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

Abstract

The high mutation rate of SARS-CoV-2 largely complicates our control of the pandemic. Particularly, it is currently unclear why the spike (S) gene has 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 world-wide SARS-CoV-2 strains, we found that both fixed and polymorphic mutations show higher mutation rates in S gene than other genes. The majority of mutation is 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 evidences indicated that S gene is more likely to be single-stranded compared to other SARS-CoV-2 genes, agreeing with the APOBEC preference on ssRNA. We conclude that the single-stranded property of S gene makes itself 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 understand the molecular mechanism underlying the mutation and evolution of SARS-CoV-2, and is believed to contribute to the control of the pandemic.

Description of a One-Year Succession of Variants of Interest and Concern of SARS-CoV-2 in Venezuela

“…This RTC includes an exonuclease, enabling proof-reading capacity and thereby limiting mutational events. However, other factors have led to the emergence of many mutations, such as the great frequency of replication of this virus (due to the extraordinary number of infected persons worldwide), its high rate of recombination, and the probable action of host deaminases on its viral genome, particularly in the spike protein (S) [ 2 , 3 ]. Around 1900 lineages of this virus have been identified [ 4 , 5 ].…”

uORF-Mediated Translational Regulation of ATF4 Serves as an Evolutionarily Conserved Mechanism Contributing to Non-Small-Cell Lung Cancer (NSCLC) and Stress Response

“…We obtained the population SNP data from multiple species. These SNP data include the human 1000 genome (Kuehn, 2008 ), Drosophila genetic reference panel (Mackay et al, 2012 ), 1000 genome project of Arabidopsis thaliana (Alonso-Blanco et al, 2016 ; Chu and Wei, 2021a ; Wei, 2020 ), and the SNPs called from millions of global SARS-CoV-2 sequences available in GISAID or relevant literatures (Cai et al, 2022 ; Li et al, 2020b ; Liu et al, 2022 ; Martignano et al, 2022 ; Shu and McCauley, 2017 ; Wei, 2022 ; Zhao et al, 2022 ; Zhu et al, 2022 ; Zong et al, 2022 ). We utilized these SNP data to test whether the mutations that abolish uORFs are most deleterious.…”

“…The SNPs in the population of Arabidopsis thaliana were retrieved from previous literatures (Alonso-Blanco et al, 2016 ; Chu and Wei, 2021a ; Wei, 2020 ). The sequences and SNPs of the world-wide SARS-CoV-2 population were downloaded from GISAID (Shu and McCauley, 2017 ) as previously literatures instructed (Liu et al, 2022 ; Zhu et al, 2022 ).…”

“…The SNP (single-nucleotide polymorphism) files of target species came from the following resources: the human 1000 genome project from (Kuehn, 2008 ) ( ftp://ftp.1000genomes.ebi.ac.uk/ ); the Drosophila genetic reference panel from (Mackay et al, 2012 ) ( http://dgrp2.gnets.ncsu.edu/ ); the 1000 genome project of Arabidopsis thaliana from (Alonso-Blanco et al, 2016 ; Chu and Wei, 2021a ; Wei, 2020 ); and the millions of world-wide SARS-CoV-2 sequences from (Liu et al, 2022 ; Shu and McCauley, 2017 ; Zhu et al, 2022 ).…”

Nothing in SARS-CoV-2 makes sense except in the light of RNA modification?

“…In this article, we will propose our perspective that when studying the mutation and evolution of SARS-CoV-2, one would inevitably come to the topic of RNA deamination systems in hosts. Without considering RNA deamination, a study on SARS-CoV-2 would hardly make sense [ 1 ]. In memory of the evolutionary biologist Theodosius Dobzhansky [ 2 ], we claim that virtually nothing in SARS-CoV-2 makes sense except in the light RNA deamination.…”