6 ms·

Can someone explain why the furin cleavage site is unusual from a natural evolutionary view?

jeremyjh 5y ago
If a feature would make the virus very unsuccessful in bats, then how did it propagate? There had to be another cross-over species or something but no one has any data to suggest what that is. China has apparently made it impossible to do the work of piecing that together, so the lab leak hypothesis may never be put to bed. Maybe the party leadership believes a lab leak is likely even if they have no specific knowledge of it.
- DarknessFalls 5y ago
  To add to my original question, is the furin cleavage site further adapted in the Omicron variant, explaining its increased infectiousness? If so, what is the difference between that and the Delta variant?
  - Sparyjerry 5y ago
    The Omicron variant is actual prior to Delta variant and prior to all other variants even so named Alpha variant. This article indicates why Omicron could be yet another lab leak. https://bprice.substack.com/p/lab-leak-20 https://bprice.substack.com/p/lab-leak-20
- tim333 5y ago
  EcoHealth Alliance, the main US funders of the Wuhan lab have been awfully shy about letting anyone see their data. There's a good chance proof is there and the data can legally forced out of them.
_Nat_ 5y ago
RootClaim discusses that claim and its perceived relevance [here](https://www.rootclaim.com/analysis/What-is-the-source-of-COVID-19-SARS-CoV-2#furin_cleavage https://www.rootclaim.com/analysis/What-is-the-source-of-COV... ).
- CamperBob2 5y ago
  Hmm, that's a nifty site, reminiscent in some ways of Metaculus but with an actual methodology behind it rather than just prediction aggregation. Very nice UI/UX as well. I'm surprised I've never heard of it.
  - _Nat_ 5y ago
    Yeah, just saw it linked [in this comment](https://news.ycombinator.com/item?id=29902330 https://news.ycombinator.com/item?id=29902330 ). Currently, it seems most helpful in aggregating some of the arguments folks put forth in examining claims, including describing the basic issues and linking some references. Plus it seems to offer some insight into what folks are thinking. Then from an academic perspective, I really like the sort of approach that they're trying to use. A well-developed implementation of that general approach would seem like it could be awesome. That said, dunno if I find their current methodology or numbers too convincing, as far as actual conclusions go.
dnautics 5y ago
it kind of doesn't matter why it is, it just is (the why might also be unknowable, or too facilely reducible to just-so stories). And it's actually not TOTALLY unusual in coronaviruses, it's unusual in the coronavirus subfamily that COVID-19 comes from. There is this very hilarious paper where they talk about this, but also rejigger the phylogenetic trees without describing how they pick what to put in and hide from the trees, e.g. they overload "trivially similar" sequences that happen to have furin cleavage sites, and then there are diagrams where they omit entire huge families of coronaviruses that don't contain the furin cleavage site to "lie to you with pictures" that the furin cleavage site is more common than it actually is. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836551/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836551/
lamontcg 5y ago
It isn't unusual at all. Many coronaviruses including MERS have a furin cleavage site and they're common and likely evolved independently multiple times, showing that this acquisition of an FCS is common: https://www.sciencedirect.com/science/article/pii/S1873506120304165 https://www.sciencedirect.com/science/article/pii/S187350612... The FCS in SARS-CoV-2 is NSPRRAR, we now know of sarbecoviruses like like the BANAL viruses in Laos which have NSPAAR, some other viruses like RmYN02 have NSPAAR or NSPVAR. If you insert an R into the BANAL spike protein you get the SARS-CoV-2 FCS. https://www.nature.com/articles/d41586-021-02596-2 https://www.nature.com/articles/d41586-021-02596-2 https://www.biorxiv.org/content/10.1101/2021.01.26.428212v1 https://www.biorxiv.org/content/10.1101/2021.01.26.428212v1 Finding bat sarbecoviruses which are one insertion away from having the original FCS really blows a gaping hole in this whole idea that the FCS is some kind of smoking gun. Delta has P681R and Omicron has P681H mutations in the FCS region which may be behind why they're more infectious/transmissible. So the FCS is also still evolving and adapting to humans.
- tim333 5y ago
  You're answering why furin cleavage sites in general are not unusual. Not why this particular furin cleavage site is unusual from a natural evolutionary view. It's if you line up the related bat coronaviruses sequences they are all much the same in that region apart from Sars-Cov-2 which seems to have a clean insert of a PRRA sequence. Hence the "bothered by the furin site and has a hard time (to) explain that as an event outside the lab, though there are possible ways in nature but highly unlikely." in the article. If it had got there through evolution you'd expect the adjacent sequences to vary more. This kind of thing https://media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs10311-021-01211-0/MediaObjects/10311_2021_1211_Fig3_HTML.png?as=webp https://media.springernature.com/lw685/springer-static/image...
  - lamontcg 5y ago
    Here is that kind of thing: https://ibb.co/T1YtShy https://ibb.co/T1YtShy That is from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211627/#mmc1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211627/#mmc1 Specifically the lower bit of figure 2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211627/figure/fig2/?report=objectonly https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211627/figure/... If RmYN02 picks up the QTQT sequence from recombination with other bat coronaviruses (or RmYN02 is a deletion away from a common progenitor we haven't found yet -- and the QTQT deletion is seen in SARS-CoV-2 variants in humans) then it is one insertion away from PRAAR which would be an active FCS, which is then one substitution away from the PRRAR SARS-CoV-2.
epakai 5y ago
> Given that furin cleavage signals are present in other coronaviruses at exactly that point in the S1/S2 boundary region, it only LOOKS unusual, especially against the backdrop of SARS. The preponderance of evidence, coupled with Ockham’s razor (that the simplest explanation is preferred) dictates that the PRRA sequence has been conserved in nCoV2019 from a long ago ancestor virus. It is not of suspicious origin. The closest bat virus sequence is really not close at all. https://virological.org/t/tackling-rumors-of-a-suspicious-origin-of-ncov2019/384 https://virological.org/t/tackling-rumors-of-a-suspicious-or...
tim333 5y ago
Here's Bob Garry, featured in the article: https://mobile.twitter.com/TheSeeker268/status/1480930691919618051/photo/1 https://mobile.twitter.com/TheSeeker268/status/1480930691919...

