The mutational landscape of SARS-CoV-2 provides new insight into viral evolution and fitness

Jori Symons, Claire Chung, Bert M. Verheijen, Sarah J. Shemtov, Dorien Jong, Gimano Amatngalim, Monique Nijhuis, Marc Vermulst () and Jean-Francois Gout ()
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Jori Symons: University Medical Center
Claire Chung: University of Southern California
Bert M. Verheijen: University of Southern California
Sarah J. Shemtov: University of Southern California
Dorien Jong: University Medical Center
Gimano Amatngalim: University Medical Center
Monique Nijhuis: University Medical Center
Marc Vermulst: University of Southern California
Jean-Francois Gout: Mississippi State University

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Although vaccines and treatments have strengthened our ability to combat the COVID-19 pandemic, new variants of SARS-CoV-2 continue to emerge in human populations. Because the evolution of SARS-CoV-2 is driven by mutation, a better understanding of its mutation rate and spectrum could improve our ability to forecast the trajectory of the pandemic. Here, we use circular RNA consensus sequencing (CirSeq) to determine the mutation rate of six SARS-CoV-2 variants and perform a short-term evolution experiment to determine the impact of these mutations on viral fitness. Our analyses indicate that the SARS-CoV-2 genome mutates at a rate of ∼1.5 × 10−6/base per viral passage and that the spectrum is dominated by C → U transitions. Moreover, we find that the mutation rate is significantly reduced in regions that form base-pairing interactions and that mutations that affect these secondary structures are especially harmful to viral fitness. In this work, we show that the biased mutation spectrum of SARS-CoV-2 is likely a result of frequent cytidine deamination and that the secondary structure of the virus plays an important role in this process, providing new insight into the parameters that guide viral evolution and highlighting fundamental weaknesses of the virus that may be exploited for therapeutic purposes.

Date: 2025
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DOI: 10.1038/s41467-025-61555-x

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