{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:53:14Z","timestamp":1792090394917,"version":"4.4.0"},"reference-count":79,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T00:00:00Z","timestamp":1623801600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Natural Sciences and Engineering Research Council (NSERC) of Canada to R.K","award":["RGPIN-2019-05622"],"award-info":[{"award-number":["RGPIN-2019-05622"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Synonymous mutations are often assumed to be neutral with respect to fitness because they do not alter the encoded amino acid and so cannot be \u201cseen\u201d by natural selection. Yet a growing body of evidence suggests that synonymous mutations can have fitness effects that drive adaptive evolution through their impacts on gene expression and protein folding. Here, we review what microbial experiments have taught us about the contribution of synonymous mutations to adaptation. A survey of site-directed mutagenesis experiments reveals the distributions of fitness effects for nonsynonymous and synonymous mutations are more similar, especially for beneficial mutations, than expected if all synonymous mutations were neutral, suggesting they should drive adaptive evolution more often than is typically observed. A review of experimental evolution studies where synonymous mutations have contributed to adaptation shows they can impact fitness through a range of mechanisms including the creation of illicit RNA polymerase binding sites impacting transcription and changes to mRNA folding stability that modulate translation. We suggest that clonal interference in evolving microbial populations may be the reason synonymous mutations play a smaller role in adaptive evolution than expected based on their observed fitness effects. We finish by discussing the impacts of falsely assuming synonymous mutations are neutral and discuss directions for future work exploring the role of synonymous mutations in adaptive evolution.<\/jats:p>","DOI":"10.1093\/gbe\/evab141","type":"journal-article","created":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T19:12:52Z","timestamp":1623784372000},"source":"Crossref","is-referenced-by-count":135,"title":["Effects of Synonymous Mutations beyond Codon Bias: The Evidence for Adaptive Synonymous Substitutions from Microbial Evolution Experiments"],"prefix":"10.1093","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2294-1229","authenticated-orcid":false,"given":"Susan F","family":"Bailey","sequence":"first","affiliation":[{"name":"Department of Biology, Clarkson University, Potsdam, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5600-9552","authenticated-orcid":false,"given":"Luz Angela","family":"Alonso Morales","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Ottawa, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rees","family":"Kassen","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Ottawa, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,16]]},"reference":[{"issue":"6","key":"2021090203311297700_evab141-B1","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1093\/molbev\/msw035","article-title":"Large-effect beneficial synonymous mutations mediate rapid and parallel adaptation in a bacterium","volume":"33","author":"Agashe","year":"2016","journal-title":"Mol Biol Evol"},{"issue":"3","key":"2021090203311297700_evab141-B2","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1093\/molbev\/mss273","article-title":"Good codons, bad transcript: large reductions in gene expression and fitness arising from synonymous mutations in a key enzyme","volume":"30","author":"Agashe","year":"2013","journal-title":"Mol Biol Evol"},{"issue":"9","key":"2021090203311297700_evab141-B3","doi-asserted-by":"crossref","first-page":"2141","DOI":"10.1093\/molbev\/msq103","article-title":"Evolution in regulatory regions rapidly compensates the cost of nonoptimal codon usage","volume":"27","author":"Amor\u00f3s-Moya","year":"2010","journal-title":"Mol Biol Evol"},{"issue":"2","key":"2021090203311297700_evab141-B4","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1128\/mr.54.2.198-210.1990","article-title":"Codon preferences in free-living microorganisms","volume":"54","author":"Andersson","year":"1990","journal-title":"Microbiol Rev"},{"issue":"3","key":"2021090203311297700_evab141-B5","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1111\/mmi.12476","article-title":"A silent mutation in mabA confers isoniazid resistance on Mycobacterium tuberculosis","volume":"91","author":"Ando","year":"2014","journal-title":"Mol Microbiol"},{"issue":"1","key":"2021090203311297700_evab141-B6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/bies.201600176","article-title":"What drives parallel evolution? 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