{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T19:43:12Z","timestamp":1772653392207,"version":"3.50.1"},"reference-count":75,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["ACI-1429467, NSF RUI-1904797, and ACCESS\/BIO230145"],"award-info":[{"award-number":["ACI-1429467, NSF RUI-1904797, and ACCESS\/BIO230145"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001774","name":"New Jersey Health Foundation","doi-asserted-by":"publisher","award":["PC 76-24"],"award-info":[{"award-number":["PC 76-24"]}],"id":[{"id":"10.13039\/100001774","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    A definitive test to measure genome-wide fitness effects of any nucleotide mutation, including translated regions (\n                    <jats:italic>TRs<\/jats:italic>\n                    ) and untranslated regions (\n                    <jats:italic>UTRs<\/jats:italic>\n                    ), is essential to help resolve the decades-long neutralist\u2013selectionist debate regarding mutation-mediated species evolution. The precise boundary, composition, and abundance of nearly neutral mutations remain disputed, highlighting the need for a rigorous framework supported by empirical sequence data. Our substitution\u2013mutation rate ratio test (\n                    <jats:italic>c\/\u03bc<\/jats:italic>\n                    ) might provide such a framework.\n                    <jats:italic>c\/\u03bc<\/jats:italic>\n                    compares the ratio of how often mutations fix into the population (substitution rate,\n                    <jats:italic>c<\/jats:italic>\n                    ) with their expected arrival (mutation rate,\n                    <jats:italic>\u00b5<\/jats:italic>\n                    ), which classifies each mutation type (\n                    <jats:italic>c\/\u00b5<\/jats:italic>\n                    \u2009&gt;\u20091: adaptive;\n                    <jats:italic>c\/\u00b5<\/jats:italic>\n                    \u2009=\u20091: neutral;\n                    <jats:italic>c\/\u00b5<\/jats:italic>\n                    \u2009&lt;\u20091: deleterious). We previously showed that SARS-CoV-2 exhibits L-shaped distributions of fitness effects (\n                    <jats:italic>DFEs<\/jats:italic>\n                    ) and a strict molecular clock, and mutation type proportions consistent only with the Near-Neutral Balanced Selectionist Theory (\n                    <jats:italic>NNBST<\/jats:italic>\n                    ) and not with conventional molecular evolution theories. However, a theoretical explanation for incidences of non-strict clock behavior in several SARS-CoV-2 segments are not formalized. Here, we extended\n                    <jats:italic>c\/\u03bc<\/jats:italic>\n                    analysis to 49 segments of SARS-CoV-2 (26 TRs, 12 UTRs, and 10 transcriptional regulatory sequences (\n                    <jats:italic>TRSs<\/jats:italic>\n                    )) and provide formal, mathematical frameworks for our\n                    <jats:italic>NNBST<\/jats:italic>\n                    and Near-Neutral Unbalanced Selectionist Theory (\n                    <jats:italic>NNUST<\/jats:italic>\n                    ) to explain non-strict clock behavior. All 49 segments displayed L-shaped\n                    <jats:italic>DFEs<\/jats:italic>\n                    : 24 segments (mostly\n                    <jats:italic>TRs<\/jats:italic>\n                    ) supported molecular clocks and balanced effects of near neutral mutations, consistent with\n                    <jats:italic>NNBST<\/jats:italic>\n                    ; meanwhile, 25 segments (mostly\n                    <jats:italic>UTRs<\/jats:italic>\n                    \/\n                    <jats:italic>TRSs<\/jats:italic>\n                    ) did not support molecular clocks or balancing of near neutral mutations, consistent with\n                    <jats:italic>NNUST<\/jats:italic>\n                    . Numerous violations of Selectionist Theory (\n                    <jats:italic>ST)<\/jats:italic>\n                    , Kimura\u2019s Neutral Theory (\n                    <jats:italic>KNT)<\/jats:italic>\n                    , and Ohta\u2019s Nearly Neutral Theory (\n                    <jats:italic>ONNT)<\/jats:italic>\n                    were observed, but none for\n                    <jats:italic>NNBST<\/jats:italic>\n                    or\n                    <jats:italic>NNUST.<\/jats:italic>\n                    Together, these results support a unified Near-Neutral Selectionist Theory (\n                    <jats:italic>NNST<\/jats:italic>\n                    ), combining neutral and selectionist perspectives to better explain the molecular evolution of SARS-CoV-2.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0343410","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T18:40:51Z","timestamp":1772649651000},"page":"e0343410","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Near Neutral Selectionist Theories (NNST) for SARS-CoV-2 suggested by the substitution-mutation ratio (c\/\u00b5) analysis"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0176-3873","authenticated-orcid":true,"given":"Chun","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4402-7315","authenticated-orcid":true,"given":"Nicholas J.","family":"Paradis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"issue":"1","key":"pone.0343410.ref001","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1111\/brv.13010","article-title":"Moderating the neutralist-selectionist debate: exactly which propositions are we debating, and which arguments are valid?","volume":"99","author":"MJ de Jong","year":"2024","journal-title":"Biol Rev Camb Philos Soc"},{"issue":"3934","key":"pone.0343410.ref002","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1126\/science.168.3934.1009","article-title":"Darwinian evolution of proteins","volume":"168","author":"B Clarke","year":"1970","journal-title":"Science"},{"issue":"3","key":"pone.0343410.ref003","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/nrg1020","article-title":"The modern molecular clock","volume":"4","author":"L Bromham","year":"2003","journal-title":"Nat Rev Genet"},{"issue":"24","key":"pone.0343410.ref004","doi-asserted-by":"crossref","first-page":"10015","DOI":"10.1073\/pnas.87.24.10015","article-title":"Molecular clock of viral evolution, and the neutral theory","volume":"87","author":"T Gojobori","year":"1990","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5129","key":"pone.0343410.ref005","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1038\/217624a0","article-title":"Evolutionary rate at the molecular level","volume":"217","author":"M Kimura","year":"1968","journal-title":"Nature"},{"key":"pone.0343410.ref006","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9780511623486","volume-title":"The neutral theory of molecular evolution","author":"M Kimura","year":"1983"},{"issue":"4","key":"pone.0343410.ref007","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1266\/jjg.66.367","article-title":"The neutral theory of molecular evolution: a review of recent evidence","volume":"66","author":"M Kimura","year":"1991","journal-title":"Jpn J Genet"},{"issue":"25","key":"pone.0343410.ref008","doi-asserted-by":"crossref","first-page":"16134","DOI":"10.1073\/pnas.252626899","article-title":"Near-neutrality in evolution of genes and gene regulation","volume":"99","author":"T Ohta","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5428","key":"pone.0343410.ref009","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/246096a0","article-title":"Slightly deleterious mutant substitutions in evolution","volume":"246","author":"T Ohta","year":"1973","journal-title":"Nature"},{"issue":"1","key":"pone.0343410.ref010","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1017\/S0016672300014245","article-title":"Fixation probability of a mutant influenced by random fluctuation of selection intensity","volume":"19","author":"T Ohta","year":"1972","journal-title":"Genet Res"},{"issue":"1","key":"pone.0343410.ref011","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1093\/genetics\/126.1.219","article-title":"Theoretical study of near neutrality. 1. 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