[lamontcg]

That means they were several decades of evolution in the wild away from each other.

It would take passage through billions of organisms to turn RaTG13 into SARS-CoV-2.

Which is probably what happened naturally through many, many millions of bats (and whatever intermediate animal) being infected and passing it on. Something that is well outside the scale of serial passage experiments in a lab.

[sterlind]

How do you arrive at several decades and billions of organisms? You can't extrapolate the current mutation rate to the spillover event; SARS-CoV-2 was already quite fit at infecting humans and didn't need to change much. In contrast, during spillover events there's heavy selection pressure to adapt to the new host.

There's also the possibility of recombination events, which can instantly cause significant drift. Now consider the case of the Mojiang miners, who contracted and slowly succumbed to viral pneumonia in 2012 after inhaling bat guano. WIV found, like, a dozen beta-coronaviruses in that cave alone (including RaTG13.) The miners could have been exposed to several at once, which recombined and adapted quickly to their new home in human lungs. Again, unlikely to have been SARS-CoV-2, since the pandemic almost certainly would have happened already, but whatever they had was virulent enough to kill half of them.

[lamontcg]

The genetic clock was estimated from bat coronavirus mutation rates in the wild, not from SARS-CoV-2 mutation in humans.

And virulence != transmissible. They got sick by inhaling everything that was floating around in that mine. To get more people sick you'd need to take them all to that mine.

Recombination to produce a viable and more successful virus is also very rare, that is unlikely to have happened to any of those miners, much less several of them (over populations it becomes likely but there we're talking many millions of infections as well).

[peteradio]

DEFUSE proposed insertion of human-specific cleavage sites not serial passage.

[lamontcg]

RaTG13 differs from SARS-CoV-2 by a lot more than just an FCS

[peteradio]

How far away would it be? Would it still take millions and millions of bats or is it now within the realm of possibility to infect humanized mice and get SARS-CoV-2 out the other end?

[lamontcg]

Yes, you're still a thousand mutations away from each other. The FCS is tiny. The mutations are spread all over the entire genome--although the main areas are in spike RBD (which suggests that RaTG13 may not be able to use ACE2 at all). The PRRAR FCS that SARS-CoV-2 uses is also a previously-unknown-to-humans FCS and not one a human scientist would have naively guessed would work.

[peteradio]

Thanks.