified into distinct evolutionary clusters. We extend our model to detect interactions between the V3 and C4 domains of the HIV-1 envelope, and account for the uncertainty in mapping substitutions to the tree with a parametric bootstrap.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Miller:2007dg", + "year": 2007, + "authors": "Miller, Webb and Rosenbloom, Kate and Hardison, Ross C and Hou, Minmei and Taylor, James and Raney, Brian and Burhans, Richard and King, David C and Baertsch, Robert and Blankenberg, Daniel and Pond, Sergei L Kosakovsky and Nekrutenko, Anton and Giardine, Belinda and Harris, Robert S and Tyekucheva, Svitlana and Diekhans, Mark and Pringle, Thomas H and Murphy, William J and Lesk, Arthur and Weinstock, George M and Lindblad-Toh, Kerstin and Gibbs, Richard A and Lander, Eric S and Siepel, Adam and Haussler, David and Kent, W James", + "title": "28-way vertebrate alignment and conservation track in the UCSC Genome Browser", + "journal": "Genome Res", + "doi": "", + "abstract": "This article describes a set of alignments of 28 vertebrate genome sequences that is provided by the UCSC Genome Browser. The alignments can be viewed on the Human Genome Browser (March 2006 assembly) at http://genome.ucsc.edu, downloaded in bulk by anonymous FTP from http://hgdownload.cse.ucsc.edu/goldenPath/hg18/multiz28way, or analyzed with the Galaxy server at http://g2.bx.psu.edu. This article illustrates the power of this resource for exploring vertebrate and mammalian evolution, using three examples. First, we present several vignettes involving insertions and deletions within protein-coding regions, including a look at some human-specific indels. Then we study the extent to which start codons and stop codons in the human sequence are conserved in other species, showing that start codons are in general more poorly conserved than stop codons. Finally, an investigation of the phylogenetic depth of conservation for several classes of functional elements in the human genome reveals striking differences in the rates and modes of decay in alignability. Each functional class has a distinctive period of stringent constraint, followed by decays that allow (for the case of regulatory regions) or reject (for coding regions and ultraconserved elements) insertions and deletions.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Poon:2007mb", + "year": 2007, + "authors": "Poon, Art F Y and Pond, Sergei L Kosakovsky and Richman, Douglas D and Frost, Simon D W", + "title": "Mapping protease inhibitor resistance to human immunodeficiency virus type 1 sequence polymorphisms within patients", + "journal": "J Virol", + "doi": "", + "abstract": "Resistance genotyping provides an important resource for the clinical management of patients infected with human immunodeficiency virus type 1 (HIV-1). However, resistance to protease (PR) inhibitors (PIs) is a complex phenotype shaped by interactions among nearly half of the residues in HIV-1 PR. Previous studies of the genetic basis of PI resistance focused on fixed substitutions among populations of HIV-1, i.e., host-specific adaptations. Consequently, they are susceptible to a high false discovery rate due to founder effects. Here, we employ sequencing \"mixtures\" (i.e., ambiguous base calls) as a site-specific marker of genetic variation within patients that is independent of the phylogeny. We demonstrate that the transient response to selection by PIs is manifested as an excess of nonsynonymous mixtures. Using a sample of 5,651 PR sequences isolated from both PI-naive and -treated patients, we analyze the joint distribution of mixtures and eight PIs as a Bayesian network, which distinguishes residue-residue interactions from direct associations with PIs. We find that selection for resistance is associated with the emergence of nonsynonymous mixtures in two distinct groups of codon sites clustered along the substrate cleft and distal regions of PR, respectively. Within-patient evolution at several positions is independent of PIs, including those formerly postulated to be involved in resistance. These positions are under strong positive selection in the PI-naive patient population, implying that other factors can produce spurious associations with resistance, e.g., mutational escape from the immune response.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Szklarczyk:2007qb", + "year": 2007, + "authors": "Szklarczyk, Radek and Heringa, Jaap and Pond, Sergei L Kosakovsky and Nekrutenko, Anton", + "title": "Rapid asymmetric evolution of a dual-coding tumor suppressor INK4a/ARF locus contradicts its function", + "journal": "Proc Natl Acad Sci U S A", + "doi": "", + "abstract": "INK4a/ARF tumor suppressor locus encodes two protein products, INK4a and ARF, essential for controlling tumorigenesis and mutated in more than half of human cancers. There is no resemblance between the two proteins: their coding regions are assembled by alternative splicing of two mutually exclusive 5' exons into a constitutive one containing overlapping out-of-phase reading frames. We show that the dual-coding arrangement conflicts with the high cost of mutations within INK4a/ARF. Unexpectedly, the locus evolves rapidly and asymmetrically, with ARF accumulating the majority of amino acid replacements. Rapid evolution drives both INK4a and ARF proteins out of sync with other members of the RB and p53 tumor suppressor pathways, both of which are controlled by the locus. Yet, the asymmetric behavior may be an intrinsic property of dual-coding exons: INK4a/ARF closely mimics the evolution of 90 newly identified genes with similar dual-coding structure. Thus, the strong link between mutations in INK4a/ARF and cancer may be a direct consequence of the architecture of the locus.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Nickle:2007kk", + "year": 2007, + "authors": "Nickle, David C and Heath, Laura and Jensen, Mark A and Gilbert, Peter B and Mullins, James I and Pond, Sergei L Kosakovsky", + "title": "HIV-specific probabilistic models of protein evolution", + "journal": "PLoS One", + "doi": "", + "abstract": "Comparative sequence analyses, including such fundamental bioinformatics techniques as similarity searching, sequence alignment and phylogenetic inference, have become a mainstay for researchers studying type 1 Human Immunodeficiency Virus (HIV-1) genome structure and evolution. Implicit in comparative analyses is an underlying model of evolution, and the chosen model can significantly affect the results. In general, evolutionary models describe the probabilities of replacing one amino acid character with another over a period of time. Most widely used evolutionary models for protein sequences have been derived from curated alignments of hundreds of proteins, usually based on mammalian genomes. It is unclear to what extent these empirical models are generalizable to a very different organism, such as HIV-1-the most extensively sequenced organism in existence. We developed a maximum likelihood model fitting procedure to a collection of HIV-1 alignments sampled from different viral genes, and inferred two empirical substitution models, suitable for describing between-and within-host evolution. Our procedure pools the information from multiple sequence alignments, and provided software implementation can be run efficiently in parallel on a computer cluster. We describe how the inferred substitution models can be used to generate scoring matrices suitable for alignment and similarity searches. Our models had a consistently superior fit relative to the best existing models and to parameter-rich data-driven models when benchmarked on independent HIV-1 alignments, demonstrating evolutionary biases in amino-acid substitution that are unique to HIV, and that are not captured by the existing models. The scoring matrices derived from the models showed a marked difference from common amino-acid scoring matrices. The use of an appropriate evolutionary model recovered a known viral transmission history, whereas a poorly chosen model introduced phylogenetic error. We argue that our model derivation procedure is immediately applicable to other organisms with extensive sequence data available, such as Hepatitis C and Influenza A viruses.