Mutations of SARS-CoV-2 nsp14 exhibit strong association with increased genome-wide mutation load

Abstract

SARS-CoV-2 is a betacoronavirus responsible for COVID-19, a pandemic with global impact that first emerged in late 2019. Since then, the viral genome has shown considerable variance as the disease spread across the world, in part due to the zoonotic origins of the virus and the human host adaptation process. As a virus with an RNA genome that codes for its own genomic replication proteins, mutations in these proteins can significantly impact the variance rate of the genome, affecting both the survival and infection rate of the virus, and attempts at combating the disease. In this study, we analyzed the mutation densities of viral isolates carrying frequently observed mutations for four proteins in the RNA synthesis complex over time in comparison to wildtype isolates. Our observations suggest mutations in nsp14, an error-correcting exonuclease protein, have the strongest association with increased mutation load without selective pressure and across the genome, compared to nsp7, nsp8 and nsp12, which form the core polymerase complex. We propose nsp14 as a priority research target for understanding genomic variance rate in SARS-CoV-2 isolates and nsp14 mutations as potential predictors for high mutability strains.

Different selection dynamics of S and RdRp between SARS-CoV-2 genomes with and without the dominant mutations

“…The mutation that most strongly affects the mutation density was the 14408C > T mutation, predicating it as a genotype of interest. In our follow-up study, we also identified the trend of a positive correlation between the presence of the 14408C > T mutation and increased mutation density in regions under low selective pressure persisted beyond our initial study ( Eskier et al, 2020c ).…”

“…RdRp is one of the SARS-CoV-2 proteins responsible for replicating the viral genome, and it is expected that mutations in its sequence and structure might lead to a change in overall mutation rates, as we have shown in previous studies ( Eskier et al, 2020b , Eskier et al, 2020c ). It is less clear how the D614G mutation in the S gene could affect the mutation rate; however, increased transmission across the population might lead to more permissive circumstances for novel mutations to arise.…”

Anti-SARS-CoV-2 Vaccines and Monoclonal Antibodies Facing Viral Variants

“…These mutations occur despite the exonuclease corrective activity (NSP14) and are associated with selection pressure induced by host immune response and vaccine/therapeutic immunity or tissue differentiation. Among these mutations, some are linked to the immune system, particularly when present in the RBD, such as E484K and S477N [ 23 , 24 ]. It has also been shown that mutations in RNA-dependent RNA polymerase (RdRp), particularly the P323 mutation in Nsp12 initially observed in the D614G variant, accelerate RdRp, thus affecting its fidelity and promoting mutations in the viral structural proteins [ 25 ].…”

Structure and dynamics of SARS-CoV-2 proofreading exoribonuclease ExoN

“…To mitigate the low fidelity of RdRp, all coronaviruses encode a 3’-to-5’ exoribonuclease (ExoN) in nsp14 ( 10 – 12 ). Mutations of SARS-CoV-2 nsp14 exhibit strong association with increased genome-wide mutation load ( 13 , 14 ), and genetic inactivation of ExoN in engineered SARS-CoV and murine hepatitis virus (MHV) leads to 15 to 20-fold increases in mutation rates ( 7 , 15 , 16 ). Furthermore, in a mouse model, SARS-CoV with inactivated ExoN shows a mutator phenotype with decreased fitness and lower virulence over serial passage, suggesting a potential strategy for generating a live, impaired-fidelity coronavirus vaccine ( 17 ).…”