{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T16:21:53Z","timestamp":1775924513161,"version":"3.50.1"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"Supplement_2","license":[{"start":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T00:00:00Z","timestamp":1609372800000},"content-version":"vor","delay-in-days":30,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000001","name":"NSF","doi-asserted-by":"publisher","award":["DBI 1356548"],"award-info":[{"award-number":["DBI 1356548"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM126567-03"],"award-info":[{"award-number":["R01GM126567-03"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000104","name":"National Aeronautics and Space Administration","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000104","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000104","name":"NASA","doi-asserted-by":"publisher","award":["NNX16AJ30G"],"award-info":[{"award-number":["NNX16AJ30G"]}],"id":[{"id":"10.13039\/100000104","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,12,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>As the number and diversity of species and genes grow in contemporary datasets, two common assumptions made in all molecular dating methods, namely the time-reversibility and stationarity of the substitution process, become untenable. No software tools for molecular dating allow researchers to relax these two assumptions in their data analyses. Frequently the same General Time Reversible (GTR) model across lineages along with a gamma (+\u0393) distributed rates across sites is used in relaxed clock analyses, which assumes time-reversibility and stationarity of the substitution process. Many reports have quantified the impact of violations of these underlying assumptions on molecular phylogeny, but none have systematically analyzed their impact on divergence time estimates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We quantified the bias on time estimates that resulted from using the GTR\u2009+\u2009\u0393 model for the analysis of computer-simulated nucleotide sequence alignments that were evolved with non-stationary (NS) and non-reversible (NR) substitution models. We tested Bayesian and RelTime approaches that do not require a molecular clock for estimating divergence times. Divergence times obtained using a GTR\u2009+\u2009\u0393 model differed only slightly (\u223c3% on average) from the expected times for NR datasets, but the difference was larger for NS datasets (\u223c10% on average). The use of only a few calibrations reduced these biases considerably (\u223c5%). Confidence and credibility intervals from GTR\u2009+\u2009\u0393 analysis usually contained correct times. Therefore, the bias introduced by the use of the GTR\u2009+\u2009\u0393 model to analyze datasets, in which the time-reversibility and stationarity assumptions are violated, is likely not large and can be reduced by applying multiple calibrations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>All datasets are deposited in Figshare: https:\/\/doi.org\/10.6084\/m9.figshare.12594638.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaa820","type":"journal-article","created":{"date-parts":[[2020,9,7]],"date-time":"2020-09-07T15:14:50Z","timestamp":1599491690000},"page":"i884-i894","source":"Crossref","is-referenced-by-count":16,"title":["Using a GTR+\u0393 substitution model for dating sequence divergence when stationarity and time-reversibility assumptions are violated"],"prefix":"10.1093","volume":"36","author":[{"given":"Jose","family":"Barba-Montoya","sequence":"first","affiliation":[{"name":"Institute for Genomics and Evolutionary Medicine"},{"name":"Department of Biology, Temple University , Philadelphia, PA 19122, USA"}]},{"given":"Qiqing","family":"Tao","sequence":"additional","affiliation":[{"name":"Institute for Genomics and Evolutionary Medicine"},{"name":"Department of Biology, Temple University , Philadelphia, PA 19122, USA"}]},{"given":"Sudhir","family":"Kumar","sequence":"additional","affiliation":[{"name":"Institute for Genomics and Evolutionary Medicine"},{"name":"Department of Biology, Temple University , Philadelphia, PA 19122, USA"},{"name":"Center for Excellence in Genome Medicine and Research, King Abdulaziz University , Jeddah 21589, Saudi Arabia"}]}],"member":"286","published-online":{"date-parts":[[2020,12,29]]},"reference":[{"key":"2023062504244825400_btaa820-B1","doi-asserted-by":"crossref","first-page":"319","DOI":"10.3389\/fgene.2015.00319","article-title":"Trends in substitution models of molecular evolution","volume":"6","author":"Arenas","year":"2015","journal-title":"Front. Genet"},{"key":"2023062504244825400_btaa820-B2","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1093\/molbev\/msl091","article-title":"A Bayesian compound stochastic process for modeling non-stationary and non-homogeneous sequence evolution","volume":"23","author":"Blanquart","year":"2006","journal-title":"Mol. Biol. Evol"},{"key":"2023062504244825400_btaa820-B3","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1093\/molbev\/msn018","article-title":"A