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Woelk:2007xc", + "year": 2007, + "authors": "Woelk, Christopher H and Frost, Simon D W and Richman, Douglas D and Higley, Prentice E and Pond, Sergei L Kosakovsky", + "title": "Evolution of the interferon alpha gene family in eutherian mammals", + "journal": "Gene", + "doi": "", + "abstract": "Interferon alpha (IFNA) genes code for proteins with important signaling roles during the innate immune response. Phylogenetically, IFNA family members in eutherians (placental mammals) cluster together in a species-specific manner except for closely related species (i.e. Homo sapiens and Pan troglodytes) where gene-specific clustering is evident. Previous research has been unable to clarify whether gene conversion or recent gene duplication accounts for gene-specific clustering, partly because the similarity of members of the IFNA family within species has made it historically difficult to identify the exact composition of IFNA gene families. IFNA gene families were fully characterized in recently available genomes from Canis familiaris, Macaca mulatta, P. troglodytes and Rattus norvegicus, and combined with previously characterized IFNA gene families from H. sapiens and Mus musculus, for the analysis of both whole and partial gene conversion events using a variety of statistical methods. Gene conversion was inferred in every eutherian species analyzed and comparison of the IFNA gene family locus between primate species revealed independent gene duplication in M. mulatta. Thus, both gene conversion and gene duplication have shaped the evolution of the IFNA gene family in eutherian species. Scenarios may be envisaged whereby the increased production of a specific IFN-alpha protein would be beneficial against a particular pathogenic infection. Gene conversion, similar to duplication, provides a mechanism by which the protein product of a specific IFNA gene can be increased.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Chung:2007vg", + "year": 2007, + "authors": "Chung, Wen-Yu and Wadhawan, Samir and Szklarczyk, Radek and Pond, Sergei L Kosakovsky and Nekrutenko, Anton", + "title": "A first look at ARFome: dual-coding genes in mammalian genomes", + "journal": "PLoS Comput Biol", + "doi": "", + "abstract": "Coding of multiple proteins by overlapping reading frames is not a feature one would associate with eukaryotic genes. Indeed, codependency between codons of overlapping protein-coding regions imposes a unique set of evolutionary constraints, making it a costly arrangement. Yet in cases of tightly coexpressed interacting proteins, dual coding may be advantageous. Here we show that although dual coding is nearly impossible by chance, a number of human transcripts contain overlapping coding regions. Using newly developed statistical techniques, we identified 40 candidate genes with evolutionarily conserved overlapping coding regions. Because our approach is conservative, we expect mammals to possess more dual-coding genes. Our results emphasize that the skepticism surrounding eukaryotic dual coding is unwarranted: rather than being artifacts, overlapping reading frames are often hallmarks of fascinating biology.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Mazumder:2007um", + "year": 2007, + "authors": "Mazumder, Raja and Hu, Zhang-Zhi and Vinayaka, C R and Sagripanti, Jose-Luis and Frost, Simon D W and Pond, Sergei L Kosakovsky and Wu, Cathy H", + "title": "Computational analysis and identification of amino acid sites in dengue E proteins relevant to development of diagnostics and vaccines", + "journal": "Virus Genes", + "doi": "", + "abstract": "We have identified 72 completely conserved amino acid residues in the E protein of major groups of the Flavivirus genus by computational analyses. In the dengue species we have identified 12 highly conserved sequence regions, 186 negatively selected sites, and many dengue serotype-specific negatively selected sites. The flavivirus-conserved sites included residues involved in forming six disulfide bonds crucial for the structural integrity of the protein, the fusion motif involved in viral infectivity, and the interface residues of the oligomers. The structural analysis of the E protein showed 19 surface-exposed non-conserved residues, 128 dimer or trimer interface residues, and regions, which undergo major conformational change during trimerization. Eleven consensus T(h)-cell epitopes common to all four dengue serotypes were predicted. Most of these corresponded to dengue-conserved regions or negatively selected sites. Of special interest are six singular sites (N(37), Q(211), D(215), P(217), H(244), K(246)) in dengue E protein that are conserved, are part of the predicted consensus T(h)-cell epitopes and are exposed in the dimer or trimer. We propose these sites and corresponding epitopic regions as potential candidates for prioritization by experimental biologists for development of diagnostics and vaccines that may be difficult to circumvent by natural or man-made alteration of dengue virus.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Nickle:2007on", + "year": 2007, + "authors": "Nickle, David C and Rolland, Morgane and Jensen, Mark A and Pond, Sergei L Kosakovsky and Deng, Wenjie and Seligman, Mark and Heckerman, David and Mullins, James I and Jojic, Nebojsa", + "title": "Coping with viral diversity in HIV vaccine design", + "journal": "PLoS Comput Biol", + "doi": "", + "abstract": "The ability of human immunodeficiency virus type 1 (HIV-1) to develop high levels of genetic diversity, and thereby acquire mutations to escape immune pressures, contributes to the difficulties in producing a vaccine. Possibly no single HIV-1 sequence can induce sufficiently broad immunity to protect against a wide variety of infectious strains, or block mutational escape pathways available to the virus after infection. The authors describe the generation of HIV-1 immunogens that minimizes the phylogenetic distance of viral strains throughout the known viral population (the center of tree [COT]) and then extend the COT immunogen by addition of a composite sequence that includes high-frequency variable sites preserved in their native contexts. The resulting COT(+) antigens compress the variation found in many independent HIV-1 isolates into lengths suitable for vaccine immunogens. It is possible to capture 62% of the variation found in the Nef protein and 82% of the variation in the Gag protein into immunogens of three gene lengths. The authors put forward immunogen designs that maximize representation of the diverse antigenic features present in a spectrum of HIV-1 strains. These immunogens should elicit immune responses against high-frequency viral strains as well as against most mutant forms of the virus.