Retrospect of the Two-Year Debate: What Fuels the Evolution of SARS-CoV-2: RNA Editing or Replication Error?

Abstract

Mutation is one of the mechanisms of the evolutionary divergence of an organism. Under this global COVID-19 pandemic, the fast evolution of SARS-CoV-2 became one of the most worrying issues. Some researchers believed that the hosts’ RNA deamination systems (APOBECs and ADARs) are the major source of mutations and have driven the evolution of SARS-CoV-2. However, apart from RNA editing, the RDRP (RNA-dependent RNA polymerase)-mediated replication errors may also contribute to the mutation of SARS-CoV-2 (just like the single-nucleotide polymorphisms/variations in eukaryotes caused by DNA replication errors). Unfortunately, it is technically unable to distinguish RNA editing and replication errors (SNPs) in this RNA virus. Here comes a fundamental question: we indeed observed the fast evolution of SARS-CoV-2, but what exactly fuels its evolution: RNA editing or replication errors? This debate lasts for 2 years. In this piece, we will retrospect the 2-year debate on RNA editing versus SNPs.

Neutralization of Different Variants of SARS-CoV-2 by a F(ab′)2 Preparation from Sera of Horses Immunized with the Viral Receptor Binding Domain

“…Each titer was obtained by logistic regression of the average of 3 replicas and is the geometric mean value of two independent experiments. 3 Protein concentration of the preparation 003 able to reduce 50% of the lytic plaques.…”

“…2 Phosphate Buffer Saline (PBS). 3 Preparation 002 is the product of the bleeding at 3 weeks plus a remnant of preparation 001. 4 The horses were immunized with 500 µg of RBD in a two-day interval.…”

“…In contrast with other RNA viruses, this viral family harbors a proofreading capacity, which limits the error induced by the RNA polymerase during replication. However, due to the enormous replication cycles that this virus has experienced during the pandemic, in addition to a high frequency of recombination and the effect of host editing enzymes, the mutation rate in the SARS-CoV-2 genome has been estimated at around 9.9 × 10 −4 to 2.2 × 10 −3 [2,3]. The high frequency of mutations has allowed the selection of variants with higher fitness, transmission capacity, and particularly evasion of the immunity present in the human host during the successive waves of infection [4].…”

RNAsselem: a Python Package for Descriptive Analysis of RNA Secondary Structure Elements in Viral Genomes

“…The ADAR family members (ADAR1-3) deaminate adenines residing in double-stranded RNA (dsRNA), converting them to inosines (A-to-I) [14], while APOBEC family members (APOBEC1-2, 3A-H, 4, and AID) deaminate cytosine into uracil (C-to-U) on single-stranded RNA (ssRNA) [15,16]. The relative mutational impact between RdRp (RNA-dependent RNA polymerase), which introduces errors during replication, and RNA editing enzymes, remains unclear [17][18][19]. Recent studies revealed an enrichment of C-to-U substitutions and, to a lesser extent, A-to-G substitutions in the SARS-CoV-2 genome, offering evidence for RNA editing by APOBEC and potentially by ADAR enzymes [20][21][22][23][24][25].…”