As I understand it, that lineage of coronaviruses is quite distinct from the sarbecoronavirus lineage and they don't generally infect the same host species in the same geographical regions:
> "For coronaviruses, furin cleavage sites at the interface of the S1 and S2 domain are not unusual, being found widely in betacoronaviruses in the embeco lineage (which are considered to be of rodent origin) as well as in avian-origin gammacoronaviruses and certain feline and canine alphacoronaviruses (with an unknown origin). Furin cleavage sites are also found in certain bat-origin MERS-like merbecovirises, but not—with the exception of SARS-CoV-2—in the sarbecovirus lineage."
For such a specific motif to arise naturally seems to require a scenario like multiple infection of a host species by several different wild-type coronaviruses.
Then there's this feature:
> "So far, a viable natural origin for the SARS-CoV-2 S1–S2 site through recombination or mutation of a bat-origin virus has proved to be elusive. Of note, the S1–S2 cleavage site of SARS-CoV-2 S does not comprise the pattern found in prototypical furin cleavage sites (it is RRxR and not RxK/RR),8
making its origin enigmatic. One feature of the S1–S2 junction for the SARS-CoV-2 spike from the original outbreak is the presence of a leading proline residue, which might have promoted furin cleavage."
Sarbecoronaviruses are a subset of betacoronaviruses. And I seriously doubt we have a comprehensive sequence database of all sarbecoronaviruses. If furin cleavage sites are present in about 21% of alpha- and betacoronaviruses I would expect they would also be present in a minority of most lineages within these clades. "Furin cleavage sites are also found in certain bat-origin MERS-like merbecovirises"
> For such a specific motif to arise naturally seems to require a scenario like multiple infection of a host species by several different wild-type coronaviruses.
Two would be enough. And we know that happens already (ala XBB, deltacron, etcetera).
> > "So far, a viable natural origin for the SARS-CoV-2 S1–S2 site through recombination or mutation of a bat-origin virus has proved to be elusive. Of note, the S1–S2 cleavage site of SARS-CoV-2 S does not comprise the pattern found in prototypical furin cleavage sites (it is RRxR and not RxK/RR),8 making its origin enigmatic. One feature of the S1–S2 junction for the SARS-CoV-2 spike from the original outbreak is the presence of a leading proline residue, which might have promoted furin cleavage."
This is interesting, indeed. I wonder why an engineered site wouldn't use the prototypical cleavage motif, instead using one that might need (if I'm reading the quote correctly) a leading proline residue in order to promote cleavage?
I suppose if people were inserting furin cleavage sites specifically into the Sars-CoV-2 precursor sequence, then they might generate a series of variants to see which one worked best when it came to results of infectivity tests in human cell lines?
Regarding bat lineages and host viruses, this 2019 paper seems to indicate that the other betacoronavirus lineage with the furin site, the Merbecovirus, has a different bat host range from the Sarbecovirus lineage that gave rise to Sars-CoV-2:
"Compared to Sarbecovirus and Nobecovirus, the bat hosts that harbor viruses from the Merbecovirus sub-genus are more diverse. This is in line with the presence of more CoV species belonging to Merbecovirus."
(I generally trust papers on this evolutionary origin stuff published before the pandemic a bit more than those published after, as there might be less conflicts-of-interest issues).
> I suppose if people were inserting furin cleavage sites specifically into the Sars-CoV-2 precursor sequence, then they might generate a series of variants to see which one worked best when it came to results of infectivity tests in human cell lines?
This makes sense.
I think here's the most relevant quote from that article: "So far, no betaCoVs from the sub-genus Merbecovirus have been detected in bats of suborder Yinpterochiroptera."
While the paper does mention one member of Yangochiroptera (Chaerephon plicatus) that has been discovered infected with sarbecoviruses, it looks like there's little room for infectious overlap of merbecoviruses and sarbecoviruses (which predominantly infect Yinpterochiropterans, at least as detected as of the paper publication).
So if the SARS-CoV-2 progenitor did get its furin cleavage site from a co-infection with a merbecovirus, this would have been a really rare event indeed. At least if the co-infection happened in a bat species, and not in another animal or a human who deals with bats.
> "For coronaviruses, furin cleavage sites at the interface of the S1 and S2 domain are not unusual, being found widely in betacoronaviruses in the embeco lineage (which are considered to be of rodent origin) as well as in avian-origin gammacoronaviruses and certain feline and canine alphacoronaviruses (with an unknown origin). Furin cleavage sites are also found in certain bat-origin MERS-like merbecovirises, but not—with the exception of SARS-CoV-2—in the sarbecovirus lineage."
For such a specific motif to arise naturally seems to require a scenario like multiple infection of a host species by several different wild-type coronaviruses.
Then there's this feature:
> "So far, a viable natural origin for the SARS-CoV-2 S1–S2 site through recombination or mutation of a bat-origin virus has proved to be elusive. Of note, the S1–S2 cleavage site of SARS-CoV-2 S does not comprise the pattern found in prototypical furin cleavage sites (it is RRxR and not RxK/RR),8 making its origin enigmatic. One feature of the S1–S2 junction for the SARS-CoV-2 spike from the original outbreak is the presence of a leading proline residue, which might have promoted furin cleavage."
https://www.thelancet.com/journals/lanmic/article/PIIS2666-5...
At this point, the lab-accident-theory looks more likely than the natural-origin-theory.