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Zarate:2007mw", + "year": 2007, + "authors": "Zarate, Selene and Pond, Sergei L Kosakovsky and Shapshak, Paul and Frost, Simon D W", + "title": "Comparative study of methods for detecting sequence compartmentalization in human immunodeficiency virus type 1", + "journal": "J Virol", + "doi": "", + "abstract": "Human immunodeficiency virus (HIV) infects different organs and tissues. During these infection events, subpopulations of HIV type 1 (HIV-1) develop and, if viral trafficking is restricted between subpopulations, the viruses can follow independent evolutionary histories, i.e., become compartmentalized. This phenomenon is usually detected via comparative sequence analysis and has been reported for viruses isolated from the central nervous system (CNS) and the genital tract. Several approaches have been proposed to study the compartmentalization of HIV sequences, but to date, no rigorous comparison of the most commonly employed methods has been made. In this study, we systematically compared inferences made by six different methods for detecting compartmentalization based on three data sets: (i) a sample of 45 patients with sequences gathered from the CNS, (ii) sequences from the female genital tract of 18 patients, and (iii) a set of simulated sequences. We found that different methods often reached contradictory conclusions. Methods based on the topology of a phylogenetic tree derived from clonal sequences were generally more sensitive in detecting compartmentalization than those that relied solely upon pairwise genetic distances between sequences. However, as the branching structure in a phylogenetic tree is often uncertain, especially for short, low-diversity, or recombinant sequences, tree-based approaches may need to be modified to take phylogenetic uncertainty into account. Given the frequently discordant predictions of different methods and the strengths and weaknesses of each particular methodology, we recommend that a suite of several approaches be used for reliable inference of compartmentalized population structure.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Poon:2007vy", + "year": 2007, + "authors": "Poon, Art F Y and Pond, Sergei L Kosakovsky and Bennett, Phil and Richman, Douglas D and Leigh Brown, Andrew J and Frost, Simon D W", + "title": "Adaptation to human populations is revealed by within-host polymorphisms in HIV-1 and hepatitis C virus", + "journal": "PLoS Pathog", + "doi": "", + "abstract": "CD8(+) cytotoxic T-lymphocytes (CTLs) perform a critical role in the immune control of viral infections, including those caused by human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV). As a result, genetic variation at CTL epitopes is strongly influenced by host-specific selection for either escape from the immune response, or reversion due to the replicative costs of escape mutations in the absence of CTL recognition. Under strong CTL-mediated selection, codon positions within epitopes may immediately \"toggle\" in response to each host, such that genetic variation in the circulating virus population is shaped by rapid adaptation to immune variation in the host population. However, this hypothesis neglects the substantial genetic variation that accumulates in virus populations within hosts. Here, we evaluate this quantity for a large number of HIV-1- (n > or = 3,000) and HCV-infected patients (n > or = 2,600) by screening bulk RT-PCR sequences for sequencing \"mixtures\" (i.e., ambiguous nucleotides), which act as site-specific markers of genetic variation within each host. We find that nonsynonymous mixtures are abundant and significantly associated with codon positions under host-specific CTL selection, which should deplete within-host variation by driving the fixation of the favored variant. Using a simple model, we demonstrate that this apparently contradictory outcome can be explained by the transmission of unfavorable variants to new hosts before they are removed by selection, which occurs more frequently when selection and transmission occur on similar time scales. Consequently, the circulating virus population is shaped by the transmission rate and the disparity in selection intensities for escape or reversion as much as it is shaped by the immune diversity of the host population, with potentially serious implications for vaccine design.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Noviello:2007tb", + "year": 2007, + "authors": "Noviello, C M and Pond, S L Kosakovsky and Lewis, M J and Richman, D D and Pillai, S K and Yang, O O and Little, S J and Smith, D M and Guatelli, J C", + "title": "Maintenance of Nef-mediated modulation of major histocompatibility complex class I and CD4 after sexual transmission of human immunodeficiency virus type 1", + "journal": "J Virol", + "doi": "", + "abstract": "Viruses encounter changing selective pressures during transmission between hosts, including host-specific immune responses and potentially varying functional demands on specific proteins. The human immunodeficiency virus type 1 Nef protein performs several functions potentially important for successful infection, including immune escape via down-regulation of class I major histocompatibility complex (MHC-I) and direct enhancement of viral infectivity and replication. Nef is also a major target of the host cytotoxic T-lymphocyte (CTL) response. To examine the impact of changing selective pressures on Nef functions following sexual transmission, we analyzed genetic and functional changes in nef clones from six transmission events. Phylogenetic analyses indicated that the diversity of nef was similar in both sources and acutely infected recipients, the patterns of selection across transmission were variable, and regions of Nef associated with distinct functions evolved similarly in sources and recipients. These results weighed against the selection of specific Nef functions by transmission or during acute infection. Measurement of Nef function provided no evidence that the down-regulation of either CD4 or MHC-I was optimized by transmission or during acute infection, although rare nef clones from sources that were impaired in these activities were not detected in recipients. Nef-specific CTL activity was detected as early as 3 weeks after infection and appeared to be an evolutionary force driving the diversification of nef. Despite the change in selective pressure between the source and recipient immune systems and concomitant genetic diversity, the majority of Nef proteins maintained robust abilities to down-regulate MHC-I and CD4. These data suggest that both functions are important for the successful establishment of infection in a new host.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Lemey:2007yt", + "year": 2007, + "authors": "Lemey, Philippe and Pond, Sergei L Kosakovsky and Drummond, Alexei J and Pybus, Oliver G and Shapiro, Beth and Barroso, Helena and Taveira, Nuno and Rambaut, Andrew", + "title": "Synonymous substitution rates predict HIV disease progression as a result of underlying replication dynamics", + "journal": "PLoS Comput Biol", + "doi": "", + "abstract": "Upon HIV transmission, some patients develop AIDS in only a few months, while others remain disease free for 20 or more years. This variation in the rate of disease progression is poorly understood and has been attributed to host genetics, host immune responses, co-infection, viral genetics, and adaptation. Here, we develop a new \"relaxed-clock\" phylogenetic method to estimate absolute rates of synonymous and nonsynonymous substitution through time. We identify an unexpected association between the synonymous substitution rate of HIV and disease progression parameters. Since immune activation is the major determinant of HIV disease progression, we propose that this process can also determine viral generation times, by creating favourable conditions for HIV replication. These conclusions may apply more generally to HIV evolution, since we also observed an overall low synonymous substitution rate for HIV-2, which is known to be less pathogenic than HIV-1 and capable of tempering the detrimental effects of immune activation. Humoral immune responses, on the other hand, are the major determinant of nonsynonymous rate changes through time in the envelope gene, and our relaxed-clock estimates support a decrease in selective pressure as a consequence of immune system collapse.