Synonymous mutations and the molecular evolution of SARS-Cov-2 origins

Abstract

1Human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is most closely 2 related, by average genetic distance, to two coronaviruses isolated from bats, RaTG13 and 3 RmYN02. However, there is a segment of high amino acid similarity between human CoV-2 and a pangolin isolated strain, GD410721, in the receptor binding domain (RBD) of 5 the spike protein, a pattern that can be caused by either recombination or by convergent 6 amino acid evolution driven by natural selection. We perform a detailed analysis of the 7 synonymous divergence, which is less likely to be affected by selection than amino acid 8 divergence, between human SARS-CoV-2 and related strains. We show that the 9 synonymous divergence between the bat derived viruses and SARS-CoV-2 is larger than 10 between GD410721 and SARS-CoV-2 in the RBD, providing strong additional support for 11 the recombination hypothesis. However, the synonymous divergence between pangolin 12 strain and SARS-CoV-2 is also relatively high, which is not consistent with a recent 13 recombination between them, instead it suggests a recombination into RaTG13. We also 14 find a 14-fold increase in the d N /d S ratio from the lineage leading to SARS-CoV-2 to the 15 strains of the current pandemic, suggesting that the vast majority of non-synonymous 16 mutations currently segregating within the human strains have a negative impact on viral 17fitness. Finally, we estimate that the time to the most recent common ancestor of SARS-18CoV-2 and RaTG13 or RmYN02 based on synonymous divergence, is 51.71 years (95% 19 C.I., 28.11-75.31) and 37.02 years (95% C.I., 18.19-55.85), respectively. 20 21 a coronavirus (Lu, et al. 2020; Zhang and Holmes 2020), Severe acute respiratory syndrome 1 coronavirus 2 (SARS-CoV-2), an RNA virus with a 29,891 bp genome consisting of four major 2 structural genes (Wu, et al. 2020; Zhou, Yang, et al. 2020). Of particular relevance to this study 3 is the spike protein which is responsible for binding to the primary receptor for the virus, 4 angiotensin-converting enzyme 2 (ACE2) (Wan, et al. 2020; Wu, et al. 2020; Zhou, Yang, et al. 5 2020). 6Human SARS-CoV-2 is related to a coronavirus (RaTG13) isolated from the bat 7Rhinolophus affinis from Yunnan province of China (Zhou, Yang, et al. 2020). RaTG13 and the 8 human strain reference sequence (Genbank accession number MN996532) are 96.2% identical 9and it was first argued that, throughout the genome, RaTG13 is the closest relative to human 10 SARS-CoV-2 (Zhou, et al. 2020). Zhang, et al. 2020 showed that RaTG13 and SARS-CoV-2 11 were 91.02% and 90.55% identical ,respectively, to coronaviruses isolated from pangolins 12 (Pangolin-CoV), which therefore form a close outgroup to the SARS-CoV-2+RaTG13 clade . 13 Furthermore, five key amino acids in the receptor-binding domain (RBD) of spike were identical 14 between SARS-CoV-2 and Pangolin-CoV, but differed between those two strains and RaTG13. 15 (Lam, et al. 2020) independently made similar observations and additionally showed that when 16 analyzing...

Natural selection in the evolution of SARS-CoV-2 in bats, not humans, created a highly capable human pathogen

“…We first analyse selection acting on the encoded amino acids of SARS-CoV-2 using 50,240 QC filtered genome sequences from the GISAID database as of the 28th of June 2020, representing a sample of the variants circulating in humans (see Methods). Purifying selection acts more strongly on nonsynonymous sites, supported by the estimate that the nonsynonymous substitution rate (dN) was only 4% of speed of the synonymous substitution rate (dS) in the divergence between SARS-CoV-2 and bat virus RaTG13 24 . We used the phylogenetically corrected SLAC counting method 25 to calculate "frequency-stratified" dN/dS estimates.…”

Profile of a killer: the complex biology powering the coronavirus pandemic

“…Then, sometime in the past 40-70 years, the ancestors of SARS-CoV-2 separated from the bat version, which subsequently lost the effective receptor binding domain that was present in its ancestors (and remains in SARS-CoV-2). A study published on 21 April came up with very similar findings using a different dating method 7 .…”

Comparisons of the genome of SARS-CoV-2 and those of other betacoronaviruses

“…Nonetheless, it is probable that SARS-2 and YN02 diverged over 20 years ago, and the two recombinant regions characteristic of the SARS-2, YN02 and RaTG13 virus genomes were acquired by their shared progenitor more than 30, but less than 80, years ago! All these datings are based on a large number of assumptions, and could be earlier as concluded by Wang et al (2020).…”

“…It is the seventh CoV of humans to be reported (Rodríguez-Román and Gibbs, 2020;Ye et al, 2020), and it has generated a pandemic with more than 10 million people infected, and 0.5 million people dead by the end of June 2020. While trying to establish from where this virus emerged, there have been conflicting claims that it may have come from bats or pangolins, and is most closely related to either the YN02 virus or the RaTG13 virus (Li et al, 2020;Lin and Chen, 2020;Wang et al, 2020;Xiao et al, 2020;Zhou et al, 2020), and in this short paper we resolve some of these differences and discus an interesting betacoronavirus region -DUF3655!…”