site- and time-heterogeneous model of amino acid replacement","volume":"25","author":"Blanquart","year":"2008","journal-title":"Mol. Biol. Evol"},{"key":"2023062504244825400_btaa820-B4","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1093\/molbev\/msr045","article-title":"Approximate likelihood calculation on a phylogeny for Bayesian Estimation of Divergence Times","volume":"28","author":"dos Reis","year":"2011","journal-title":"Mol. Biol. Evol"},{"key":"2023062504244825400_btaa820-B5","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1093\/molbev\/msp098","article-title":"INDELible: a flexible simulator of biological sequence evolution","volume":"26","author":"Fletcher","year":"2009","journal-title":"Mol. Biol. Evol"},{"key":"2023062504244825400_btaa820-B6","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1080\/10635150490445779","article-title":"Modeling compositional heterogeneity","volume":"53","author":"Foster","year":"2004","journal-title":"Syst. Biol"},{"key":"2023062504244825400_btaa820-B7","doi-asserted-by":"crossref","first-page":"171780","DOI":"10.1098\/rsos.171780","article-title":"The polyphyly of Plasmodium: comprehensive phylogenetic analyses of the malaria parasites (Order Haemosporida) reveal widespread taxonomic conflict","volume":"5","author":"Galen","year":"2018","journal-title":"R. Soc. Open Sci"},{"key":"2023062504244825400_btaa820-B8","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1093\/oxfordjournals.molbev.a025991","article-title":"Inferring pattern and process: maximum-likelihood implementation of a non-homogeneous model of DNA sequence evolution for phylogenetic analysis","volume":"15","author":"Galtier","year":"1998","journal-title":"Mol. Biol. Evol"},{"key":"2023062504244825400_btaa820-B9","doi-asserted-by":"crossref","first-page":"11317","DOI":"10.1073\/pnas.92.24.11317","article-title":"Inferring phylogenies from DNA sequences of\u00a0unequal base compositions","volume":"92","author":"Galtier","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023062504244825400_btaa820-B10","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1007\/BF02101694","article-title":"Dating of the human-ape splitting by a molecular clock of mitochondrial DNA","volume":"22","author":"Hasegawa","year":"1985","journal-title":"J. Mol. Evol"},{"key":"2023062504244825400_btaa820-B11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1093\/oso\/9780199535033.003.0001","volume-title":"The Timetree of Life,","author":"Hedges","year":"2009"},{"key":"2023062504244825400_btaa820-B12","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1093\/sysbio\/syq047","article-title":"Sources of error inherent in species-tree estimation: impact of mutational and coalescent effects on accuracy and implications for choosing among different methods","volume":"59","author":"Huang","year":"2010","journal-title":"Syst. Biol"},{"key":"2023062504244825400_btaa820-B13","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1093\/sysbio\/syq076","article-title":"Two stationary non-homogeneous Markov models of nucleotide sequence evolution","volume":"60","author":"Jayaswal","year":"2011","journal-title":"Syst. Biol"},{"key":"2023062504244825400_btaa820-B14","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/BF01731581","article-title":"A simple method for estimating evolutionary rate of base substitution through comparative studies of nucleotide sequences","volume":"16","author":"Kimura","year":"1980","journal-title":"J. Mol. Evol"},{"key":"2023062504244825400_btaa820-B15","doi-asserted-by":"crossref","first-page":"2685","DOI":"10.1093\/bioinformatics\/bts507","article-title":"MEGA-CC: computing core of molecular evolutionary genetics analysis program for automated and iterative data analysis","volume":"28","author":"Kumar","year":"2012","journal-title":"Bioinformatics"},{"key":"2023062504244825400_btaa820-B16","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1093\/molbev\/msy096","article-title":"MEGA X: molecular evolutionary genetics analysis across computing platforms","volume":"35","author":"Kumar","year":"2018","journal-title":"Mol. Biol. Evol"},{"key":"2023062504244825400_btaa820-B17","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1093\/genetics\/158.3.1321","article-title":"Disparity index: a simple statistic to measure and test the homogeneity of substitution patterns between molecular sequences","volume":"158","author":"Kumar","year":"2001","journal-title":"Genetics"},{"key":"2023062504244825400_btaa820-B18","first-page":"605","article-title":"Recovering evolutionary trees under a more realistic model of sequence evolution","volume":"11","author":"Lockhart","year":"1994","journal-title":"Mol. Biol. Evol"},{"key":"2023062504244825400_btaa820-B19","doi-asserted-by":"crossref","DOI":"10.1093\/oso\/9780195135848.001.0001","volume-title":"Molecular Evolution and Phylogenetics","author":"Nei","year":"2000"},{"key":"2023062504244825400_btaa820-B20","first-page":"1","article-title":"Pitfalls in supermatrix