{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T21:17:02Z","timestamp":1774473422374,"version":"3.50.1"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T00:00:00Z","timestamp":1648512000000},"content-version":"vor","delay-in-days":87,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u2018Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia\u2019","award":["PD\/BD\/138735\/2018"],"award-info":[{"award-number":["PD\/BD\/138735\/2018"]}]},{"name":"FCT Project","award":["PTDC\/BIA-EVL\/31528\/2017 to I.G."],"award-info":[{"award-number":["PTDC\/BIA-EVL\/31528\/2017 to I.G."]}]},{"name":"Portuguese NIH"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,1,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and objectives<\/jats:title>\n                    <jats:p>To understand how organisms evolve, it is fundamental to study how mutations emerge and establish. Here, we estimated the rate of mutation accumulation of SARS-CoV-2 in vitro and investigated the repeatability of its evolution when facing a new cell type but no immune or drug pressures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methodology<\/jats:title>\n                    <jats:p>We performed experimental evolution with two strains of SARS-CoV-2, one carrying the originally described spike protein (CoV-2-D) and another carrying the D614G mutation that has spread worldwide (CoV-2-G). After 15 passages in Vero cells and whole genome sequencing, we characterized the spectrum and rate of the emerging mutations and looked for evidences of selection across the genomes of both strains.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>From the frequencies of the mutations accumulated, and excluding the genes with signals of selection, we estimate a spontaneous mutation rate of 1.3 \u00d7 10\u22126 \u00b1 0.2 \u00d7 10\u22126 per-base per-infection cycle (mean across both lineages of SARS-CoV-2 \u00b1 2SEM). We further show that mutation accumulation is larger in the CoV-2-D lineage and heterogeneous along the genome, consistent with the action of positive selection on the spike protein, which accumulated five times more mutations than the corresponding genomic average. We also observe the emergence of mutators in the CoV-2-G background, likely linked to mutations in the RNA-dependent RNA polymerase and\/or in the error-correcting exonuclease protein.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and implications<\/jats:title>\n                    <jats:p>These results provide valuable information on how spontaneous mutations emerge in SARS-CoV-2 and on how selection can shape its genome toward adaptation to new environments.<\/jats:p>\n                    <jats:p>Lay Summary: Each time a virus replicates inside a cell, errors (mutations) occur. Here, via laboratory propagation in cells originally isolated from the kidney epithelium of African green monkeys, we estimated the rate at which the SARS-CoV-2 virus mutates\u2014an important parameter for understanding how it can evolve within and across humans. We also confirm the potential of its Spike protein to adapt to a new environment and report the emergence of mutators\u2014viral populations where mutations occur at a significantly faster rate.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/emph\/eoac010","type":"journal-article","created":{"date-parts":[[2022,3,18]],"date-time":"2022-03-18T16:10:46Z","timestamp":1647619846000},"page":"142-155","source":"Crossref","is-referenced-by-count":171,"title":["Mutation rate of SARS-CoV-2 and emergence of mutators during experimental evolution"],"prefix":"10.1093","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2221-606X","authenticated-orcid":false,"given":"Massimo","family":"Amicone","sequence":"first","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia , Oeiras, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3767-2209","authenticated-orcid":false,"given":"V\u00edtor","family":"Borges","sequence":"additional","affiliation":[{"name":"Bioinformatics Unit, Department of Infectious Diseases, National Institute of Health Doutor Ricardo Jorge (INSA) , Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0065-9000","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Alves","sequence":"additional","affiliation":[{"name":"Centre for Vectors and Infectious Diseases Research, Department of Infectious Diseases, National Institute of Health Doutor Ricardo Jorge (INSA) , Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8529-9878","authenticated-orcid":false,"given":"Joana","family":"Isidro","sequence":"additional","affiliation":[{"name":"Bioinformatics Unit, Department of Infectious Diseases, National Institute of Health Doutor Ricardo Jorge (INSA) , Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7258-1439","authenticated-orcid":false,"given":"L\u00edbia","family":"Z\u00e9-Z\u00e9","sequence":"additional","affiliation":[{"name":"Centre for Vectors and Infectious Diseases Research, Department of Infectious Diseases, National Institute of Health Doutor Ricardo Jorge (INSA) , Lisbon, Portugal"},{"name":"BioISI\u2014Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon , Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2943-5975","authenticated-orcid":false,"given":"S\u00edlvia","family":"Duarte","sequence":"additional","affiliation":[{"name":"Innovation and Technology Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge (INSA) , Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7703-1409","authenticated-orcid":false,"given":"Lu\u00eds","family":"Vieira","sequence":"additional","affiliation":[{"name":"Innovation and Technology Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge (INSA) , Lisbon, Portugal"},{"name":"Centre for Toxicogenomics and Human Health (ToxOmics), Genetics, Oncology and Human Toxicology, Nova Medical School|Faculdade de Ci\u00eancias 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