Key result
Synonymous C-to-U RNA editing events creating 58 novel out-of-frame AUGs in SARS-CoV-2 showed significantly higher allele frequency and increasing rates, indicating positive selection for novel ORFs.
Why the study?
While missense mutations from C-to-U RNA editing in SARS-CoV-2 have received attention, C-to-U events leading to AUG and creating novel ORFs remained uninvestigated.
C-to-U RNA editing in SARS-CoV-2 creates novel ORFs with optimized expressibility, suggesting a mechanism for de novo gene emergence and viral evolution.
May generate novel SARS-CoV-2 proteins; leaves open their impact on fitness or pathogenesis pending validation.
Rampant C-to-U RNA editing drives the mutation and evolution of SARS-CoV-2. While much attention has been paid to missense mutations, the C-to-U events leading to AUG and thus creating novel ORFs were uninvestigated. By utilizing the public time-course mutation data from the worldwide SARS-CoV-2 population, we systematically identified the “AUG-gain mutations” caused by C-to-U RNA editing. Synonymous mutations were of special focus. A total of 58 synonymous C-to-U sites are able to create out-of-frame AUG in coding sequence (CDS). These 58 synonymous sites showed significantly higher allele frequency (AF) and increasing rate (dAF/dt) than other C-to-U synonymous sites in the SARS-CoV-2 population, suggesting that these 58 AUG-gain events conferred additional benefits to the virus and are subjected to positive selection. The 58 predicted new ORFs created by AUG-gain events showed the following advantages compared to random expectation: they have longer lengths, higher codon adaptation index (CAI), higher Kozak scores, and higher tRNA adaptation index (tAI). The 58 putatively novel ORFs have high expressibility and are very likely to be functional, providing an explanation for the positive selection on the 58 AUG-gain mutations. Our study proposed a possible mechanism of the emergence of de novo genes in SARS-CoV-2. This idea should be helpful in studying the mutation and evolution of SARS-CoV-2.
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Zhang et al. (2024) studied SARS-CoV-2. Synonymous C-to-U RNA editing creating out-of-frame AUG vs. Other C-to-U synonymous mutations not creating AUG was evaluated on Allele frequency (AF) and increasing rate (dAF/dt). Synonymous C-to-U RNA editing events creating 58 novel out-of-frame AUGs in SARS-CoV-2 showed significantly higher allele frequency and increasing rates, indicating positive selection for novel ORFs.
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