@article {Wang2020.04.20.052019, author = {Hongru Wang and Lenore Pipes and Rasmus Nielsen}, title = {Synonymous mutations and the molecular evolution of SARS-Cov-2 origins}, elocation-id = {2020.04.20.052019}, year = {2020}, doi = {10.1101/2020.04.20.052019}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is most closely related, by average genetic distance, to two coronaviruses isolated from bats, RaTG13 and RmYN02. However, there is a segment of high amino acid similarity between human SARS-CoV-2 and a pangolin isolated strain, GD410721, in the receptor binding domain (RBD) of the spike protein, a pattern that can be caused by either recombination or by convergent amino acid evolution driven by natural selection. We perform a detailed analysis of the synonymous divergence, which is less likely to be affected by selection than amino acid divergence, between human SARS-CoV-2 and related strains. We show that the synonymous divergence between the bat derived viruses and SARS-CoV-2 is larger than between GD410721 and SARS-CoV-2 in the RBD, providing strong additional support for the recombination hypothesis. However, the synonymous divergence between pangolin strain and SARS-CoV-2 is also relatively high, which is not consistent with a recent recombination between them, instead it suggests a recombination into RaTG13. We also find a 14-fold increase in the dN/dS ratio from the lineage leading to SARS-CoV-2 to the strains of the current pandemic, suggesting that the vast majority of non-synonymous mutations currently segregating within the human strains have a negative impact on viral fitness. Finally, we estimate that the time to the most recent common ancestor of SARS-CoV-2 and RaTG13 or RmYN02 based on synonymous divergence, is 51.71 years (95\% C.I., 28.11-75.31) and 37.02 years (95\% C.I., 18.19-55.85), respectively.Competing Interest StatementThe authors have declared no competing interest.}, URL = {https://www.biorxiv.org/content/early/2020/04/21/2020.04.20.052019}, eprint = {https://www.biorxiv.org/content/early/2020/04/21/2020.04.20.052019.full.pdf}, journal = {bioRxiv} }