Mutation rate of SARS-CoV-2 and emergence of mutators during experimental evolution

Abstract

"How predictable is evolution?" is a key question in evolutionary biology. Experimental evolution has shown that the evolutionary path of microbes can be extraordinarily reproducible. Here, using experimental evolution in two circulating SARS-CoV-2, we estimate its mutation rate and demonstrate the repeatability of its evolution when facing a new cell type but no immune or drug pressures. We estimate a genomic mutation rate of 3.7x10^-6 nt^-1 cycle^-1 for a lineage of SARS-CoV-2 with the originally described spike protein (CoV-2-D) and of 2.9x10^-6 nt^-1 cycle-1 for a lineage carrying the D614G mutation that has spread worldwide (CoV-2-G). We further show that mutation accumulation is heterogeneous along the genome, with the spike gene accumulating mutations at a mean rate 16x10^-6 nt^-1 per infection cycle across backgrounds, five-fold higher than the genomic average. We observe the emergence of mutators in the CoV-2-G background, likely linked to mutations in the RNA-dependent RNA polymerase and/or in the error-correcting exonuclease protein. Despite strong bottlenecks, several de novo mutations spread to high frequencies by selection and considerable convergent evolution in spike occurs. These results demonstrate the high adaptive potential of SARS-CoV-2 during the first stages of cell infection in the absence of immune surveillance.

SARS-CoV-2 Vaccination and the Bridge between First and Fourth Dose: Where Are We?

“…The spike of SARS-CoV-2 evolves faster than other genomic regions via both point mutations [ 41 , 42 ] and recombination [ 43 ]. Therefore, several evolutionary scenarios for the future trajectory of SARS-CoV-2 [ 44 ] show that this pandemic may not yet be over.…”

Molecular Determinants of SARS-CoV-2 Variants

“…The SARS-CoV-2 genomic mutation rate in humans is estimated at 0.8-2.38 × 10 -3 nucleotide substitutions per site per year largely based on analysis of sequencing data archived in public repositories [5]. Emerging studies are attempting to confirm this mutation rate using experimental investigations [6]. By comparison, mutations rates for influenza A virus and Middle East respiratory syndrome CoV (MERS-CoV) are 2.3 × 10 -3 and 1.12 × 10 -3 nucleotide substitutions per site per year, respectively [7][8][9][10].…”

“…Human CoVs (HCoV)-OC43 and HCoV-229E have an average mutation rate of 3-6 × 10 -4 nucleotide substitutions per site per year [8]. Emerging experimental data suggest that SARS-CoV-2 is capable of mutating and accumulating changes when facing a new cell type, albeit in the absence of immune surveillance in a singlecell-type infection model [6]. A clinical study also reported the rapid evolution of SARS-CoV-2 variants in the presence of antibodies from convalescent plasma therapy [11].…”

In-Flight Transmission of a SARS-CoV-2 Lineage B.1.617.2 Harbouring the Rare S:E484Q Immune Escape Mutation

“…Mutations that either increase transmissibility or render immune escape typically result in an evolutionary gain and might quickly become dominant. The global prevalence of SARS-CoV-2, results in a high number of mutations, even though the mutation rate of the virus itself is considered to be low (0.1 per genome per infection cycle) [ 2 ]. The B.1.617.2 (Delta) lineage emerged in India during the spring of 2021 and has since become one dominant variant globally [ 3 ].…”