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Poon:2007nu", + "year": 2007, + "authors": "Poon, Art F Y and Lewis, Fraser I and Pond, Sergei L Kosakovsky and Frost, Simon D W", + "title": "Evolutionary interactions between N-linked glycosylation sites in the HIV-1 envelope", + "journal": "PLoS Comput Biol", + "doi": "", + "abstract": "The addition of asparagine (N)-linked polysaccharide chains (i.e., glycans) to the gp120 and gp41 glycoproteins of human immunodeficiency virus type 1 (HIV-1) envelope is not only required for correct protein folding, but also may provide protection against neutralizing antibodies as a \"glycan shield.\" As a result, strong host-specific selection is frequently associated with codon positions where nonsynonymous substitutions can create or disrupt potential N-linked glycosylation sites (PNGSs). Moreover, empirical data suggest that the individual contribution of PNGSs to the neutralization sensitivity or infectivity of HIV-1 may be critically dependent on the presence or absence of other PNGSs in the envelope sequence. Here we evaluate how glycan-glycan interactions have shaped the evolution of HIV-1 envelope sequences by analyzing the distribution of PNGSs in a large-sequence alignment. Using a \"covarion\"-type phylogenetic model, we find that the rates at which individual PNGSs are gained or lost vary significantly over time, suggesting that the selective advantage of having a PNGS may depend on the presence or absence of other PNGSs in the sequence. Consequently, we identify specific interactions between PNGSs in the alignment using a new paired-character phylogenetic model of evolution, and a Bayesian graphical model. Despite the fundamental differences between these two methods, several interactions are jointly identified by both. Mapping these interactions onto a structural model of HIV-1 gp120 reveals that negative (exclusive) interactions occur significantly more often between colocalized glycans, while positive (inclusive) interactions are restricted to more distant glycans. Our results imply that the adaptive repertoire of alternative configurations in the HIV-1 glycan shield is limited by functional interactions between the N-linked glycans. This represents a potential vulnerability of rapidly evolving HIV-1 populations that may provide useful glycan-based targets for neutralizing antibodies.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kosakovsky-Pond:2006qh", + "year": 2006, + "authors": "Pond, Sergei L Kosakovsky and Posada, David and Gravenor, Michael B and Woelk, Christopher H and Frost, Simon D W", + "title": "GARD: a genetic algorithm for recombination detection", + "journal": "Bioinformatics", + "doi": "", + "abstract": "MOTIVATION: Phylogenetic and evolutionary inference can be severely misled if recombination is not accounted for, hence screening for it should be an essential component of nearly every comparative study. The evolution of recombinant sequences can not be properly explained by a single phylogenetic tree, but several phylogenies may be used to correctly model the evolution of non-recombinant fragments.\nRESULTS: We developed a likelihood-based model selection procedure that uses a genetic algorithm to search multiple sequence alignments for evidence of recombination breakpoints and identify putative recombinant sequences. GARD is an extensible and intuitive method that can be run efficiently in parallel. Extensive simulation studies show that the method nearly always outperforms other available tools, both in terms of power and accuracy and that the use of GARD to screen sequences for recombination ensures good statistical properties for methods aimed at detecting positive selection.\nAVAILABILITY: Freely available http://www.datamonkey.org/GARD/", + "category": "METHODS", + "isRecent": false, + "isLegendary": true, + "stats": "Landmark Method" + }, + { + "id": "Kosakovsky-Pond:2007mf", + "year": 2007, + "authors": "Pond, Sergei L Kosakovsky and Mannino, Frank V and Gravenor, Michael B and Muse, Spencer V and Frost, Simon D W", + "title": "Evolutionary model selection with a genetic algorithm: a case study using stem RNA", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "The choice of a probabilistic model to describe sequence evolution can and should be justified. Underfitting the data through the use of overly simplistic models may miss out on interesting phenomena and lead to incorrect inferences. Overfitting the data with models that are too complex may ascribe biological meaning to statistical artifacts and result in falsely significant findings. We describe a likelihood-based approach for evolutionary model selection. The procedure employs a genetic algorithm (GA) to quickly explore a combinatorially large set of all possible time-reversible Markov models with a fixed number of substitution rates. When applied to stem RNA data subject to well-understood evolutionary forces, the models found by the GA 1) capture the expected overall rate patterns a priori; 2) fit the data better than the best available models based on a priori assumptions, suggesting subtle substitution patterns not previously recognized; 3) cannot be rejected in favor of the general reversible model, implying that the evolution of stem RNA sequences can be explained well with only a few substitution rate parameters; and 4) perform well on simulated data, both in terms of goodness of fit and the ability to estimate evolutionary rates. We also investigate the utility of several distance measures for comparing and contrasting inferred evolutionary models. Using widely available small computer clusters, our approach allows, for the first time, to evaluate the performance of existing RNA evolutionary models by comparing them with a large pool of candidate models and to validate common modeling assumptions. In addition, the new method provides the foundation for rigorous selection and comparison of substitution models for other types of sequence data.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Sorhannus:2006ja", + "year": 2006, + "authors": "Sorhannus, Ulf and Pond, Sergei L Kosakovsky", + "title": "Evidence for positive selection on a sexual reproduction gene in the diatom genus Thalassiosira (Bacillariophyta)", + "journal": "J Mol Evol", + "doi": "", + "abstract": "Single likelihood ancestor counting (SLAC), fixed effects likelihood (FEL), and several random effects likelihood (REL) methods were utilized to identify positively and negatively selected sites in sexually induced gene 1 (Sig1) of four different Thalassiosira species. The SLAC analysis did not find any sites affected by positive selection but suggested 13 sites influenced by negative selection. The SLAC approach may be too conservative because of low sequence divergence. The FEL and REL analyses revealed over 60 negatively selected sites and two positively selected sites that were unique to each method. The REL method may not be able to reliably identify individual sites under selection when applied to short sequences with low divergence. Instead, we proposed a new alignment-wide test for adaptive evolution based on codon models with variation in synonymous and nonsynonymous substitution rates among sites and found evidence for diversifying evolution without relying on site-by-site testing. The performance of the FEL and REL approaches was evaluated by subjecting the tests to a type I error rate simulation analysis, using the specific characteristics of the Sig1 data set. Simulation results indicated that the FEL test had reasonable Type I errors, while REL might have been too liberal, suggesting that the two positively selected sites identified by FEL (codons 94 and 174) are not likely to be false positives. The evolution of these codon sites, one of which is located in functional domain II, appears to be associated with divergence among the three major Thalassiosira lineages.