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> The BANAL viruses are a couple of mutations away from a workable furin cleavage site, That's true, but you can argue it in either direction. It proves the mu

> The BANAL viruses are a couple of mutations away from a workable furin cleavage site, That's true, but you can argue it in either direction. It proves the mutations to create that FCS are possible and indeed likely; but it also proves they're selected against in their usual hosts, or else we'd have observed the complete FCS. So you need the mutation to happen concurrently with the species jump (or in a yet-undiscovered intermediate host), which gets less likely.

lamontcg 4y ago
> it also proves they're selected against in their usual hosts No it doesn't. They can be neutral. And BtCoV-HKU5 is a MERS-like bat coronavirus with a functional FCS and BtHpCoV-ZJ13 is even closer to sarbecoviruses than MERS and is another bat coronavirus with an FCS. It is more likely that the absence of an FCS in BANAL-like viruses is due to us not having found them yet, our surveillance coverage is immeasurably poor. And a species jump involving coinfection with proto-SARS-CoV-2 and some other coronavirus and a recombination event is actually a likely way to start a pandemic. The 2009 H1N1 pandemic was started by a triple reassortment with three viruses in a pig. Pandemics are very uncommon infection events so the conditions that create them are necessarily highly unlikely.
- tripletao 4y ago
  > No it doesn't. They can be neutral. That's a fair point. Properly I guess we should try to quantify the number of samples expected before we observe an FCS if it's neutral, but that math seems nontrivial. It's at least definitely not beneficial, though. I do agree that the FCS could have evolved naturally, though I guess we'll continue to disagree on the relative probabilities of natural vs. lab-inserted. That sick pig was probably infected with each virus for days or longer, so that coinfection seems less unlikely to me than a simultaneous species jump and mutation to create the FCS (since those are both roughly instantaneous by comparison). I'm not sure what I'd consider the most likely zoonotic path now; the close identity between the BANAL and SARS-CoV-2 spikes seems like it removes the need for an intermediate host with human-like ACE2, though it's pretty mysterious.
  - lamontcg 4y ago
    > a simultaneous species jump and mutation to create the FCS (since those are both roughly instantaneous by comparison). I don't know why you think this is necessary. The FCS shouldn't preclude the infection continuing in the original species, like I said it probably doesn't infectivity in bats and is neutral. And if the intermediate animal was infected with a common coronavirus for the species, all it takes is coinfection from a bat with the precursor to SARS-CoV-2 and a recombination event to create the FCS. Animals and humans across china are almost certainly getting infected with novel sarbecoviruses from bats every day. Most of them don't go anywhere. This one got "lucky" and stole some genetic material which made it better in the new host organism and now it is off to the races. Which is unlikely, but, again, pandemics are unlikely.
    - tripletao 4y ago
      Assuming the FCS is neutral in bats (which I don't think we could prove or disprove without more sampling, but which I agree is possible), I agree that the mutation wouldn't have to happen concurrently with the species jump. Even if the FCS is negative in bats, it's also possible that the FCS evolved naturally in a different animal host. I agree there's no evidence to exclude those scenarios; I just don't see any specific evidence to favor them either.

lamontcg 4y ago

> it also proves they're selected against in their usual hosts No it doesn't. They can be neutral. And BtCoV-HKU5 is a MERS-like bat coronavirus with a functional FCS and BtHpCoV-ZJ13 is even closer to sarbecoviruses than MERS and is another bat coronavirus with an FCS. It is more likely that the absence of an FCS in BANAL-like viruses is due to us not having found them yet, our surveillance coverage is immeasurably poor. And a species jump involving coinfection with proto-SARS-CoV-2 and some other coronavirus and a recombination event is actually a likely way to start a pandemic. The 2009 H1N1 pandemic was started by a triple reassortment with three viruses in a pig. Pandemics are very uncommon infection events so the conditions that create them are necessarily highly unlikely.

tripletao 4y ago
> No it doesn't. They can be neutral. That's a fair point. Properly I guess we should try to quantify the number of samples expected before we observe an FCS if it's neutral, but that math seems nontrivial. It's at least definitely not beneficial, though. I do agree that the FCS could have evolved naturally, though I guess we'll continue to disagree on the relative probabilities of natural vs. lab-inserted. That sick pig was probably infected with each virus for days or longer, so that coinfection seems less unlikely to me than a simultaneous species jump and mutation to create the FCS (since those are both roughly instantaneous by comparison). I'm not sure what I'd consider the most likely zoonotic path now; the close identity between the BANAL and SARS-CoV-2 spikes seems like it removes the need for an intermediate host with human-like ACE2, though it's pretty mysterious.
- lamontcg 4y ago
  > a simultaneous species jump and mutation to create the FCS (since those are both roughly instantaneous by comparison). I don't know why you think this is necessary. The FCS shouldn't preclude the infection continuing in the original species, like I said it probably doesn't infectivity in bats and is neutral. And if the intermediate animal was infected with a common coronavirus for the species, all it takes is coinfection from a bat with the precursor to SARS-CoV-2 and a recombination event to create the FCS. Animals and humans across china are almost certainly getting infected with novel sarbecoviruses from bats every day. Most of them don't go anywhere. This one got "lucky" and stole some genetic material which made it better in the new host organism and now it is off to the races. Which is unlikely, but, again, pandemics are unlikely.
  - tripletao 4y ago
    Assuming the FCS is neutral in bats (which I don't think we could prove or disprove without more sampling, but which I agree is possible), I agree that the mutation wouldn't have to happen concurrently with the species jump. Even if the FCS is negative in bats, it's also possible that the FCS evolved naturally in a different animal host. I agree there's no evidence to exclude those scenarios; I just don't see any specific evidence to favor them either.