Kristian G. AndersenGeverifieerd account

Do you mean that it is unsurprising because this RBD (97% identity between GD pangolin CoV and SARS2) already exists in nature?

Yes - the RBD from SARS-CoV-2 clearly exists in nature as we have now seen it from a couple of pangolin CoVs. That means that the RBD from SARS2 is so "well adapted" to human ACE2 binding because of evolution in some (unknown) animal reservoir / intermediate host.

I think there are 2 issues: (1) Regarding the pangolin CoV - there is only the -1- pangolin CoV with a highly similar RBD to SARS2. It also remains a mystery how that single batch of pangolins contracted this CoV, possibly during smuggling when exposed to other animals & humans.

(2) Although a 97% identical RBD exists in another CoV, this doesn't explain the purifying selection and genetic stability of the circulating SARS2 RBD as early as Dec 2019.

That's a separate question. The lack of strong positive selection in the SARS2 spike is definitely of interest, but is it unusual? Sure, compared to SARS it is, but compared to other viruses? Not necessarily. In our paper we also consider potential 'pre'-circulation in humans.

Can you point out similar (RNA) viruses that do not have strong positive selection in their external proteins, and signs of purifying selection within weeks of emergence in humans? Agreed- we think pre-circulation in humans is possible as well and should be investigated.

Answering that question would require a broad formal analysis across multiple viruses, which I haven't done. Ebola (early) I have looked at previously, and there we get a dN/dS of ~0.5, while SARS2 (early) is ~0.3 and SARS1 (early) ~1.8.

Thank you. We can take a look at the Ebola genomes to see if it's a fair comparison. We are mainly waiting on the new mink<>human SARS2 isolates from the NL to do dN/dS and sitewise modeling. The authors said that they may release some of those genomes after a few weeks.