phylogenomics","volume":"2017","author":"Philippe","year":"2017","journal-title":"Eur. J. Taxon"},{"key":"2023062504244825400_btaa820-B21","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1080\/10635150701420643","article-title":"Inferring speciation times under an episodic molecular clock","volume":"56","author":"Rannala","year":"2007","journal-title":"Syst. Biol"},{"key":"2023062504244825400_btaa820-B22","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1093\/molbev\/msg067","article-title":"Heterogeneity of nucleotide frequencies among evolutionary lineages and phylogenetic inference","volume":"20","author":"Rosenberg","year":"2003","journal-title":"Mol. Biol. Evol"},{"key":"2023062504244825400_btaa820-B23","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1093\/molbev\/msp071","article-title":"Strong evidence for lineage and sequence specificity of\u00a0substitution rates and patterns in Drosophila","volume":"26","author":"Singh","year":"2009","journal-title":"Mol. Biol. Evol"},{"key":"2023062504244825400_btaa820-B24","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1093\/bioinformatics\/btu033","article-title":"RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies","volume":"30","author":"Stamatakis","year":"2014","journal-title":"Bioinformatics"},{"key":"2023062504244825400_btaa820-B25","doi-asserted-by":"crossref","first-page":"19333","DOI":"10.1073\/pnas.1213199109","article-title":"Estimating divergence times in large molecular phylogenies","volume":"109","author":"Tamura","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023062504244825400_btaa820-B26","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1093\/oxfordjournals.molbev.a003995","article-title":"Evolutionary distance estimation under heterogeneous substitution pattern among lineages","volume":"19","author":"Tamura","year":"2002","journal-title":"Mol. Biol. Evol"},{"key":"2023062504244825400_btaa820-B27","first-page":"512","article-title":"Estimation of the number of nucleotide substitutions in the control region of mitochondrial DNA in humans and chimpanzees","volume":"10","author":"Tamura","year":"1993","journal-title":"Mol. Biol. Evol"},{"key":"2023062504244825400_btaa820-B28","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1093\/molbev\/msz014","article-title":"A Machine Learning Method for Detecting Autocorrelation of Evolutionary Rates in Large Phylogenies","volume":"36","author":"Tao","year":"2019","journal-title":"Molecular Biology and Evolution"},{"key":"2023062504244825400_btaa820-B29","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1093\/molbev\/msaa049","article-title":"Relative efficiencies of simple and complex substitution models in estimating divergence times in phylogenomics","volume":"37","author":"et","year":"2020","journal-title":"Evol. Biol"},{"key":"2023062504244825400_btaa820-B30","first-page":"57","article-title":"Some probabilistic and statistical problems in the analysis of DNA sequences","volume":"17","author":"Tavar\u00e9","year":"1986","journal-title":"Am. Math. Soc. Lect. Math. Life Sci"},{"key":"2023062504244825400_btaa820-B31","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1093\/oxfordjournals.molbev.a025892","article-title":"Estimating the rate of evolution of the rate of molecular evolution","volume":"15","author":"Thorne","year":"1998","journal-title":"Mol. Biol. Evol"},{"key":"2023062504244825400_btaa820-B32","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/BF00178256","article-title":"Estimating the Pattern of Nucleotide Substitution","volume":"39","author":"Yang","year":"1994","journal-title":"J. Mol. Evol"},{"key":"2023062504244825400_btaa820-B33","doi-asserted-by":"crossref","DOI":"10.1093\/acprof:oso\/9780199602605.001.0001","volume-title":"Molecular Evolution: A Statistical Approach.","author":"Yang","year":"2014"},{"key":"2023062504244825400_btaa820-B34","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1093\/molbev\/msm088","article-title":"PAML 4: phylogenetic analysis by maximum likelihood","volume":"24","author":"Yang","year":"2007","journal-title":"Mol. Biol. Evol"},{"key":"2023062504244825400_btaa820-B35","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1093\/molbev\/msj024","article-title":"Bayesian estimation of species divergence times under a molecular clock using multiple fossil calibrations with soft bounds","volume":"23","author":"Yang","year":"2006","journal-title":"Mol. Biol. Evol"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/Supplement_2\/i884\/50693510\/btaa820.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/Supplement_2\/i884\/50693510\/btaa820.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T05:31:47Z","timestamp":1723527107000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/36\/Supplement_2\/i884\/6055914"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12]]},"references-count":35,"journal-issue":{"issue":"Supplement_2","published-print":{"date-parts":[[2020,12,30]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btaa820","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.07.09.195487","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":[[2020,12]]},"published":{"date-parts":[[2020,12]]}}}