The mutation rate of SARS-CoV-2 is highly variable between sites and is influenced by sequence context, genomic region, and RNA structure
RNA viruses like SARS-CoV-2 have high mutation rates, which contribute to their rapid evolution. Mutation rates depend on mutation type and can vary between sites in a virus's genome. Understanding this variation can shed light on the mutational processes at play, and is crucial for quantitative modeling of viral evolution. Using millions of SARS-CoV-2 full-genome sequences, we estimate rates of synonymous mutations for each mutation type and examine how much these rates vary between sites. We find a surprisingly high level of variability. A substantial fraction of this variability can be explained by local sequence context, genomic region, and RNA secondary structure. We estimate fitness effects of each mutation based on the number of times it actually occurs versus the number of times it is expected to occur based on a model of the above features. We identify small regions of the genome where synonymous or noncoding mutations occur much less often than expected, indicative of strong purifying selection on the RNA sequence independent of protein sequence. Overall, this work expands our basic understanding of SARS-CoV-2's evolution by characterizing the virus's mutation process at the level of individual sites and uncovering several striking mutational patterns that arise from unknown mechanisms.
Authors
- William S. DeWitt (ORCID: https://orcid.org/0000-0002-6802-9139)
- Angie S. Hinrichs (ORCID: https://orcid.org/0000-0002-1697-1130)
- Richard A. Neher (ORCID: https://orcid.org/0000-0003-2525-1407)
- Chris Jennings-Shaffer (ORCID: https://orcid.org/0000-0002-6492-3854)
- Hugh K. Haddox (ORCID: https://orcid.org/0000-0001-8324-8324)
- Jared Galloway (ORCID: https://orcid.org/0000-0001-5838-7840)
- Luca Sesta (ORCID: https://orcid.org/0000-0002-6051-0972)
- F. A. Matsen (ORCID: https://orcid.org/0000-0003-0607-6025)
- Jesse D. Bloom (ORCID: https://orcid.org/0000-0003-1267-3408)
- Seth D Temple (ORCID: https://orcid.org/0000-0002-7651-6527)
- Georg Angehrn
Institutions
- SIB Swiss Institute of Bioinformatics (CH)
- Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA)
- Howard Hughes Medical Institute (US)
- University of Basel (CH)
- University of California, Santa Cruz (US)
- University of Washington (US)
- University of Michigan (US)
- Fred Hutch Cancer Center (US)
Publication Details
- Journal
- Nucleic Acids Research
- Published
- 2025-05-29
- DOI
- https://doi.org/10.1093/nar/gkaf503
- Citations
- 8
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 11.17
Funders
- National Science Foundation
- Howard Hughes Medical Institute
- James S. McDonnell Foundation
- Gordon and Betty Moore Foundation
- Fred Hutchinson Cancer Research Center
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- Centers for Disease Control and Prevention
- National Defense Science and Engineering Graduate
- Kavli Institute for Theoretical Physics, University of California, Santa Barbara
- Office of Research Infrastructure Programs, National Institutes of Health