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Slack / Private Message Drop, p.59 [SLACK_000273] · slack_pm:msg:00592

Date: 2020-06-06 10:14
Type: chat message · slack
recipient: Robert F. Garry, Edward C. Holmes, Andrew Rambaut
speaker: Kristian G. Andersen

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Yeah, I think Bill's explanation is basically the "hairpin followed by polymerase slippage in flu" CoV equivalent. Issueis - 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)

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2020-06-06 09:21 Kristian G. Andersen open

The eLife and flu 'polymerase slippage' papers are very interesting indeed. As to how beneficial the furin site is inhumans, I thought this one was reasonably interesting (although I don't believe we have seen this in our sequences- we'll dig deeper):https://www.biorxiv.org/content/10.1101/2020.06.03.129585v1Between the flu and eLife papers, how about a hypothesis where the virus might have been introduced into (denselypacked) 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 isusing 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 Kristian G. Andersen open

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 Andrew Rambaut open

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 amink/ferret/pangolin/civet/cat/etc.
2020-06-06 10:14 Kristian G. Andersen

Yeah, I think Bill's explanation is basically the "hairpin followed by polymerase slippage in flu" CoV equivalent. Issueis - 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 Andrew Rambaut open

Farm sounds good to me.
2020-06-06 10:35 Kristian G. Andersen open

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 insome places currently).In the bioRxiv paper above, they observe loss of the site in a subset of patients, but only intra-host, so based onthat, it might be possible that the site _can_ be lost in human infections too, and not just in tissue culture. To see ifthere'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...

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