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kosakovsky-Pond:2006qt", + "year": 2006, + "authors": "Pond, Sergei L Kosakovsky and Posada, David and Gravenor, Michael B and Woelk, Christopher H and Frost, Simon D W", + "title": "Automated phylogenetic detection of recombination using a genetic algorithm", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "The evolution of homologous sequences affected by recombination or gene conversion cannot be adequately explained by a single phylogenetic tree. Many tree-based methods for sequence analysis, for example, those used for detecting sites evolving nonneutrally, have been shown to fail if such phylogenetic incongruity is ignored. However, it may be possible to propose several phylogenies that can correctly model the evolution of nonrecombinant fragments. We propose a model-based framework that uses a genetic algorithm to search a multiple-sequence alignment for putative recombination break points, quantifies the level of support for their locations, and identifies sequences or clades involved in putative recombination events. The software implementation can be run quickly and efficiently in a distributed computing environment, and various components of the methods can be chosen for computational expediency or statistical rigor. We evaluate the performance of the new method on simulated alignments and on an array of published benchmark data sets. Finally, we demonstrate that prescreening alignments with our method allows one to analyze recombinant sequences for positive selection.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Pond:2006gn", + "year": 2006, + "authors": "Pond, Sergei L Kosakovsky and Frost, Simon D W and Grossman, Zehava and Gravenor, Michael B and Richman, Douglas D and Brown, Andrew J Leigh", + "title": "Adaptation to different human populations by HIV-1 revealed by codon-based analyses", + "journal": "PLoS Comput Biol", + "doi": "", + "abstract": "Several codon-based methods are available for detecting adaptive evolution in protein-coding sequences, but to date none specifically identify sites that are selected differentially in two populations, although such comparisons between populations have been historically useful in identifying the action of natural selection. We have developed two fixed effects maximum likelihood methods: one for identifying codon positions showing selection patterns that persist in a population and another for detecting whether selection is operating differentially on individual codons of a gene sampled from two different populations. Applying these methods to two HIV populations infecting genetically distinct human hosts, we have found that few of the positively selected amino acid sites persist in the population; the other changes are detected only at the tips of the phylogenetic tree and appear deleterious in the long term. Additionally, we have identified seven amino acid sites in protease and reverse transcriptase that are selected differentially in the two samples, demonstrating specific population-level adaptation of HIV to human populations.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Pillai:2006gc", + "year": 2006, + "authors": "Pillai, Satish K and Pond, Sergei L Kosakovsky and Liu, Yang and Good, Benjamin M and Strain, Matthew C and Ellis, Ronald J and Letendre, Scott and Smith, Davey M and Gunthard, Huldrych F and Grant, Igor and Marcotte, Thomas D and McCutchan, J Allen and Richman, Douglas D and Wong, Joseph K", + "title": "Genetic attributes of cerebrospinal fluid-derived HIV-1 env", + "journal": "Brain", + "doi": "", + "abstract": "HIV-1 often invades the CNS during primary infection, eventually resulting in neurological disorders in up to 50% of untreated patients. The CNS is a distinct viral reservoir, differing from peripheral tissues in immunological surveillance, target cell characteristics and antiretroviral penetration. Neurotropic HIV-1 likely develops distinct genotypic characteristics in response to this unique selective environment. We sought to catalogue the genetic features of CNS-derived HIV-1 by analysing 456 clonal RNA sequences of the C2-V3 env subregion generated from CSF and plasma of 18 chronically infected individuals. Neuropsychological performance of all subjects was evaluated and summarized as a global deficit score. A battery of phylogenetic, statistical and machine learning tools was applied to these data to identify genetic features associated with HIV-1 neurotropism and neurovirulence. Eleven of 18 individuals exhibited significant viral compartmentalization between blood and CSF (P < 0.01, Slatkin-Maddison test). A CSF-specific genetic signature was identified, comprising positions 9, 13 and 19 of the V3 loop. The residue at position 5 of the V3 loop was highly correlated with neurocognitive deficit (P < 0.0025, Fisher's exact test). Antibody-mediated HIV-1 neutralizing activity was significantly reduced in CSF with respect to autologous blood plasma (P < 0.042, Student's t-test). Accordingly, CSF-derived sequences exhibited constrained diversity and contained fewer glycosylated and positively selected sites. Our results suggest that there are several genetic features that distinguish CSF- and plasma-derived HIV-1 populations, probably reflecting altered cellular entry requirements and decreased immune pressure in the CNS. Furthermore, neurological impairment may be influenced by mutations within the viral V3 loop sequence.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Huelsenbeck:2006wk", + "year": 2006, + "authors": "Huelsenbeck, John P and Jain, Sonia and Frost, Simon W D and Pond, Sergei L Kosakovsky", + "title": "A Dirichlet process model for detecting positive selection in protein-coding DNA sequences", + "journal": "Proc Natl Acad Sci U S A", + "doi": "", + "abstract": "Most methods for detecting Darwinian natural selection at the molecular level rely on estimating the rates or numbers of nonsynonymous and synonymous changes in an alignment of protein-coding DNA sequences. In some of these methods, the nonsynonymous rate of substitution is allowed to vary across the sequence, permitting the identification of single amino acid positions that are under positive natural selection. However, it is unclear which probability distribution should be used to describe how the nonsynonymous rate of substitution varies across the sequence. One widely used solution is to model variation in the nonsynonymous rate across the sequence as a mixture of several discrete or continuous probability distributions. Unfortunately, there is little population genetics theory to inform us of the appropriate probability distribution for among-site variation in the nonsynonymous rate of substitution. Here, we describe an approach to modeling variation in the nonsynonymous rate of substitution by using a Dirichlet process mixture model. The Dirichlet process allows there to be a countably infinite number of nonsynonymous rate classes and is very flexible in accommodating different potential distributions for the nonsynonymous rate of substitution. We implemented the model in a fully Bayesian approach, with all parameters of the model considered as random variables.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Frost:2005uz", + "year": 2005, + "authors": "Frost, Simon D W and Wrin, Terri and Smith, Davey M and Pond, Sergei L Kosakovsky and Liu, Yang and Paxinos, Ellen and Chappey, Colombe and Galovich, Justin and Beauchaine, Jeff and Petropoulos, Christos J and Little, Susan J and Richman, Douglas D", + "title": "Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection", + "journal": "Proc Natl Acad Sci U S A", + "doi": "", + "abstract": "HIV type 1 (HIV-1) can rapidly escape from neutralizing antibody responses. The genetic basis of this escape in vivo is poorly understood. We compared the pattern of evolution of the HIV-1 env gene between individuals with recent HIV infection whose virus exhibited either a low or a high rate of escape from neutralizing antibody responses. We demonstrate that the rate of viral escape at a phenotypic level is highly variable among individuals, and is strongly correlated with the rate of amino acid substitutions. We show that dramatic escape from neutralizing antibodies can occur in the relative absence of changes in glycosylation or insertions and deletions (\"indels\") in the envelope; conversely, changes in glycosylation and indels occur even in the absence of neutralizing antibody responses. Comparison of our data with the predictions of a mathematical model support a mechanism in which escape from neutralizing antibodies occurs via many amino acid substitutions, with low cross-neutralization between closely related viral strains. Our results suggest that autologous neutralizing antibody responses may play a pivotal role in the diversification of HIV-1 envelope during the early stages of infection.