{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T09:12:30Z","timestamp":1778058750346,"version":"3.51.4"},"reference-count":21,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T00:00:00Z","timestamp":1648080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"U.S. National Science Foundation","doi-asserted-by":"crossref","award":["DEB-2034228"],"award-info":[{"award-number":["DEB-2034228"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000001","name":"U.S. National Science Foundation","doi-asserted-by":"crossref","award":["DBI-2027196"],"award-info":[{"award-number":["DBI-2027196"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"U.S. National Institutes of Health","doi-asserted-by":"crossref","award":["GM-139504"],"award-info":[{"award-number":["GM-139504"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"U.S. National Institutes of Health","doi-asserted-by":"crossref","award":["AI-134384"],"award-info":[{"award-number":["AI-134384"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"U.S. National Institutes of Health","doi-asserted-by":"crossref","award":["LM-014005"],"award-info":[{"award-number":["LM-014005"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,5,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\u00a0057 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>TopHap is available at https:\/\/github.com\/SayakaMiura\/TopHap.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Supplementary information<\/jats:title>\n                    <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btac186","type":"journal-article","created":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T16:13:00Z","timestamp":1648051980000},"page":"2719-2726","source":"Crossref","is-referenced-by-count":8,"title":["TopHap: rapid inference of key phylogenetic structures from common haplotypes in large genome collections with limited diversity"],"prefix":"10.1093","volume":"38","author":[{"given":"Marcos A","family":"Caraballo-Ortiz","sequence":"first","affiliation":[{"name":"Institute for Genomics and Evolutionary Medicine, Temple University , Philadelphia, PA 19122, USA"},{"name":"Department of Biology, Temple University , Philadelphia, PA 19122, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9881-2848","authenticated-orcid":false,"given":"Sayaka","family":"Miura","sequence":"additional","affiliation":[{"name":"Institute for Genomics and Evolutionary Medicine, Temple University , Philadelphia, PA 19122, USA"},{"name":"Department of Biology, Temple University , Philadelphia, PA 19122, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maxwell","family":"Sanderford","sequence":"additional","affiliation":[{"name":"Institute for Genomics and Evolutionary Medicine, Temple University , Philadelphia, PA 19122, USA"},{"name":"Department of Biology, Temple University , Philadelphia, PA 19122, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tenzin","family":"Dolker","sequence":"additional","affiliation":[{"name":"Institute for Genomics and Evolutionary Medicine, Temple University , Philadelphia, PA 19122, USA"},{"name":"Department of Biology, Temple University , Philadelphia, PA 19122, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7360-409X","authenticated-orcid":false,"given":"Qiqing","family":"Tao","sequence":"additional","affiliation":[{"name":"Institute for Genomics and Evolutionary Medicine, Temple University , Philadelphia, PA 19122, USA"},{"name":"Department of Biology, Temple University , Philadelphia, PA 19122, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6931-7191","authenticated-orcid":false,"given":"Steven","family":"Weaver","sequence":"additional","affiliation":[{"name":"Institute for Genomics and Evolutionary Medicine, Temple University , Philadelphia, PA 19122, USA"},{"name":"Department of Biology, Temple University , Philadelphia, PA 19122, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergei L K","family":"Pond","sequence":"additional","affiliation":[{"name":"Institute for Genomics and Evolutionary Medicine, Temple University , Philadelphia, PA 19122, USA"},{"name":"Department of Biology, Temple University , Philadelphia, PA 19122, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9918-8212","authenticated-orcid":false,"given":"Sudhir","family":"Kumar","sequence":"additional","affiliation":[{"name":"Institute for Genomics and Evolutionary Medicine, Temple University , Philadelphia, PA 19122, USA"},{"name":"Department of Biology, Temple University , Philadelphia, PA 19122, USA"},{"name":"Center of Excellence in Genomic Medicine Research, King Abdulaziz University , Jeddah, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,3,24]]},"reference":[{"key":"2023020109123706300_btac186-B1","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/s41591-020-0820-9","article-title":"The proximal origin of SARS-CoV-2","volume":"26","author":"Andersen","year":"2020","journal-title":"Nat. Med"},{"key":"2023020109123706300_btac186-B2","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1093\/sysbio\/syr010","article-title":"Performance, accuracy, and web server for evolutionary placement of short sequence reads under maximum likelihood","volume":"60","author":"Berger","year":"2011","journal-title":"Syst. Biol"},{"key":"2023020109123706300_btac186-B3","doi-asserted-by":"crossref","first-page":"5211","DOI":"10.1093\/molbev\/msab246","article-title":"Recovery of deleted deep sequencing data sheds more light on the early Wuhan SARS-CoV-2 epidemic","volume":"38","author":"Bloom","year":"2021","journal-title":"Mol. Biol. Evol"},{"key":"2023020109123706300_btac186-B4","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1093\/bioinformatics\/btq110","article-title":"DensiTree: making sense of sets