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SARS-CoV-2 variants are defined by their unique combinations of mutations and there has been a clear adaptation to more efficient human infection since the emergence of this new human coronavirus in late 2019. Here, we use machine learning models to identify shared signatures, i.e., common underlying mutational processes and link these to the subset of mutations that define the variants of concern (VOCs). First, we examined the global SARS-CoV-2 genomes and associated metadata to determine how viral properties and public health measures have influenced the magnitude of waves, as measured by the number of infection cases, in different geographic locations using regression models. This analysis showed that, as expected, both public health measures and virus properties were associated with the waves of regional SARS-CoV-2 reported infection numbers and this impact varies geographically. We attribute this to intrinsic differences such as vaccine coverage, testing and sequencing capacity and the effectiveness of government stringency. To assess underlying evolutionary change, we used non-negative matrix factorisation and observed three distinct mutational signatures, unique in their substitution patterns and exposures from the SARS-CoV-2 genomes. Signatures 1, 2 and 3 were biased to C\u2192T, T\u2192C\/A\u2192G and G\u2192T point mutations. We hypothesise assignments of these mutational signatures to the host antiviral molecules APOBEC, ADAR and ROS respectively. We observe a shift amidst the pandemic in relative mutational signature activity from predominantly Signature 1 changes to an increasingly high proportion of changes consistent with Signature 2. This could represent changes in how the virus and the host immune response interact and indicates how SARS-CoV-2 may continue to generate variation in the future. Linkage of the detected mutational signatures to the VOC-defining amino acids substitutions indicates the majority of SARS-CoV-2\u2019s evolutionary capacity is likely to be associated with the action of host antiviral molecules rather than virus replication errors.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011795","type":"journal-article","created":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T18:47:49Z","timestamp":1706208469000},"page":"e1011795","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["Mutational signature dynamics indicate SARS-CoV-2\u2019s evolutionary capacity is driven by host antiviral molecules"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3011-5189","authenticated-orcid":true,"given":"Kieran D.","family":"Lamb","sequence":"first","affiliation":[]},{"given":"Martha M.","family":"Luka","sequence":"additional","affiliation":[]},{"given":"Megan","family":"Saathoff","sequence":"additional","affiliation":[]},{"given":"Richard J.","family":"Orton","sequence":"additional","affiliation":[]},{"given":"My V. T.","family":"Phan","sequence":"additional","affiliation":[]},{"given":"Matthew","family":"Cotten","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2318-1460","authenticated-orcid":true,"given":"Ke","family":"Yuan","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6338-0221","authenticated-orcid":true,"given":"David L.","family":"Robertson","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2024,1,25]]},"reference":[{"key":"pcbi.1011795.ref001","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/S2213-2600(20)30079-5","article-title":"Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study","volume":"8","author":"X Yang","year":"2020","journal-title":"The Lancet Respiratory Medicine"},{"key":"pcbi.1011795.ref002","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1056\/NEJMoa2001316","article-title":"Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus\u2013Infected Pneumonia","volume":"382","author":"Q Li","year":"2020","journal-title":"New England Journal of Medicine"},{"key":"pcbi.1011795.ref003","doi-asserted-by":"crossref","first-page":"e238","DOI":"10.1016\/S1473-3099(20)30484-9","article-title":"Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics","volume":"20","author":"E Petersen","year":"2020","journal-title":"The Lancet Infectious Diseases"},{"key":"pcbi.1011795.ref004","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41564-020-00838-z","article-title":"Genomic epidemiology reveals multiple introductions of SARS-CoV-2 from mainland Europe into Scotland","volume":"6","author":"A da Silva Filipe","year":"2020","journal-title":"Nature Microbiology"},{"key":"pcbi.1011795.ref005","doi-asserted-by":"crossref","first-page":"359","DOI":"10.34172\/hpp.2020.54","article-title":"Global policy responses to the COVID-19 pandemic: proportionate adaptation and policy experimentation: a study of country policy response variation to the COVID-19 pandemic","volume":"10","author":"A Dewi","year":"2020","journal-title":"Health Promotion Perspectives"},{"key":"pcbi.1011795.ref006","doi-asserted-by":"crossref","first-page":"e20","DOI":"10.1016\/S2213-2600(21)00005-9","article-title":"New variant of SARS-CoV-2 in UK causes surge of COVID-19","volume":"9","author":"T Kirby","year":"2021","journal-title":"The Lancet Respiratory medicine"},{"key":"pcbi.1011795.ref007","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1001\/jama.2020.27124","article-title":"Genetic Variants of SARS-CoV-2\u2014What Do They Mean?","volume":"325","author":"AS Lauring","year":"2021","journal-title":"JAMA"},{"key":"pcbi.1011795.ref008","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1038\/s41564-020-0770-5","article-title":"A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology","volume":"5","author":"A Rambaut","year":"2020","journal-title":"Nature Microbiology"},{"key":"pcbi.1011795.ref009","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/s41579-021-00573-0","article-title":"SARS-CoV-2 variants, spike mutations and immune escape","volume":"19","author":"WT Harvey","year":"2021","journal-title":"Nature Reviews Microbiology"},{"key":"pcbi.1011795.ref010","unstructured":"WHO. 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