If a feature would make the virus very unsuccessful in bats, then how did it propagate? There had to be another cross-over species or something but no one has any data to suggest what that is. China has apparently made it impossible to do the work of piecing that together, so the lab leak hypothesis may never be put to bed. Maybe the party leadership believes a lab leak is likely even if they have no specific knowledge of it.

DarknessFalls 5y ago
To add to my original question, is the furin cleavage site further adapted in the Omicron variant, explaining its increased infectiousness? If so, what is the difference between that and the Delta variant?
- Sparyjerry 5y ago
  The Omicron variant is actual prior to Delta variant and prior to all other variants even so named Alpha variant. This article indicates why Omicron could be yet another lab leak. https://bprice.substack.com/p/lab-leak-20 https://bprice.substack.com/p/lab-leak-20
tim333 5y ago
EcoHealth Alliance, the main US funders of the Wuhan lab have been awfully shy about letting anyone see their data. There's a good chance proof is there and the data can legally forced out of them.

_Nat_ 5y ago

RootClaim discusses that claim and its perceived relevance [here](https://www.rootclaim.com/analysis/What-is-the-source-of-COVID-19-SARS-CoV-2#furin_cleavage https://www.rootclaim.com/analysis/What-is-the-source-of-COV... ).

CamperBob2 5y ago
Hmm, that's a nifty site, reminiscent in some ways of Metaculus but with an actual methodology behind it rather than just prediction aggregation. Very nice UI/UX as well. I'm surprised I've never heard of it.
- _Nat_ 5y ago
  Yeah, just saw it linked [in this comment](https://news.ycombinator.com/item?id=29902330 https://news.ycombinator.com/item?id=29902330 ). Currently, it seems most helpful in aggregating some of the arguments folks put forth in examining claims, including describing the basic issues and linking some references. Plus it seems to offer some insight into what folks are thinking. Then from an academic perspective, I really like the sort of approach that they're trying to use. A well-developed implementation of that general approach would seem like it could be awesome. That said, dunno if I find their current methodology or numbers too convincing, as far as actual conclusions go.

