Rampant C-to-U deamination accounts for the intrinsically high mutation rate in SARS-CoV-2 spike gene

  1. Wenqing Jiang3
  1. 1Institute of Integrative Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266073, China
  2. 2Department of Disease Prevention, Qingdao Hiser Medical Group, Qingdao, Shandong 266033, China
  3. 3Respiratory and Critical Illness Medicine Department II, Qingdao Hiser Medical Group, Qingdao, Shandong 266033, China
  4. 4Nursing Department, Qingdao Central Hospital, Qingdao, Shandong 266042, China
  5. 5Interventional Catheterization Lab, Qingdao Central Hospital, Qingdao, Shandong 266042, China
  1. 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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