Contributions of adaptation and purifying selection to SARS-CoV-2 evolution

Abstract

Continued evolution and adaptation of SARS-CoV-2 has lead to more transmissible and immune-evasive variants with profound impact on the course of the pandemic. Here I analyze the evolution of the virus over 2.5 years since its emergence and estimate rates of evolution for synonymous and non-synonymous changes separately for evolution within clades -- well defined mono-phyletic groups with gradual evolution -- and for the pandemic overall. The rate of synonymous mutations is found to be around 6 changes per year. Synonymous rates within variants vary little from variant to variant and are compatible with the overall rate. In contrast, the rate at which variants accumulate amino acid changes (non-synonymous mutation) was initially around 12-16 changes per year, but in 2021 and 2022 dropped to 6-9 changes per year. The overall rate of non-synonymous evolution, that is across variants, is estimated to be about 25 amino acid changes per year. This 2-fold higher rate indicates that the evolutionary process that gave rise to the different variants is qualitatively different from that in typical transmission chains and likely dominated by adaptive evolution. I further quantify the spectrum of mutations and purifying selection in different SARS-CoV-2 proteins. Many accessory proteins evolve under limited evolutionary constraint with little short term purifying selection. About half of the mutations in other proteins are strongly deleterious and rarely observed, not even at low frequency.

A pseudovirus system enables deep mutational scanning of the full SARS-CoV-2 spike

“…The approach for calculating the enrichment of observed versus expected mutations is inspired by the strategy used in (Neher, 2022). Briefly, we downloaded the pre-built UShER tree of all publicly available SARS-CoV-2 sequences (Turakhia et al, 2021) as of Sept-26-2022 from http://hgdownload.soe.ucsc.edu/goldenPath/wuhCor1/UShER_SARS-CoV-2/2022/09/26/public-2022-09-26.all.masked.nextclade.pangolin.pb.gz.…”

“…This is an important distinction, as a mutation could be common in the final aligned sequences even if it only had one or a few occurrences. In counting these occurrences, we ignored mutations on any branch with more than four nucleotide mutations, or more than one nucleotide mutation to either the Wuhan-Hu-1 reference sequence or the founder sequence for that clade, as taken from (Neher, 2022). The reason for excluding mutations on branches with high numbers of mutations as these can often indicate problematic sequences; the reason for excluding mutations on branches with multiple reversions to reference is that sometimes sequences with missing coverage have identities automatically called to reference.…”

<strong>Attenuation and Degeneration of SARS-CoV-2 Despite of Adaptive Evolution</strong>

“…These findings by Kim et al indicate that the virus can take advantage of the host cell RNA editing enzymes for adaptive evolution. But as expected, most mutations turn out to be destructive and subject to purifying selection [57][58][59], whether they are imposed on the virus by the host or due to errors during viral replication.…”

“…Neher compared the synonymous and nonsynonymous mutation rates of the viral clades that arose from 2019 to 2022. Synonymous mutation rates remained constant at about five to eight base changes per genome per year for all clades, but nonsynonymous mutation rates dropped from the highest of 16.41 per genome per year (clade 19B++) to the lowest of 2.81 per genome per year (clade 22A) [58]. Figure 1 is plotted using Neher's data, demonstrating a negative correlation between intra-clade mutation rates and time.…”

“…Even though nonsynonymous mutations concentrate in the spike protein, they also accumulate in other genes throughout the viral genome. Unlike the surface protein and the RNA polymerase, accessory proteins demonstrate little restraint on amino acid substitutions [58,66]. Accumulation of mutations in proteins that are loosely selected may contribute to genetic degradation in the long term.…”