Slack / Private Message Drop — page 268

[2020-11-20 21:50:52] [Eddie Holmes] We do! You can almost hear the squelching of the underpants on the couch. [2020-11-21 04:25:37] [Andrew Rambaut] I jotted down some scribbled notes I had been making about why SC2 is likely natural origins: https://docs.google.com/document/d/1lPzBuXW0BY0okNljUBjmOSzDvwMsiW_UGMHYcyCWD4E/edit Basically it comes down to the only lab-escape scenario that could give you SC2 is if SC2 was in the lab and then escaped. And this is a very-very-specific version of all the other (infinitely more numerous) paths from bats->humans. [2020-11-21 06:22:25] [Robert Garry] Thanks for the link Andrew - great list... [2020-11-21 07:17:54] [Robert Garry] *I do agree that Proximal Origins 2 should happen sooner than later - just not certain of the best approach or approaches -we seem to have attracted some attention with PO1 so a sequel - given the persistence of the unnatural crowd would likely be noticed. @Andrew Rambaut has made a good start. Virological posts for sure - another correspondence in Nature/Nat Med - And, though it might be considered bad form but I could even see a hard cover book for popular consumption (lot of work, but might be worth it).* [2020-11-21 07:18:33] [Robert Garry] *Naturally occurring indels in multiple coronavirus spikes* *Introduction* Proponents of theories for the unnatural origin of SARS-CoV-2 have asserted that the 12 nucleotide insert in the SARS-CoV-2 spike gene, which results in acquisition of a furin cleavage site, may have arisen by laboratory manipulation (Relman, 2020; Segreto and Deigin, 2020; Seyran et al., 2020; Sirotkin and Sirotkin, 2020). Here, we compile evidence demonstrating that that insertion/deletion (indel) events at the S1/S2 and S2' protease cleavage sites of the spike precursor are commonly occurring natural features of coronavirus evolution. We also identify heretofore undescribed similarities in the S1/S2 and S2' junctions of multiple diverse coronavirus spikes that provide further evidence again a laboratory origin of SARS-CoV-2. *Methods* The _Orthocoronaviridae_ includes four genuses, _Alpha-_, _Beta-_, _Gamma-_ and the newly described _Deltacoronavirus (Taxonomy)_. The _Betacoronavirus_ genus is further subdivided into six subgenuses, including the three subgenuses _Sarbecoviruses_, _Merbecoviruses and Embecoviruses_ with human pathogens. We performed an alignment of the S1/S2 junction of representative alpha-, beta-, and gammacoronaviruses (Fig. 1). To facilitate the identification of insertions we aligned conserved amino acids and other features that flank the S1/S2 junctions, and included viruses that appear to be ancestral to the subgenuses where known. O-linked glycosylation sites were predicted by Net-O-Glyc v. 4.0 (Steentoft et al., 2013). *Results* While recent analyses suggest the existence of as yet unsampled sarbecovirus lineages, it is likely that SARS-CoV-2 and recently described coronaviruses isolated from pangolins share common ancestors with the bat sarbecovirus RaTG13 (Boni et al., 2020). As previously discussed (Andersen et al., 2020; Coutard et al., 2020; Gallaher, 2020a), alignment of the spike protein of SARS-CoV-2 with spike proteins of RaTG13 and other sarbecoviruses demonstrates that the 12 base insertion in the SARS-CoV-2 spike gene adds 4 amino acids (PRRA) at the S1/S2 junction and converts a monobasic cleavage site (R) to a minimal furin (polybasic) cleavage site (RRAR) (Fig. 1A). As previously described (Zhou et al., 2020), alignment of the spike of newly detected RmYN02 with other sarbecovirus spikes demonstrates that the S1/S2 junction of sarbecoviruses is variable. The neural network prediction algorithm Net-O-Glyc predicts that the S1/S2 junction of SARS-CoV-2 spike contains 3 O-linked glycans.