From RNA World to SARS-CoV-2: The Edited Story of RNA Viral Evolution

Abstract

The current SARS- CoV-2 pandemic underscores the importance of understanding the evolution of RNA genomes. While RNA is subject to the formation of similar lesions as DNA, the evolutionary and physiological impacts RNA lesions have on viral genomes are yet to be characterized. Lesions that may drive the evolution of RNA genomes can induce breaks that are repaired by recombination or can cause base substitution mutagenesis, also known as base editing. Over the past decade or so, base editing mutagenesis of DNA genomes has been subject to many studies, revealing that exposure of ssDNA is subject to hypermutation that is involved in the etiology of cancer. However, base editing of RNA genomes has not been studied to the same extent. Recently hypermutation of single-stranded RNA viral genomes have also been documented though its role in evolution and population dynamics. Here, we will summarize the current knowledge of key mechanisms and causes of RNA genome instability covering areas from the RNA world theory to the SARS- CoV-2 pandemic of today. We will also highlight the key questions that remain as it pertains to RNA genome instability, mutations accumulation, and experimental strategies for addressing these questions.

The Roles of APOBEC-mediated RNA Editing in SARS-CoV-2 Mutations, Replication and Fitness

“…2-3). A high mutation rate of C in AC motif was also noted in SARS-CoV-2 and Rubella Virus by prior bioinformatic analysis (3,9,25). A3A showed a preferred dinucleotide UC motif, consistent with previous reports about the preferred motif for A3A-mediated editing of cellular RNA targets (23,44).…”

“…2C, D). Interestingly, analysis of SARS-CoV-2 variants from the database also showed higher AC motif mutations (38.3%) than UC motif mutations (31.2%) (Fig S3), as also reported in the previous bioinformatic database analysis (3,9,25). These results indicate that many of the AC-to-AU mutations in the SARS-CoV-2 genome from patients can be driven by A1+A1CF mediated RNA-editing in the small intestine and liver with SARS-CoV-2 infection.…”

“…The causative agent of the COVID-19 pandemic, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a member of the enveloped Coronaviridae family that has a single-stranded positivesense RNA genome ( 1, 2 ). Unlike most RNA viruses that exhibit high mutation rates (( 3 ) and references therein), SARS-CoV-2 and other coronaviruses have moderate genetic variability because they have built-in proofreading mechanism in their RNA-dependent RNA-polymerase (RdRP) to correct the errors during viral genome replication and transcription ( 4 ).…”

“…However, sequencing data of SARS-CoV-2 from patients revealed persistent accumulation of new mutations over time, leading to the emergence of new viral strains that can be more transmissible or virulent ( 5, 6 ) or evade vaccines ( 7, 8 ), highlighting the importance of understanding the driving force of viral mutation and evolution of SARS-CoV-2 genome. There are two possible main sources for SARS-CoV-2 viral mutations: spontaneous random errors that are not corrected by the build-in proofreading mechanism of the RdRP and the host-factor mediated mutations of viral genome (( 3 ) and references therein). Recent analysis of SARS-CoV-2 and rubella vaccine virus genome data derived from patients show predominant mutational patterns with specific signatures rather than random genetic variations, suggesting that the hostfactor induced mutations play an important role in shaping the viral genomic RNA mutational outcome and evolution ( 9-12 ).…”

SARS‐CoV‐2 Omicron variant: Immune escape and vaccine development

“…Consistent with most RNA viruses, the RNA‐dependent RNA polymerase (RdRp) of SARS‐CoV‐2 incorporates mismatches during the replication of the viral genome, resulting in relative instability of the SARS‐CoV‐2 genome. This instability, in combination with a selection pressure, drives the emergence of genetic diversity and evolution of SARS‐CoV‐2 1,2 . The end result of this genetic diversification and evolution is the emergence of variants.…”