Rampant C-to-U deamination accounts for the intrinsically high mutation rate in SARS-CoV-2 spike gene
- 1Institute of Integrative Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266073, China
- 2Department of Disease Prevention, Qingdao Hiser Medical Group, Qingdao, Shandong 266033, China
- 3Respiratory and Critical Illness Medicine Department II, Qingdao Hiser Medical Group, Qingdao, Shandong 266033, China
- 4Nursing Department, Qingdao Central Hospital, Qingdao, Shandong 266042, China
- 5Interventional Catheterization Lab, Qingdao Central Hospital, Qingdao, Shandong 266042, China
- Corresponding author: sdhospit{at}126.com
Abstract
The high mutation rate of SARS-CoV-2 largely complicates our control of the pandemic. In particular, it is currently unclear why the spike (S) gene has an extraordinarily high mutation rate among all SARS-CoV-2 genes. By analyzing the occurrence of fixed synonymous mutations between SARS-CoV-2 and RaTG13, and profiling the DAF (derived allele frequency) of polymorphic synonymous sites among millions of worldwide SARS-CoV-2 strains, we found that both fixed and polymorphic mutations show higher mutation rates in the S gene than other genes. The majority of mutations are C-to-T, representing the APOBEC-mediated C-to-U deamination instead of the previously proposed A-to-I deamination. Both in silico and in vivo evidence indicated that the S gene is more likely to be single-stranded compared to other SARS-CoV-2 genes, agreeing with the APOBEC preference of ssRNA. We conclude that the single-stranded property of the S gene makes it a favorable target for C-to-U deamination, leading to its excessively high mutation rate compared to other non-S genes. In conclusion, APOBEC, rather than ADAR, is the “editor-in-chief” of SARS-CoV-2 RNAs. This work helps us to understand the molecular mechanism underlying the mutation and evolution of SARS-CoV-2, and we believe it will contribute to the control of the pandemic.
Keywords
- Received March 10, 2022.
- Accepted April 24, 2022.
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