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Pond:2005ya", + "year": 2005, + "authors": "Pond, Sergei L Kosakovsky and Muse, Spencer V", + "title": "Site-to-site variation of synonymous substitution rates", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "We develop a new model for studying the molecular evolution of protein-coding DNA sequences. In contrast to existing models, we incorporate the potential for site-to-site heterogeneity of both synonymous and nonsynonymous substitution rates. We demonstrate that within-gene heterogeneity of synonymous substitution rates appears to be common. Using the new family of models, we investigate the utility of a variety of new statistical inference procedures, and we pay particular attention to issues surrounding the detection of sites undergoing positive selection. We discuss how failure to model synonymous rate variation in the model can lead to misidentification of sites as positively selected.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Pillai:2005mn", + "year": 2005, + "authors": "Pillai, Satish K and Pond, Sergei L Kosakovsky and Woelk, Christopher H and Richman, Douglas D and Smith, Davey M", + "title": "Codon volatility does not reflect selective pressure on the HIV-1 genome", + "journal": "Virology", + "doi": "", + "abstract": "Codon volatility is defined as the proportion of a codon's point-mutation neighbors that encode different amino acids. The cumulative volatility of a gene in relation to its associated genome was recently reported to be an indicator of selection pressure. We used this approach to measure selection on all available full-length HIV-1 subtype B genomes in the Los Alamos HIV Sequence Database, and compared these estimates against those obtained via established likelihood- and distance-based comparative methods. Volatility failed to correlate with the results of any of the comparative methods demonstrating that it is not a reliable indicator of selection pressure.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Frost:2005er", + "year": 2005, + "authors": "Frost, Simon D W and Liu, Yang and Pond, Sergei L Kosakovsky and Chappey, Colombe and Wrin, Terri and Petropoulos, Christos J and Little, Susan J and Richman, Douglas D", + "title": "Characterization of human immunodeficiency virus type 1 (HIV-1) envelope variation and neutralizing antibody responses during transmission of HIV-1 subtype B", + "journal": "J Virol", + "doi": "", + "abstract": "We analyzed neutralization sensitivity and genetic variation of transmitted subtype B human immunodeficiency virus type 1 (HIV-1) in eight recently infected men who have sex with men and the virus from the six subjects who infected them. In contrast to reports of heterosexual transmission of subtype C HIV-1, in which the transmitted virus appears to be more neutralization sensitive, we demonstrate that in our study population, relatively few phenotypic changes in neutralization sensitivity or genotypic changes in envelope occurred during transmission of subtype B HIV-1. We suggest that limited genetic variation within the infecting host reduces the likelihood of selective transmission of neutralization-sensitive HIV.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Pond:2005ph", + "year": 2005, + "authors": "Pond, Sergei L Kosakovsky and Frost, Simon D W", + "title": "Datamonkey: rapid detection of selective pressure on individual sites of codon alignments", + "journal": "Bioinformatics", + "doi": "", + "abstract": "UNLABELLED: Datamonkey is a web interface to a suite of cutting edge maximum likelihood-based tools for identification of sites subject to positive or negative selection. The methods range from very fast data exploration to the some of the most complex models available in public domain software, and are implemented to run in parallel on a cluster of computers.\nAVAILABILITY: http://www.datamonkey.org. In the future, we plan to expand the collection of available analytic tools, and provide a package for installation on other systems.", + "category": "METHODS", + "isRecent": false, + "isLegendary": true, + "stats": "Landmark Platform" + }, + { + "id": "Kosakovsky-Pond:2005fm", + "year": 2005, + "authors": "Pond, Sergei L Kosakovsky and Frost, Simon D W", + "title": "Not so different after all: a comparison of methods for detecting amino acid sites under selection", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "We consider three approaches for estimating the rates of nonsynonymous and synonymous changes at each site in a sequence alignment in order to identify sites under positive or negative selection: (1) a suite of fast likelihood-based \"counting methods\" that employ either a single most likely ancestral reconstruction, weighting across all possible ancestral reconstructions, or sampling from ancestral reconstructions; (2) a random effects likelihood (REL) approach, which models variation in nonsynonymous and synonymous rates across sites according to a predefined distribution, with the selection pressure at an individual site inferred using an empirical Bayes approach; and (3) a fixed effects likelihood (FEL) method that directly estimates nonsynonymous and synonymous substitution rates at each site. All three methods incorporate flexible models of nucleotide substitution bias and variation in both nonsynonymous and synonymous substitution rates across sites, facilitating the comparison between the methods. We demonstrate that the results obtained using these approaches show broad agreement in levels of Type I and Type II error and in estimates of substitution rates. Counting methods are well suited for large alignments, for which there is high power to detect positive and negative selection, but appear to underestimate the substitution rate. A REL approach, which is more computationally intensive than counting methods, has higher power than counting methods to detect selection in data sets of intermediate size but may suffer from higher rates of false positives for small data sets. A FEL approach appears to capture the pattern of rate variation better than counting methods or random effects models, does not suffer from as many false positives as random effects models for data sets comprising few sequences, and can be efficiently parallelized. Our results suggest that previously reported differences between results obtained by counting methods and random effects models arise due to a combination of the conservative nature of counting-based methods, the failure of current random effects models to allow for variation in synonymous substitution rates, and the naive application of random effects models to extremely sparse data sets. We demonstrate our methods on sequence data from the human immunodeficiency virus type 1 env and pol genes and simulated alignments.", + "category": "METHODS", + "isRecent": false, + "isLegendary": true, + "stats": "Landmark Method" + }, + { + "id": "Pillai:2005we", + "year": 2005, + "authors": "Pillai, Satish K and Good, Benjamin and Pond, Sergei L Kosakovsky and Wong, Joseph K and Strain, Matt C and Richman, Douglas D and Smith, Davey M", + "title": "Semen-specific genetic characteristics of