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.

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

“…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.…”

The roles of APOBEC-mediated RNA editing in SARS-CoV-2 mutations, replication and fitness

“…Unlike most RNA viruses that exhibit high mutation rates (Ref. 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 .…”

“…Therefore the continued emergence of more transmissible and vaccine evasion strains of the SARS-CoV-2 highlights the importance of understanding the driving force of viral mutation and evolution of SARS-CoV-2 genome. There are several possible sources for SARS-CoV-2 viral mutations: spontaneous random errors that are not corrected by the build-in proofreading mechanism of the RdRP, the host-factor mediated mutations of viral genome 3 (and references therein), and mutations induced by enriched local nucleic acid structure within inverted repeat and epigenetic modification, such as CpG island loci 10 . 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 host-factor induced mutations play an important role in shaping the viral genomic RNA mutational outcome and evolution 11 – 14 .…”

Azide‐Modified Nucleosides as Versatile Tools for Bioorthogonal Labeling and Functionalization

“…In particular the discovery of the many different RNA types involved in the regulation of cellular processes, such as for example siRNAs, [1] ncRNAs, [2] or riboswitches [3–5] has put demand on synthetic chemistry to provide oligonucleotides (ONs) carrying specific labels or modifications. Catalytically active ONs (ribozymes) as integral part of the RNA world hypothesis have been synthesized in variants decorated with various modifications in the context of studies regarding the origin of life [6–8] …”