of phylogenetic trees","volume":"26","author":"Bouckaert","year":"2010","journal-title":"Bioinformatics"},{"key":"2023020109123706300_btac186-B5","doi-asserted-by":"crossref","first-page":"783","DOI":"10.2307\/2408678","article-title":"Confidence limits on phylogenies: an approach using the bootstrap","volume":"39","author":"Felsenstein","year":"1985","journal-title":"Evolution"},{"key":"2023020109123706300_btac186-B6","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s13059-016-0936-x","article-title":"Tree inference for single-cell data","volume":"17","author":"Jahn","year":"2016","journal-title":"Genome Biol"},{"key":"2023020109123706300_btac186-B7","doi-asserted-by":"crossref","first-page":"4453","DOI":"10.1093\/bioinformatics\/btz305","article-title":"RAxML-NG: a fast, scalable and user-friendly tool for maximum likelihood phylogenetic inference","volume":"35","author":"Kozlov","year":"2019","journal-title":"Bioinformatics"},{"key":"2023020109123706300_btac186-B8","doi-asserted-by":"crossref","first-page":"3046","DOI":"10.1093\/molbev\/msab118","article-title":"An evolutionary portrait of the progenitor SARS-CoV-2 and its dominant offshoots in COVID-19 pandemic","volume":"38","author":"Kumar","year":"2021","journal-title":"Mol. Biol. Evol"},{"key":"2023020109123706300_btac186-B9","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1080\/106351501753462876","article-title":"A likelihood approach to estimating phylogeny from discrete morphological character data","volume":"50","author":"Lewis","year":"2001","journal-title":"Syst. Biol"},{"key":"2023020109123706300_btac186-B10","doi-asserted-by":"crossref","first-page":"e1008421","DOI":"10.1371\/journal.ppat.1008421","article-title":"Are pangolins the intermediate host of the 2019 novel coronavirus (SARS-CoV-2)?","volume":"16","author":"Liu","year":"2020","journal-title":"PLoS Pathog"},{"key":"2023020109123706300_btac186-B11","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1186\/1471-2105-11-538","article-title":"pplacer: linear time maximum-likelihood and Bayesian phylogenetic placement of sequences onto a fixed reference tree","volume":"11","author":"Matsen","year":"2010","journal-title":"BMC Bioinformatics"},{"key":"2023020109123706300_btac186-B12","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1093\/molbev\/msaa314","article-title":"Phylogenetic analysis of SARS-CoV-2 data is difficult","volume":"38","author":"Morel","year":"2021","journal-title":"Mol. Biol. Evol"},{"key":"2023020109123706300_btac186-B13","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1101\/gr.191098.115","article-title":"The first five years of single-cell cancer genomics and beyond","volume":"25","author":"Navin","year":"2015","journal-title":"Genome Res"},{"key":"2023020109123706300_btac186-B14","doi-asserted-by":"crossref","first-page":"198098","DOI":"10.1016\/j.virusres.2020.198098","article-title":"Phylogenetic and phylodynamic analyses of SARS-CoV-2","volume":"287","author":"Nie","year":"2020","journal-title":"Virus Res"},{"key":"2023020109123706300_btac186-B15","author":"Pekar","year":"2021"},{"key":"2023020109123706300_btac186-B16","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1093\/molbev\/msaa316","article-title":"Assessing uncertainty in the rooting of the SARS-CoV-2 phylogeny","volume":"38","author":"Pipes","year":"2021","journal-title":"Mol. Biol. Evol"},{"key":"2023020109123706300_btac186-B17","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1038\/s41564-020-0770-5","article-title":"A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology","volume":"5","author":"Rambaut","year":"2020","journal-title":"Nat. Microbiol"},{"key":"2023020109123706300_btac186-B18","doi-asserted-by":"crossref","first-page":"3022","DOI":"10.1093\/molbev\/msab120","article-title":"MEGA11: Molecular Evolutionary Genetics Analysis Version 11","volume":"38","author":"Tamura","year":"2021","journal-title":"Mol. Biol. Evol"},{"key":"2023020109123706300_btac186-B19","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1038\/s41588-021-00862-7","article-title":"Ultrafast Sample placement on Existing tRees (UShER) enables real-time phylogenetics for the SARS-CoV-2 pandemic","volume":"53","author":"Turakhia","year":"2021","journal-title":"Nat. Genet"},{"key":"2023020109123706300_btac186-B20","doi-asserted-by":"crossref","first-page":"104351","DOI":"10.1016\/j.meegid.2020.104351","article-title":"Emergence of genomic diversity and recurrent mutations in SARS-CoV-2","volume":"83","author":"van Dorp","year":"2020","journal-title":"Infect. Genet. Evol"},{"key":"2023020109123706300_btac186-B21","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-020-2012-7","article-title":"A pneumonia outbreak associated with a new coronavirus of probable bat origin","volume":"579","author":"Zhou","year":"2020","journal-title":"Nature"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btac186\/43293486\/btac186.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/38\/10\/2719\/49010590\/btac186.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/38\/10\/2719\/49010590\/btac186.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T16:05:56Z","timestamp":1675267556000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/38\/10\/2719\/6553661"}},"subtitle":[],"editor":[{"given":"Russell","family":"Schwartz","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,3,24]]},"references-count":21,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2022,5,13]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btac186","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.12.13.472454","asserted-by":"object"}]},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,5,15]]},"published":{"date-parts":[[2022,3,24]]}}}