human immunodeficiency virus type 1 env", + "journal": "J Virol", + "doi": "", + "abstract": "Human immunodeficiency virus type 1 (HIV-1) in the male genital tract may comprise virus produced locally in addition to virus transported from the circulation. Virus produced in the male genital tract may be genetically distinct, due to tissue-specific cellular characteristics and immunological pressures. HIV-1 env sequences derived from paired blood and semen samples from the Los Alamos HIV Sequence Database were analyzed to ascertain a male genital tract-specific viral signature. Machine learning algorithms could predict seminal tropism based on env sequences with accuracies exceeding 90%, suggesting that a strong genetic signature does exist for virus replicating in the male genital tract. Additionally, semen-derived viral populations exhibited constrained diversity (P < 0.05), decreased levels of positive selection (P < 0.025), decreased CXCR4 coreceptor utilization, and altered glycosylation patterns. Our analysis suggests that the male genital tract represents a distinct selective environment that contributes to the apparent genetic bottlenecks associated with the sexual transmission of HIV-1.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Kosakovsky-Pond:2004vh", + "year": 2004, + "authors": "Pond, Sergei L Kosakovsky and Muse, Spencer V", + "title": "Column sorting: rapid calculation of the phylogenetic likelihood function", + "journal": "Syst Biol", + "doi": "", + "abstract": "Likelihood applications have become a central approach for molecular evolutionary analyses since the first computationally tractable treatment two decades ago. Although Felsenstein's original pruning algorithm makes likelihood calculations feasible, it is usually possible to take advantage of repetitive structure present in the data to arrive at even greater computational reductions. In particular, alignment columns with certain similarities have components of the likelihood calculation that are identical and need not be recomputed if columns are evaluated in an optimal order. We develop an algorithm for exploiting this speed improvement via an application of graph theory. The reductions provided by the method depend on both the tree and the data, but typical savings range between 15%and 50%. Real-data examples with time reductions of 80%have been identified. The overhead costs associated with implementing the algorithm are minimal, and they are recovered in all but the smallest data sets. The modifications will provide faster likelihood algorithms, which will allow likelihood methods to be applied to larger sets of taxa and to include more thorough searches of the tree topology space.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Pond:2005wl", + "year": 2005, + "authors": "Pond, Sergei L Kosakovsky and Frost, Simon D W", + "title": "A genetic algorithm approach to detecting lineage-specific variation in selection pressure", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "The ratio of nonsynonymous (dN) to synonymous (dS) substitution rates, omega, provides a measure of selection at the protein level. Models have been developed that allow omega to vary among lineages. However, these models require the lineages in which differential selection has acted to be specified a priori. We propose a genetic algorithm approach to assign lineages in a phylogeny to a fixed number of different classes of omega, thus allowing variable selection pressure without a priori specification of particular lineages. This approach can identify models with a better fit than a single-ratio model, and with fits that are better than (in an information theoretic sense) a fully local model, in which all lineages are assumed to evolve under different values of omega, but with far fewer parameters. By averaging over models which explain the data reasonably well, we can assess the robustness of our conclusions to uncertainty in model estimation. Our approach can also be used to compare results from models in which branch classes are specified a priori with a wide range of credible models. We illustrate our methods on primate lysozyme sequences and compare them with previous methods applied to the same data sets.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Pond:2005ez", + "year": 2005, + "authors": "Pond, Sergei L Kosakovsky and Frost, Simon D W and Muse, Spencer V", + "title": "HyPhy: hypothesis testing using phylogenies", + "journal": "Bioinformatics", + "doi": "", + "abstract": "UNLABELLED: The HyPhypackage is designed to provide a flexible and unified platform for carrying out likelihood-based analyses on multiple alignments of molecular sequence data, with the emphasis on studies of rates and patterns of sequence evolution.\nAVAILABILITY: http://www.hyphy.org\nCONTACT: muse@stat.ncsu.edu\nSUPPLEMENTARY INFORMATION: HyPhydocumentation and tutorials are available at http://www.hyphy.org.", + "category": "METHODS", + "isRecent": false, + "isLegendary": true, + "stats": "Landmark Software" + }, + { + "id": "Pond:2005oh", + "year": 2005, + "authors": "Pond, Sergei L Kosakovsky and Frost, Simon D W", + "title": "A simple hierarchical approach to modeling distributions of substitution rates", + "journal": "Mol Biol Evol", + "doi": "", + "abstract": "Genetic sequence data typically exhibit variability in substitution rates across sites. In practice, there is often too little variation to fit a different rate for each site in the alignment, but the distribution of rates across sites may not be well modeled using simple parametric families. Mixtures of different distributions can capture more complex patterns of rate variation, but are often parameter-rich and difficult to fit. We present a simple hierarchical model in which a baseline rate distribution, such as a gamma distribution, is discretized into several categories, the quantiles of which are estimated using a discretized beta distribution. Although this approach involves adding only two extra parameters to a standard distribution, a wide range of rate distributions can be captured. Using simulated data, we demonstrate that a \"beta-\" model can reproduce the moments of the rate distribution more accurately than the distribution used to simulate the data, even when the baseline rate distribution is misspecified. Using hepatitis C virus and mammalian mitochondrial sequences, we show that a beta- model can fit as well or better than a model with multiple discrete rate categories, and compares favorably with a model which fits a separate rate category to each site. We also demonstrate this discretization scheme in the context of codon models specifically aimed at identifying individual sites undergoing adaptive or purifying evolution.", + "category": "METHODS", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Israel:2002ye", + "year": 2002, + "authors": "Israel, Rachel L and Pond, Sergei L Kosakovsky and Muse, Spencer V and Katz, Laura A", + "title": "Evolution of duplicated alpha-tubulin genes in ciliates", + "journal": "Evolution", + "doi": "", + "abstract": "Ciliates provide a powerful system to analyze the evolution of duplicated alpha-tubulin genes in the context of single-celled organisms. Genealogical analyses of ciliate alpha-tubulin sequences reveal five apparently recent gene duplications. Comparisons of paralogs in different ciliates implicate differing patterns of substitutions (e.g., ratios of replacement/synonymous nucleotides and radical/conservative amino acids) following duplication. Most substitutions between paralogs in Euplotes crassus, Halteria grandinella and Paramecium tetraurelia are synonymous. In contrast, alpha-tubulin paralogs within Stylonychia lemnae and Chilodonella uncinata are evolving at significantly different rates and have higher ratios of both replacement substitutions to synonymous substitutions and radical amino acid changes to conservative amino acid