Thread by @Ayjchan

Our peer-reviewed @MolBioEvol Perspective on the SARS-CoV-2 furin cleavage site is now available to read online.

We review the FCS in the context of pathogenesis, origin & how virus sampling may alter the interpretation of existing data.
@shingheizhan

academic.oup.com/mbe/advance-ar…

@MolBioEvol @shingheizhan Against a backdrop of scientists introducing FCSs into the spikes of various CoVs including SARSr-CoVs, the discovery of a unique FCS at the spike S1/S2 boundary in SARS-CoV-2 continues to fuel heated debates about the #OriginOfCovid

@MolBioEvol @shingheizhan Without its FCS, it is unlikely that SARS-CoV-2 would have resulted in a pandemic.

Even in early 2020, it was a straightforward deduction for independent groups of scientists that an S1/S2 FCS could confer functional advantages to a SARSr-CoV.

In humans, mutations impacting the FCS have been rare.

Less than 0.05% of the sequences have mutations at R682 or R683, and even fewer (0.0007%) have mutations at R685.

Leading scientists to suggest that the FCS may be experiencing strong purifying selection in humans.

It is currently difficult to know exactly how unique the SARS-CoV-2 PRRA motif is among SARS-CoV-2-like spike sequences because these viral lineages are relatively under-sampled.

Some papers have proposed alignments that suggest "natural insertions" at the S1/S2 region in some SARS2-like CoVs; however, these still do not result in a polybasic motif or an FCS.

From our analysis, these alignments represent only one of numerous possible alignments.

The most closely related spike genes do not have an apparent S1/S2 FCS.

These observations suggest that among sarbecoviruses, an S1/S2 FCS recently emerged in SARS-CoV-2.

Jack Nunberg, whose group first inserted an S1/S2 FCS into the spike of SARS-CoV, said: “there is no way to know whether humans or nature inserted the site” in SARS-CoV-2.
nature.com/articles/d4158…

Gary Whittaker, another virologist whose group also inserted an S1/S2 FCS into the spike of SARS-CoV recently published a comment describing the SARS-CoV-2 FCS as “highly unusual”.

thelancet.com/journals/lanmi…

Virologist David Baltimore commented that “these features make a powerful challenge to the idea of a natural origin for SARS2,” later clarifying that “you can't distinguish between the two origins from just looking at the sequence”.
caltech.edu/about/news/the…

A group of scientists (including frm the Wuhan Institute of Virology) had, in March 2018, proposed a roadmap for detecting novel proteolytic cleavage sites (including FCSs) in the spike sequences of novel SARSrCoVs and inserting these into other SARSrCoVs. theintercept.com/2021/09/23/cor…

After reading the DEFUSE proposal, Nunberg told @theintercept "Whether that particular study did or didn’t [lead to the pandemic], it certainly could have. Once you make an unnatural virus, you’re basically setting it up in an unstable evolutionary place."

An S1/S2 FCS emerging in a SARSrCoV is consistent with natural evolution. Even so, the knowledge that scientists had a workflow for introducing novel cleavage sites into novel SARSrCoVs makes it challenging to determine the origin of the SARS-CoV-2 S1/S2 FCS.