Causes and Consequences of Purifying Selection on SARS-CoV-2

Abstract

Owing to a lag between a deleterious mutation’s appearance and its selective removal, gold-standard methods for mutation rate estimation assume no meaningful loss of mutations between parents and offspring. Indeed, from analysis of closely related lineages, in SARS-CoV-2 the Ka/Ks ratio was previously estimated as 1.008, suggesting no within-host selection. By contrast, we find a higher number of observed SNPs at 4-fold degenerate sites than elsewhere and, allowing for the virus’s complex mutational and compositional biases, estimate that the mutation rate is at least 49-67% higher than would be estimated based on the rate of appearance of variants in sampled genomes. Given the high Ka/Ks one might assume that the majority of such intra-host selection is the purging of nonsense mutations. However, we estimate that selection against nonsense mutations accounts for only ∼10% of all the “missing” mutations. Instead, classical protein-level selective filters (against chemically disparate amino acids and those predicted to disrupt protein functionality) account for many missing mutations. It is less obvious why for an intracellular parasite, amino acid cost parameters, notably amino acid decay rate, are also significant. Perhaps most surprisingly, we also find evidence for real time selection against synonymous mutations that move codon usage away from that of humans. We conclude that there is common intra-host selection on SARS-CoV-2 that acts on nonsense, missense and possibly synonymous mutations. This has implications for methods of mutation rate estimation, for determining times to common ancestry and the potential for intra-host evolution including vaccine escape.

A global analysis of conservative and non-conservative mutations in SARS-CoV-2 detected in the first year of the COVID-19 world-wide diffusion

“…The analysis of the diffusion of specific missense mutations in the human population has received particular attention throughout the pandemic evolution 3 , 8 , 9 , 12 – 22 . It has been pointed out that the D614G mutation, a non-conservative mutation with a PAM value of 11, in the Spike protein, which occurred through a single base change, has increased the virus infectivity 23 – 25 .…”

Emergence of SARS-CoV-2 Variants in the World: How Could This Happen?

“…Regarding the genetic diversity of SARS-CoV-2, a study evaluating hospitalized patients in China in early 2020 found a mutation rate of 1.1-6.2 × 10 −3 /site/year [37]. More recent studies suggest a lower mutation rate, between 1.5-1.7 × 10 −3 /site/year [38]. This rate is similar than other RNA viruses such as seasonal influenza (H1N1, H3N2) with a rate between 0.6-2.0 × 10 −3 /site/year [37].…”

Aggregation of high‐frequency RBD mutations of SARS‐CoV‐2 with three VOCs did not cause significant antigenic drift

“…Mutation statistics by the National Genomics Data Center ( https://ngdc.cncb.ac.cn/ ) and other reports showed that the rate of viral mutation of the spike protein has continued to increase since the SARS‐CoV‐2 pandemic 13 and new variants continue to emerge. Based on this, the World Health Organization (WHO) classifies variants into variants of concern (VOCs) and variants of interest (VOI) based on the degree of variability in transmissibility, virulence, or diagnostic/therapeutic/vaccine efficacy.…”