Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic

Maciej F Boni; Philippe Lemey; Xiaowei Jiang; Tommy Tsan-Yuk Lam; Blair Perry; Todd Castoe; Andrew Rambaut; David L Robertson

However, on closer inspection, the relative divergences in the phylogenetic tree (Figure 3 , bottom) show that SARS-CoV-2 is unlikely to have acquired the variable loop from an ancestor of Pangolin-2019 as these two sequences are approximately 10% divergent throughout the entire S protein (excluding the NTD). It is RaTG13 that is divergent in the variable loop region and is the likely product of recombination, acquiring a divergent . CC-BY-NC 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.30.015008 doi: bioRxiv preprint 7 / 25 variable loop from an as yet unsampled bat sarbecovirus. This is notable because the variable loop region contains the six key contact residues in the receptor binding domain (RBD) that give SARS-CoV-2 its ACE2 binding specificity Wan et al., 2020) . These residues are also in the 2019 pangolin coronavirus sequence. The most parsimonious explanation for these shared residues is a single bat virus lineage (including the common ancestor of SARS-CoV-2, RaTG13, and Pangolin Guangdong 2019) has the ACE2 specific residues, rather than the SARS-CoV-2 being recombinant. This provides compelling support for the SARS-CoV-2 lineage being the consequence of a direct or nearly-direct zoonotic jump from bats because the key ACE2 binding residues were present in viruses circulating in bats.