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

Continued evolution and adaptation of SARS-CoV-2 has led to more transmissible and immune-evasive variants with profound impacts on the course of the pandemic. Here I analyze the evolution of the virus over 2.5 years since its emergence and estimate the rates of evolution for synonymous and non-synonymous changes separately for evolution within clades-well-defined monophyletic groups with gradual evolution-and for the pandemic overall. The rate of synonymous mutation 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 of 7 changes per year (or [Formula: see text] per year and codon). In contrast, the rate at which variants accumulate amino acid changes (non-synonymous mutations) was initially around 12-16 changes per year, but in 2021 and 2022 it dropped to 6-9 changes per year. The overall rate of non-synonymous evolution, that is across variants, is estimated to be about 26 amino acid changes per year (or [Formula: see text] per year and codon). This strong acceleration of the overall rate compared to within clade evolution 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 and show that the massive global sampling of SARS-CoV-2 is sufficient to estimate site-specific fitness costs across the entire genome. Many accessory proteins evolve under limited evolutionary constraints with little short-term purifying selection. About half of the mutations in other proteins are strongly deleterious.