The continuing discovery on the evidence for RNA editing in SARS-CoV-2.

Recent studies have presented strong evidence that C-to-U RNA editing is the driving force that fuels severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution. The findings finally ended the long-term debate on the evolutionary driving force behind SARS-CoV-2 evolution. Here, we would first acknowledge the breakthroughs made by the recent works, such as using the global SARS-CoV-2 data to demonstrate the major mutation source of this virus. Meanwhile, we would raise a few concerns on the accuracy of their interpretation on C-to-U RNA editing. By re-analysing the SARS-CoV-2 population data, we found that the editing frequency on C-to-U sites did not perfectly correlate with the binding motif of the editing enzyme APOBEC, suggesting that there might be false-positive sites among the C-to-U mutations or the original data did not fully represent the novel mutation rate. We hope our work could help people understand the molecular basis underlying SARS-CoV-2 mutation and also be useful to guide future studies on SARS-CoV-2 evolution.

Evidence Supporting That C-to-U RNA Editing Is the Major Force That Drives SARS-CoV-2 Evolution.

Mutations of DNA organisms are introduced by replication errors. However, SARS-CoV-2, as an RNA virus, is additionally subjected to rampant RNA editing by hosts. Both resources contributed to SARS-CoV-2 mutation and evolution, but the relative prevalence of the two origins is unknown. We performed comparative genomic analyses at intra-species (world-wide SARS-CoV-2 strains) and inter-species (SARS-CoV-2 and RaTG13 divergence) levels. We made prior predictions of the proportion of each mutation type (nucleotide substitution) under different scenarios and compared the observed versus the expected. C-to-T alteration, representing C-to-U editing, is far more abundant that all other mutation types. Derived allele frequency (DAF) as well as novel mutation rate of C-to-T are the highest in SARS-CoV-2 population, and C-T substitution dominates the divergence sites between SARS-CoV-2 and RaTG13. This is compelling evidence suggesting that C-to-U RNA editing is the major source of SARS-CoV-2 mutation. While replication errors serve as a baseline of novel mutation rate, the C-to-U editing has elevated the mutation rate for orders of magnitudes and accelerates the evolution of the virus.