{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:06:00Z","timestamp":1792598760346,"version":"4.5.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2000,5,1]],"date-time":"2000-05-01T00:00:00Z","timestamp":957139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2000,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Comparison of relative fixation rates of synonymous (silent) and nonsynonymous (amino acid-altering) mutations provides a means for understanding the mechanisms of molecular sequence evolution. The nonsynonymous\/synonymous rate ratio (\u03c9 = dN\/dS) is an important indicator of selective pressure at the protein level, with \u03c9 = 1 meaning neutral mutations, \u03c9 &amp;lt; 1 purifying selection, and \u03c9 &amp;gt; 1 diversifying positive selection. Amino acid sites in a protein are expected to be under different selective pressures and have different underlying \u03c9 ratios. We develop models that account for heterogeneous \u03c9 ratios among amino acid sites and apply them to phylogenetic analyses of protein-coding DNA sequences. These models are useful for testing for adaptive molecular evolution and identifying amino acid sites under diversifying selection. Ten data sets of genes from nuclear, mitochondrial, and viral genomes are analyzed to estimate the distributions of \u03c9 among sites. In all data sets analyzed, the selective pressure indicated by the \u03c9 ratio is found to be highly heterogeneous among sites. Previously unsuspected Darwinian selection is detected in several genes in which the average \u03c9 ratio across sites is &amp;lt;1, but in which some sites are clearly under diversifying selection with \u03c9 &amp;gt; 1. Genes undergoing positive selection include the \u03b2-globin gene from vertebrates, mitochondrial protein-coding genes from hominoids, the hemagglutinin (HA) gene from human influenza virus A, and HIV-1 env, vif, and pol genes. Tests for the presence of positively selected sites and their subsequent identification appear quite robust to the specific distributional form assumed for \u03c9 and can be achieved using any of several models we implement. However, we encountered difficulties in estimating the precise distribution of \u03c9 among sites from real data sets.<\/jats:p>","DOI":"10.1093\/genetics\/155.1.431","type":"journal-article","created":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T23:12:03Z","timestamp":1619565123000},"page":"431-449","source":"Crossref","is-referenced-by-count":1944,"title":["Codon-Substitution Models for Heterogeneous Selection Pressure at Amino Acid Sites"],"prefix":"10.1093","volume":"155","author":[{"given":"Ziheng","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Biology, University College London, London NW1 2HE, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasmus","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Goldman","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Cambridge, Cambridge CB2 3EH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Mette Krabbe","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Department of Ecology and Genetics, University of \u00c5rhus, Ny Munkegade, DK-8000 \u00c5rhus C, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2000,5,1]]},"reference":[{"key":"2022010405072625700_R1","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1109\/TAC.1974.1100705","article-title":"A new look at the statistical model identification","volume":"19","author":"Akaike","year":"1974","journal-title":"IEEE Trans. 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