PHYRN: A Robust Method for Phylogenetic Analysis of Highly Divergent Sequences
Identifieur interne : 000477 ( Main/Merge ); précédent : 000476; suivant : 000478PHYRN: A Robust Method for Phylogenetic Analysis of Highly Divergent Sequences
Auteurs : Gaurav Bhardwaj [États-Unis] ; Kyung Dae Ko [États-Unis] ; Yoojin Hong [États-Unis] ; Zhenhai Zhang [États-Unis] ; Ngai Lam Ho [États-Unis] ; Sree V. Chintapalli [États-Unis] ; Lindsay A. Kline [États-Unis] ; Matthew Gotlin [États-Unis] ; David Nicholas Hartranft [États-Unis] ; Morgen E. Patterson [États-Unis] ; Foram Dave [États-Unis] ; Evan J. Smith [États-Unis] ; Edward C. Holmes [États-Unis] ; Randen L. Patterson [États-Unis] ; Damian B. Van Rossum [États-Unis]Source :
- PLoS ONE [ 1932-6203 ] ; 2012.
Abstract
Both multiple sequence alignment and phylogenetic analysis are problematic in the “twilight zone” of sequence similarity (≤25% amino acid identity). Herein we explore the accuracy of phylogenetic inference at extreme sequence divergence using a variety of simulated data sets. We evaluate four leading multiple sequence alignment (MSA) methods (MAFFT, T-COFFEE, CLUSTAL, and MUSCLE) and six commonly used programs of tree estimation (Distance-based: Neighbor-Joining; Character-based: PhyML, RAxML, GARLI, Maximum Parsimony, and Bayesian) against a novel MSA-independent method (PHYRN) described here. Strikingly, at “midnight zone” genetic distances (∼7% pairwise identity and 4.0 gaps per position), PHYRN returns high-resolution phylogenies that outperform traditional approaches. We reason this is due to PHRYN's capability to amplify informative positions, even at the most extreme levels of sequence divergence. We also assess the applicability of the PHYRN algorithm for inferring deep evolutionary relationships in the divergent DANGER protein superfamily, for which PHYRN infers a more robust tree compared to MSA-based approaches. Taken together, these results demonstrate that PHYRN represents a powerful mechanism for mapping uncharted frontiers in highly divergent protein sequence data sets.
Url:
DOI: 10.1371/journal.pone.0034261
PubMed: 22514627
PubMed Central: 3325999
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PMC:3325999Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">PHYRN: A Robust Method for Phylogenetic Analysis of Highly Divergent Sequences</title>
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff6"><addr-line>Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff8"><addr-line>Center for Translational Bioscience and Computing, University of California Davis, Davis, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Translational Bioscience and Computing, University of California Davis, Davis, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ko, Kyung Dae" sort="Ko, Kyung Dae" uniqKey="Ko K" first="Kyung Dae" last="Ko">Kyung Dae Ko</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
</author>
<author><name sortKey="Hong, Yoojin" sort="Hong, Yoojin" uniqKey="Hong Y" first="Yoojin" last="Hong">Yoojin Hong</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff3"><addr-line>Department of Computer Science and Engineering, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Computer Science and Engineering, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
</author>
<author><name sortKey="Zhang, Zhenhai" sort="Zhang, Zhenhai" uniqKey="Zhang Z" first="Zhenhai" last="Zhang">Zhenhai Zhang</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff4"><addr-line>Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
</author>
<author><name sortKey="Ho, Ngai Lam" sort="Ho, Ngai Lam" uniqKey="Ho N" first="Ngai Lam" last="Ho">Ngai Lam Ho</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff3"><addr-line>Department of Computer Science and Engineering, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Computer Science and Engineering, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
</author>
<author><name sortKey="Chintapalli, Sree V" sort="Chintapalli, Sree V" uniqKey="Chintapalli S" first="Sree V." last="Chintapalli">Sree V. Chintapalli</name>
<affiliation wicri:level="2"><nlm:aff id="aff7"><addr-line>Department of Physiology and Membrane Biology, School of Medicine, University of California Davis, Davis, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Physiology and Membrane Biology, School of Medicine, University of California Davis, Davis, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff8"><addr-line>Center for Translational Bioscience and Computing, University of California Davis, Davis, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Translational Bioscience and Computing, University of California Davis, Davis, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kline, Lindsay A" sort="Kline, Lindsay A" uniqKey="Kline L" first="Lindsay A." last="Kline">Lindsay A. Kline</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
</author>
<author><name sortKey="Gotlin, Matthew" sort="Gotlin, Matthew" uniqKey="Gotlin M" first="Matthew" last="Gotlin">Matthew Gotlin</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
</author>
<author><name sortKey="Hartranft, David Nicholas" sort="Hartranft, David Nicholas" uniqKey="Hartranft D" first="David Nicholas" last="Hartranft">David Nicholas Hartranft</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
</author>
<author><name sortKey="Patterson, Morgen E" sort="Patterson, Morgen E" uniqKey="Patterson M" first="Morgen E." last="Patterson">Morgen E. Patterson</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
</author>
<author><name sortKey="Dave, Foram" sort="Dave, Foram" uniqKey="Dave F" first="Foram" last="Dave">Foram Dave</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
</author>
<author><name sortKey="Smith, Evan J" sort="Smith, Evan J" uniqKey="Smith E" first="Evan J." last="Smith">Evan J. Smith</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
</author>
<author><name sortKey="Holmes, Edward C" sort="Holmes, Edward C" uniqKey="Holmes E" first="Edward C." last="Holmes">Edward C. Holmes</name>
<affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff5"><addr-line>Fogarty International Center, National Institutes of Health, Bethesda, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Fogarty International Center, National Institutes of Health, Bethesda, Maryland</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Patterson, Randen L" sort="Patterson, Randen L" uniqKey="Patterson R" first="Randen L." last="Patterson">Randen L. Patterson</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff6"><addr-line>Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff7"><addr-line>Department of Physiology and Membrane Biology, School of Medicine, University of California Davis, Davis, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Physiology and Membrane Biology, School of Medicine, University of California Davis, Davis, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff8"><addr-line>Center for Translational Bioscience and Computing, University of California Davis, Davis, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Translational Bioscience and Computing, University of California Davis, Davis, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Van Rossum, Damian B" sort="Van Rossum, Damian B" uniqKey="Van Rossum D" first="Damian B." last="Van Rossum">Damian B. Van Rossum</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Computational Proteomics, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biology, The Pennsylvania State University, University Park, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">University Park (Pennsylvanie)</settlement>
</placeName>
<orgName type="university">Université d'État de Pennsylvanie</orgName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff8"><addr-line>Center for Translational Bioscience and Computing, University of California Davis, Davis, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Translational Bioscience and Computing, University of California Davis, Davis, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">PLoS ONE</title>
<idno type="eISSN">1932-6203</idno>
<imprint><date when="2012">2012</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Both multiple sequence alignment and phylogenetic analysis are problematic in the “twilight zone” of sequence similarity (≤25% amino acid identity). Herein we explore the accuracy of phylogenetic inference at extreme sequence divergence using a variety of simulated data sets. We evaluate four leading multiple sequence alignment (MSA) methods (MAFFT, T-COFFEE, CLUSTAL, and MUSCLE) and six commonly used programs of tree estimation (Distance-based: Neighbor-Joining; Character-based: PhyML, RAxML, GARLI, Maximum Parsimony, and Bayesian) against a novel MSA-independent method (PHYRN) described here. Strikingly, at “midnight zone” genetic distances (∼7% pairwise identity and 4.0 gaps per position), PHYRN returns high-resolution phylogenies that outperform traditional approaches. We reason this is due to PHRYN's capability to amplify informative positions, even at the most extreme levels of sequence divergence. We also assess the applicability of the PHYRN algorithm for inferring deep evolutionary relationships in the divergent DANGER protein superfamily, for which PHYRN infers a more robust tree compared to MSA-based approaches. Taken together, these results demonstrate that PHYRN represents a powerful mechanism for mapping uncharted frontiers in highly divergent protein sequence data sets.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Blake, Jd" uniqKey="Blake J">JD Blake</name>
</author>
<author><name sortKey="Cohen, Fe" uniqKey="Cohen F">FE Cohen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Yona, G" uniqKey="Yona G">G Yona</name>
</author>
<author><name sortKey="Levitt, M" uniqKey="Levitt M">M Levitt</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ko, Kd" uniqKey="Ko K">KD Ko</name>
</author>
<author><name sortKey="Hong, Y" uniqKey="Hong Y">Y Hong</name>
</author>
<author><name sortKey="Chang, Gs" uniqKey="Chang G">GS Chang</name>
</author>
<author><name sortKey="Bhardwaj, G" uniqKey="Bhardwaj G">G Bhardwaj</name>
</author>
<author><name sortKey="Van Rossum, Db" uniqKey="Van Rossum D">DB van Rossum</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Liu, K" uniqKey="Liu K">K Liu</name>
</author>
<author><name sortKey="Linder, Cr" uniqKey="Linder C">CR Linder</name>
</author>
<author><name sortKey="Warnow, T" uniqKey="Warnow T">T Warnow</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Edgar, Rc" uniqKey="Edgar R">RC Edgar</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Roch, S" uniqKey="Roch S">S Roch</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bergsten, J" uniqKey="Bergsten J">J Bergsten</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Chang, Gs" uniqKey="Chang G">GS Chang</name>
</author>
<author><name sortKey="Hong, Y" uniqKey="Hong Y">Y Hong</name>
</author>
<author><name sortKey="Ko, Kd" uniqKey="Ko K">KD Ko</name>
</author>
<author><name sortKey="Bhardwaj, G" uniqKey="Bhardwaj G">G Bhardwaj</name>
</author>
<author><name sortKey="Holmes, Ec" uniqKey="Holmes E">EC Holmes</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ko, Kd" uniqKey="Ko K">KD Ko</name>
</author>
<author><name sortKey="Hong, Y" uniqKey="Hong Y">Y Hong</name>
</author>
<author><name sortKey="Bhardwaj, G" uniqKey="Bhardwaj G">G Bhardwaj</name>
</author>
<author><name sortKey="Killick, Tm" uniqKey="Killick T">TM Killick</name>
</author>
<author><name sortKey="Van Rossum, Db" uniqKey="Van Rossum D">DB van Rossum</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bhardwaj, G" uniqKey="Bhardwaj G">G Bhardwaj</name>
</author>
<author><name sortKey="Zhang, Z" uniqKey="Zhang Z">Z Zhang</name>
</author>
<author><name sortKey="Hong, Y" uniqKey="Hong Y">Y Hong</name>
</author>
<author><name sortKey="Ko, Kd" uniqKey="Ko K">KD Ko</name>
</author>
<author><name sortKey="Chang, Gs" uniqKey="Chang G">GS Chang</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hong, Y" uniqKey="Hong Y">Y Hong</name>
</author>
<author><name sortKey="Lee, D" uniqKey="Lee D">D Lee</name>
</author>
<author><name sortKey="Kang, J" uniqKey="Kang J">J Kang</name>
</author>
<author><name sortKey="Van Rossum, Db" uniqKey="Van Rossum D">DB van Rossum</name>
</author>
<author><name sortKey="Patterson, Rl" uniqKey="Patterson R">RL Patterson</name>
</author>
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</biblStruct>
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