changes. Moreover, the amino acid substitutions in C. uncinata and S. lemnae paralogs are limited to short stretches that correspond to functionally important regions of the alpha-tubulin protein. The topology of ciliate alpha-tubulin genealogies are inconsistent with taxonomy based on morphology and other molecular markers, which may be due to taxonomic sampling, gene conversion, unequal rates of evolution, or asymmetric patterns of gene duplication and loss.", + "category": "ADAPTATION", + "isRecent": false, + "isLegendary": false + }, + { + "id": "Zhang:2001eh", + "year": 2001, + "authors": "Zhang, L and Pond, S K and Gaut, B S", + "title": "A survey of the molecular evolutionary dynamics of twenty-five multigene families from four grass taxa", + "journal": "J Mol Evol", + "doi": "", + "abstract": "We surveyed the molecular evolutionary characteristics of 25 plant gene families, with the goal of better understanding general processes in plant gene family evolution. The survey was based on 247 GenBank sequences representing four grass species (maize, rice, wheat, and barley). For each gene family, orthology and paralogy relationships were uncertain. Recognizing this uncertainty, we characterized the molecular evolution of each gene family in four ways. First, we calculated the ratio of nonsynonymous to synonymous substitutions (d(N)/d(S)) both on branches of gene phylogenies and across codons. Our results indicated that the d(N)/d(S) ratio was statistically heterogeneous across branches in 17 of 25 (68%) gene families. The vast majority of d(N)/d(S) estimates were <1.0, suggestive of selective constraint on amino acid replacements, and no estimates were >1.0, either across phylogenetic lineages or across codons. Second, we tested separately for nonsynonymous and synonymous molecular clocks. Sixty-eight percent of gene families rejected a nonsynonymous molecular clock, and 52% of gene families rejected a synonymous molecular clock. Thus, most gene families in this study deviated from clock-like evolution at either synonymous or nonsynonymous sites. Third, we calculated the effective number of codons and the proportion of G+C synonymous sites for each sequence in each gene family. One or both quantities vary significantly within 18 of 25 gene families. Finally, we tested for gene conversion, and only six gene families provided evidence of gene conversion events. Altogether, evolution for these 25 gene families is marked by selective constraint that varies among gene family members, a lack of molecular clock at both synonymous and nonsynonymous sites, and substantial variation in codon usage.", + "category": "VIRAL_DYNAMICS", + "isRecent": false, + "isLegendary": false + } +] \ No newline at end of file diff --git a/src/data/projects.json b/src/data/projects.json new file mode 100644 index 0000000..3ee7386 --- /dev/null +++ b/src/data/projects.json @@ -0,0 +1,110 @@ +[ + { + "id": "hyphy", + "name": "HyPhy", + "class": "The Engine", + "description": "Hypothesis Testing using Phylogenies. A high-performance framework for building and testing stochastic evolutionary models.", + "stats": { + "power": 99, + "speed": 85, + "complexity": 90, + "citations": "3,000+", + "users": "10,000+" + }, + "powers": [ + { "name": "LIMITLESS_CUSTOMIZATION", "desc": "Allows researchers to define any evolutionary model via its rich scripting language." }, + { "name": "PARALLEL_PROCESSING", "desc": "Optimized for clusters, tearing through massive sequence alignments with MPI support." } + ], + "image": "/images/projects/Hyphy.jpeg", + "links": { + "website": "http://hyphy.org", + "github": "https://github.com/veg/hyphy" + } + }, + { + "id": "datamonkey", + "name": "Datamonkey.org", + "class": "The Oracle", + "description": "The public web-interface for the world's most advanced evolutionary models.", + "stats": { + "accessibility": 100, + "wisdom": 95, + "analyses": "500,000+", + "citations": "1,000+", + "uptime": "99.9%" + }, + "powers": [ + { "name": "ZERO_INSTALL", "desc": "Run state-of-the-art HyPhy models directly in your browser without touching a terminal." }, + { "name": "GRID_INVOCATION", "desc": "Offloads complex computations to high-performance clusters automatically." } + ], + "image": "/images/projects/Datamonkey.jpeg", + "links": { + "website": "https://datamonkey.org", + "github": "https://github.com/veg/datamonkey-js" + } + }, + { + "id": "hivtrace", + "name": "HIV-TRACE", + "class": "The Scout", + "description": "Transmission Cluster Engine. Maps the hidden connections in molecular epidemiology.", + "stats": { + "detection": 98, + "accuracy": 92, + "stealth": 80, + "user_base": "CDC / Global PH", + "latency": "Real-time" + }, + "powers": [ + { "name": "CLUSTER_MAPPING", "desc": "Identifies transmission chains from viral sequence data in minutes." }, + { "name": "SECURE_SURVEILLANCE", "desc": "Built for public health departments to monitor outbreaks while protecting data privacy." } + ], + "image": "/images/projects/Trace.jpeg", + "links": { + "website": "https://veg.github.io/hivtrace-viz/", + "github": "https://github.com/veg/hivtrace" + } + }, + { + "id": "phylotree", + "name": "phylotree.js", + "class": "The Architect", + "description": "A modular JavaScript library for interactive phylogenetic tree visualization.", + "stats": { + "flexibility": 95, + "render_speed": 90, + "extensibility": 99, + "framework": "d3.js", + "license": "MIT" + }, + "powers": [ + { "name": "INTERACTIVE_MORPHING", "desc": "Allows users to manipulate, prune, and annotate trees dynamically in real-time." }, + { "name": "MIDDLEWARE_INTEGRATION", "desc": "Seamlessly plugs into larger web applications as a modular visualization core." } + ], + "image": "/images/projects/Phylotree.jpeg", + "links": { + "website": "http://phylotree.hyphy.org/", + "github": "https://github.com/veg/phylotree.js" + } + }, + { + "id": "tn93", + "name": "tn93", + "class": "The Blade", + "description": "High-speed C++ implementation for calculating Tamura-Nei 93 genetic distances.", + "stats": { + "velocity": 100, + "sharpness": 95, + "weight": "0.1 MB", + "language": "C++", + "usage": "Core Utility" + }, + "powers": [ + { "name": "INSTANT_METRIC", "desc": "Calculates pairwise distances between thousands of sequences in the blink of an eye." }, + { "name": "STREAMING_COMPUTE", "desc": "Designed to handle massive data streams with minimal memory overhead." } + ], + "links": { + "github": "https://github.com/veg/tn93" + } + } +] diff --git a/yarn-error.log b/yarn-error.log deleted file mode 100644 index ca91962..0000000 --- a/yarn-error.log +++ /dev/null @@ -1,7953 +0,0 @@ -Arguments: - /usr/local/Cellar/node/10.4.1/bin/node /usr/local/bin/yarn add upath==1.1.0 - -PATH: - /usr/local/opt/python/bin/:/usr/local/Cellar/tmux/2.3_3/bin:/usr/local/texlive/2016/bin/x86_64-darwin/:/Users/sweaver/bin:/usr/local/bin:/usr/local/bin:/usr/bin:/bin:/usr/sbin:/sbin:/opt/X11/bin:/Library/TeX/texbin:/usr/local/opt/python/bin/:/usr/local/Cellar/tmux/2.3_3/bin:/usr/local/texlive/2016/bin/x86_64-darwin/:/Users/sweaver/bin - -Yarn version: - 0.24.6 - -Node version: - 10.4.1 - -Platform: - darwin x64 - -npm manifest: - { - "name": "LabSite", - "version": "0.1.0", - "private": true, - "dependencies": { - "babel": "^6.23.0", - "babel-loader": "^7.1.4", - "babel-preset-es2015": "^6.24.1", - "babel-preset-react": "^6.24.1", - "babel-preset-stage-1": "^6.24.1", - "bootstrap": "^4.1.0", - "express": "^4.16.3", - "font-awesome": "4.x", - "react": "^16.3.1", - "react-dom": "^16.3.1", - "react-router": "^4.2.0", - "react-scripts": "1.1.4", - "reactstrap": "^5.0.0", - "supervisor": "^0.12.0" - }, - "scripts": { - "start": "react-scripts start", - "build": "react-scripts build", - "test": "react-scripts test --env=jsdom", - "eject": "react-scripts eject" - } - } - -yarn manifest: - No manifest - -Lockfile: - # THIS IS AN AUTOGENERATED FILE. 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