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By the analysis of close to 200,000 genomes we show that the patterns of the SARS-CoV-2 virus mutations along its genome are closely correlated with the structural and functional features of the encoded proteins. Requirements of foldability of proteins\u2019 3D structures and the conservation of their key functional regions, such as protein-protein interaction interfaces, are the dominant factors driving evolutionary selection in protein-coding genes. At the same time, avoidance of the host immunity leads to the abundance of mutations in other regions, resulting in high variability of the missense mutation rate along the genome. \u201cUnexplained\u201d peaks and valleys in the mutation rate provide hints on function for yet uncharacterized genomic regions and specific protein structural and functional features they code for. Some of these observations have immediate practical implications for the selection of target regions for PCR-based COVID-19 tests and for evaluating the risk of mutations in epitopes targeted by specific antibodies and vaccine design strategies.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009147","type":"journal-article","created":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T13:37:02Z","timestamp":1625751422000},"page":"e1009147","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":39,"title":["The interplay of SARS-CoV-2 evolution and constraints imposed by the structure and functionality of its proteins"],"prefix":"10.1371","volume":"17","author":[{"given":"Lukasz","family":"Jaroszewski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0474-0594","authenticated-orcid":true,"given":"Mallika","family":"Iyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arghavan","family":"Alisoltani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1121-2661","authenticated-orcid":true,"given":"Mayya","family":"Sedova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2425-852X","authenticated-orcid":true,"given":"Adam","family":"Godzik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,7,8]]},"reference":[{"issue":"1","key":"pcbi.1009147.ref001","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/gch2.1018","article-title":"Data, disease and diplomacy: GISAID\u2019s innovative contribution to global health.","volume":"1","author":"S Elbe","year":"2017","journal-title":"Glob Chall."},{"issue":"4","key":"pcbi.1009147.ref002","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/s41564-020-0690-4","article-title":"We shouldn\u2019t worry when a virus mutates during disease outbreaks.","volume":"5","author":"ND Grubaugh","year":"2020","journal-title":"Nat Microbiol."},{"key":"pcbi.1009147.ref003","article-title":"Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2.","author":"B Korber","year":"2020","journal-title":"bioRxiv"},{"issue":"1","key":"pcbi.1009147.ref004","doi-asserted-by":"crossref","first-page":"6013","DOI":"10.1038\/s41467-020-19808-4","article-title":"SARS-CoV-2 spike-protein D614G mutation increases virion spike density and infectivity.","volume":"11","author":"L Zhang","year":"2020","journal-title":"Nat Commun."},{"key":"pcbi.1009147.ref005","article-title":"Early empirical assessment of the N501Y mutant strains of SARS-CoV-2 in the United Kingdom, October to November 2020.","author":"K Leung","year":"2020","journal-title":"medRxiv"},{"key":"pcbi.1009147.ref006","article-title":"Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa.","author":"H Tegally","year":"2020","journal-title":"medRxiv"},{"issue":"1\u20132","key":"pcbi.1009147.ref007","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.gene.2007.09.013","article-title":"More effective purifying selection on RNA viruses than in DNA viruses","volume":"404","author":"AL Hughes","year":"2007","journal-title":"Gene"},{"issue":"12","key":"pcbi.1009147.ref008","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.00411-20","article-title":"Computational Inference of Selection Underlying the Evolution of the Novel Coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2","volume":"94","author":"R Cagliani","year":"2020","journal-title":"J Virol"},{"issue":"3","key":"pcbi.1009147.ref009","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/S0022-2836(65)80134-6","article-title":"Structure and function of haemoglobin: II. 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