Positive selection within the genomes of SARS-CoV-2 and other Coronaviruses independent of impact on protein function

Abstract

Background The emergence of a novel coronavirus (SARS-CoV-2) associated with severe acute respiratory disease (COVID-19) has prompted efforts to understand the genetic basis for its unique characteristics and its jump from non-primate hosts to humans. Tests for positive selection can identify apparently nonrandom patterns of mutation accumulation within genomes, highlighting regions where molecular function may have changed during the origin of a species. Several recent studies of the SARS-CoV-2 genome have identified signals of conservation and positive selection within the gene encoding Spike protein based on the ratio of synonymous to nonsynonymous substitution. Such tests cannot, however, detect changes in the function of RNA molecules. Methods Here we apply a test for branch-specific oversubstitution of mutations within narrow windows of the genome without reference to the genetic code. Results We recapitulate the finding that the gene encoding Spike protein has been a target of both purifying and positive selection. In addition, we find other likely targets of positive selection within the genome of SARS-CoV-2, specifically within the genes encoding Nsp4 and Nsp16. Homology-directed modeling indicates no change in either Nsp4 or Nsp16 protein structure relative to the most recent common ancestor. These SARS-CoV-2-specific mutations may affect molecular processes mediated by the positive or negative RNA molecules, including transcription, translation, RNA stability, and evasion of the host innate immune system. Our results highlight the importance of considering mutations in viral genomes not only from the perspective of their impact on protein structure, but also how they may impact other molecular processes critical to the viral life cycle.

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

“…In addition to the gene-level mutation rate analysis, we next sought to estimate the synonymous and non-synonymous mutation rates per site per day, and the daily dN/dS ratio for each gene and country, using the conservative model previously described by Vega et al (Supplementary File 1). Our results show that most SARS-CoV-2 genes have undergone negative selection, consistent with previous findings (Berrio, Gartner & Wray, 2020). In both the UK and the US, the dN/dS ratio is highly similar for the majority of genes across genotypes.…”

The Mutation Profile of SARS-CoV-2 Is Primarily Shaped by the Host Antiviral Defense

“…The highest mutational position, 11,083, has been associated with the severity of the virus [ 29 ]. Together with 11,083, mutations at 23,403, 21,575, 28,881, and 28,883 positions [ 30 , 31 , 32 , 33 ] have been associated with significant indication towards selection. In particular, the D614G mutation on Spike protein is associated with the fitness of the virus by both computational and clinical studies [ 32 , 33 , 34 ].…”

Mutations in Animal SARS-CoV-2 Induce Mismatches with the Diagnostic PCR Assays

“…The SARS-CoV-2, like SARS-CoV and HCoV-NL63, uses the angiotensin-converting enzyme 2 (ACE2) receptor for host cell entry [ 2 , 64 , 65 ]. As the virus infects the animals and evolves during the outbreak, nucleotide substitutions may emerge in the primer/probe binding regions including the S gene [ 54 , 66 , 67 ]. The current SARS-CoV-2 genomes were isolated from animals where there are considerable differences in the ACE2 receptors compared with humans.…”

“…Therefore, adaptation of the virus to animals will likely be different from humans, resulting in the accumulation of different mutations in the S gene due to the differences in the ACE2 [ 26 , 68 , 69 ]. The S gene was reported to be under persistent positive selection [ 66 ], which may result in additional mutations accumulating in the S gene in the future.…”