dnautics 5y ago

it kind of doesn't matter why it is, it just is (the why might also be unknowable, or too facilely reducible to just-so stories). And it's actually not TOTALLY unusual in coronaviruses, it's unusual in the coronavirus subfamily that COVID-19 comes from. There is this very hilarious paper where they talk about this, but also rejigger the phylogenetic trees without describing how they pick what to put in and hide from the trees, e.g. they overload "trivially similar" sequences that happen to have furin cleavage sites, and then there are diagrams where they omit entire huge families of coronaviruses that don't contain the furin cleavage site to "lie to you with pictures" that the furin cleavage site is more common than it actually is. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836551/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836551/

lamontcg 5y ago

It isn't unusual at all. Many coronaviruses including MERS have a furin cleavage site and they're common and likely evolved independently multiple times, showing that this acquisition of an FCS is common: https://www.sciencedirect.com/science/article/pii/S1873506120304165 https://www.sciencedirect.com/science/article/pii/S187350612... The FCS in SARS-CoV-2 is NSPRRAR, we now know of sarbecoviruses like like the BANAL viruses in Laos which have NSPAAR, some other viruses like RmYN02 have NSPAAR or NSPVAR. If you insert an R into the BANAL spike protein you get the SARS-CoV-2 FCS. https://www.nature.com/articles/d41586-021-02596-2 https://www.nature.com/articles/d41586-021-02596-2 https://www.biorxiv.org/content/10.1101/2021.01.26.428212v1 https://www.biorxiv.org/content/10.1101/2021.01.26.428212v1 Finding bat sarbecoviruses which are one insertion away from having the original FCS really blows a gaping hole in this whole idea that the FCS is some kind of smoking gun. Delta has P681R and Omicron has P681H mutations in the FCS region which may be behind why they're more infectious/transmissible. So the FCS is also still evolving and adapting to humans.

tim333 5y ago
You're answering why furin cleavage sites in general are not unusual. Not why this particular furin cleavage site is unusual from a natural evolutionary view. It's if you line up the related bat coronaviruses sequences they are all much the same in that region apart from Sars-Cov-2 which seems to have a clean insert of a PRRA sequence. Hence the "bothered by the furin site and has a hard time (to) explain that as an event outside the lab, though there are possible ways in nature but highly unlikely." in the article. If it had got there through evolution you'd expect the adjacent sequences to vary more. This kind of thing https://media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs10311-021-01211-0/MediaObjects/10311_2021_1211_Fig3_HTML.png?as=webp https://media.springernature.com/lw685/springer-static/image...
- lamontcg 5y ago
  Here is that kind of thing: https://ibb.co/T1YtShy https://ibb.co/T1YtShy That is from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211627/#mmc1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211627/#mmc1 Specifically the lower bit of figure 2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211627/figure/fig2/?report=objectonly https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211627/figure/... If RmYN02 picks up the QTQT sequence from recombination with other bat coronaviruses (or RmYN02 is a deletion away from a common progenitor we haven't found yet -- and the QTQT deletion is seen in SARS-CoV-2 variants in humans) then it is one insertion away from PRAAR which would be an active FCS, which is then one substitution away from the PRRAR SARS-CoV-2.

epakai 5y ago

> Given that furin cleavage signals are present in other coronaviruses at exactly that point in the S1/S2 boundary region, it only LOOKS unusual, especially against the backdrop of SARS. The preponderance of evidence, coupled with Ockham’s razor (that the simplest explanation is preferred) dictates that the PRRA sequence has been conserved in nCoV2019 from a long ago ancestor virus. It is not of suspicious origin. The closest bat virus sequence is really not close at all. https://virological.org/t/tackling-rumors-of-a-suspicious-origin-of-ncov2019/384 https://virological.org/t/tackling-rumors-of-a-suspicious-or...

tim333 5y ago

Here's Bob Garry, featured in the article: https://mobile.twitter.com/TheSeeker268/status/1480930691919618051/photo/1 https://mobile.twitter.com/TheSeeker268/status/1480930691919...