Slack / Private Message Drop — page 59

https://www.biorxiv.org/content/10.1101/2020.06.03.129585v1 Between the flu and eLife papers, how about a hypothesis where the virus might have been introduced into (densely packed) farmed animals and then maybe bouncing back and forth between the animals and humans for a (little) while. That'd explain the lack of positive selection in the spike (which really is *highly* unusual IMO) and also the acquisition of the furin site - it clearly seems like some sort of heavy passaging must have been required to gain that site. Checking ENaC and SARS-2, while the AAs are indeed conserved, the nucleotides are not - specifically ENaC is using human high-frequency codons, whereas SARS-2 is not. Need to check out loop structures around the furin site in SARS-1, as well as in a putative SARS-2 without the furin site. How close are we to the scenario described in the flu paper? [2020-06-06 09:22:30] [Kristian Andersen] Here's the alignment of furin site ENaC and SARS-2 [shared file(s): Screen Shot 2020-06-06 at 8.58.49 AM.png] [2020-06-06 09:49:27] [Andrew Rambaut] So only one codon the same. I got to say - Bill's HKU9 source still seems good to me. But perhaps it did happen in a mink/ferret/pangolin/civet/cat/etc. [2020-06-06 10:14:28] [Kristian Andersen] Yeah, I think Bill's explanation is basically the "hairpin followed by polymerase slippage in flu" CoV equivalent. Issue is - it could have happened anywhere.... I'm thinking a theory involving a farm isn't completely crazy - I believe Drosten is leaning that way too (and thought maybe even SARS1 could have started that way) [2020-06-06 10:20:34] [Andrew Rambaut] Farm sounds good to me. [2020-06-06 10:35:17] [Kristian Andersen] Actually, this just occurred to me and I'm wondering if the UK dataset could help investigate. Is it possible that the furin site is advantageous during high passage scenarios (transmission) but maybe not so much within host? In that scenario, maybe the furin cleavage site is maintained during exponentially increasing outbreaks (like we have observed up until about a month ago), but might be lost during more low-transmission periods? (as is the case in some places currently). In the bioRxiv paper above, they observe loss of the site in a subset of patients, but only intra-host, so based on that, it might be possible that the site _can_ be lost in human infections too, and not just in tissue culture. To see if there's a link to transmissions, if we look at viruses sequenced in low-transmission places (or during low-transmission times) vs viruses sequenced in high-transmission places (or times), is there an association with the former showing more evidence of furin site loss than the latter? Would be pretty cool if that was the case... [2020-06-06 13:42:06] [Robert Garry] The early samples in NOLA were definitely during a high-transmission period - super-spreading perhaps. Transmission has cooled down a lot - maybe a "steady-state" even - so samples from May/June may answer your question. [2020-06-06 13:49:26] [Robert Garry]