Private channel session 708
53 messages over 4h 45m, 2020-12-21 – 2020-12-21.
A “conversation” here is an activity session — a run of messages with under 60 minutes of silence inside it. The channel had no native conversation boundaries.
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The Starr ref from Andrew's *brilliant* virological post [destined to be in the top 2 or 3 in importance] has this figure.As noted therein N501Y one of *very* few including the mink N501T that increase ACE2 binding. Kudos to Starr etal. who also picked up Y453F (a mink mutation that appears to be another monoclonal antibody resistant mutation)as a change that enhances ACE2 binding. [shared file(s): image.png]
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What was the Nigeria post?
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Just to revisit Baric https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081895/ "Second, residue 501 in 2019-nCoV RBD (corresponding to residue 487 in SARS-CoV) is an asparagine. Based on our previous structural analysis, residue 487 in SARS-CoV is located near virus-binding hot spot Lys353 (i.e., hot spot 353) on human ACE2 Fig.1C. Hot spot 353 consists of a salt bridge between Lys353 and Asp38 also buried in a hydrophobic environment. In civet SARS-CoV RBD (year 2002), residue 487 is a serine, which cannot provide favorable support for hot spot 353. Inhuman SARS-CoV isolated in year 2002, residue 487 is a threonine, which strengthens the structural stability of hot spot 353. The S487T mutation adds the favorable interaction at the RBD-human ACE2 interface, enhances viral binding to human ACE2, and plays a critical role in the human-to-human transmission of SARS-CoV. In human SARS-CoV isolated in year 2003, residue 487 is a serine and there was no human-to-human transmission for this SARS-CoV strain. Asn501 in 2019-nCoV RBD provides more support to hot spot 353 than Ser487 but less thanThr487. This analysis suggests that 2019-nCoV recognizes human ACE2 less efficiently than human SARS-CoV (year 2002) but more efficiently than human SARS-CoV (year 2003). Hence, at least when considering the ACE2-RBD interactions, 2019-nCoV has gained some capability to transmit from human to human." It's not held uptoo well.
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Next up: the DRASTIC krewe advances their theory that the UK variant is a lab escape. Don't bother, but this from one of the DRASTIC stars: "Both the S1, the RBM and the FCS of the UK variant show obvious sign of adaptation inmice." Will Alina, Relman Ebright jump on the bandwagon?:exploding_head:
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It is a way more likely hypothesis than the Wuhan lab in that there is provably SARS-CoV-2 in hundreds of labs doing a thousand different experiments.
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SO3
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We even considered it for a bit
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Porton Down does have that bad rap after all
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But given the South African outbreak has a very similar pattern I am still going for chronic immunocompromised human (and there are obviously lots in South Africa).
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Totally agree. Might be good if DRASTIC were distracted for a while.
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Chronic infection seems more likely to me - however, I don't think we can rule out potential epizootic spilling back into humans. But all these mutations certainly look consistent with chronic infection
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Bob, from the paper above - really does seem 501 is a key 'transmission' residue. Of course, 501T has also been observed.
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It wouldn't be a simple epizootic - extensive transmission in mink didn't produce more than a few mutations
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Mink > rodents > humans - or some weird shit. But yeah, I agree - not consistent with what has been observedin mink and fully consistent with what has been observed in chronic infections.
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South Africa are really worried about E484K (in conjunction with 501Y)
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Actually might be good to ask about for others that are adapting SC2 to mice - we've got a few groups here as well. Baric got Q493K by passing SC2 in mice. https://www.cell.com/cell/fulltext/S0092-8674(20)31247-2?rss=yes It was Sun et al. got N501Y, Q493H, and K417N. https://www.biorxiv.org/content/10.1101/2020.11.10.377333v1
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E484K - yeah, I _do_ wonder if there's some weird synergy going on between mutations here - I have a hard time believing all of this is down to 501 alone. But hey :man-shrugging:
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They also have K417N in ZA
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Heh. Oooookay.
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2/3 mutations associated with rodents?
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Yeah, so SA is K417N and N501Y - SA/UK both Q493
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So really major amino acid changes in the few they have - flipping around charges, etc.
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That E484K gotta be making some major differences in the structure
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Going full in: the FCS of some strains of mouse hepatitis virus is *H*RARRS.
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There you go. It's time we go back to Andrew's London sewage theory.
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@Andrew Rambaut - do you have a good reference for the best "Wales" lineages?
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You mean what muts it has?
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A GISAID ID? Creating an alignment for Andrew Ward so he can get a cryo guy on it and he wanted a prioritized listof sequences
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https://www.propublica.org/article/here-are-six-accidents-unc-researchers-had-with-lab-created-coronaviruses"*April2020*: A UNC scientist underwent 14 days of self-quarantine at home after a mouse bite caused potential exposureto a strain of SARS-CoV-2, the virus that causes COVID-19, that had been adapted for growth in mice. The incidentin a biosafety level 3 lab happened when a researcher attempted to read the ID number on a tag on a mouse's ear.The mouse flipped over in the researcher's hand and bit an index finger through two layers of gloves. It did not appear to break the researcher's skin, but UNC told NIH in its reports that "given the uncertainty surrounding the exposure, we are treating this as a medium/high risk exposure." The researcher was instructed to self-quarantine and do twice-daily temperature checks. UNC also notified the local Health Department. No further information about the worker's health was included in the incident reports."
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Very confusingly (and coincidentally) it is lineage B.1.1.70
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Here are all the mutations from Wuhan: Spike D614G, Spike N501Y, N G204R, N Q9H, N R203K, NS3 Y156C, NS7a T14I, NSP3 H1539Y, NSP3 S126L, NSP5 G71S, NSP5 P132L, NSP12 P323L, NSP15 A217V, NSP15 M271I, NSP15 T33I
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EPI_ISL_710967
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Awesome - thanks
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(most 501Y from Wales are this lineage at the moment but it is changing)
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So no other spikes apart from 614G but everyone has one of those these days
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That's interesting about the Wales lineage - so if that's really spreading fast too and we believe there's a causalrelationship, then it's down to N501Y - potentially with D614G, but as you say, they all have that one (including that earlier cluster in Australia that didn't go anywhere).
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guess not - color blind
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My feeling is the Welsh cluster isn't growing at the same rate. It is at least as old but hasn't taken over or spread toother places. Also may have been amplified by some hospital outbreaks.
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Makes sense.
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Just found a genome from mid July that has N501Y and the ORF8 stop Possibly part of the precursor lineage.
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From Sun: "In our previous study, we generated a mouse-adapted strain of SARS-CoV-2 (MASCp6) by 6 serial passages of a SARS-CoV-2 in the lung of *aged* BALB/c mice, which caused moderate lung damage and no fatality in mice. Herein, we further serially passaged for additional 30 times to generate a more virulent SARS-CoV-2, and the resulting virus at passage 36 ( named as MASCp36) was used for stock preparation and titration." And a little deeper dive into the supplement reveals that N501Y came up early - by 6 passages [and it wasn't pathogenic] the other 2 muts took more passages [and tjhose mutations - probably Q493K actually made the virus pathogenic for mice. . Aged mice are definitely immunosuppressed. So, evidence for the immunocompromised theory.
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https://www.bbc.com/news/world-asia-china-55364445
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We should offer to go do it.
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YES - we can collect our fat checks at the same time!
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One question I'd ask - "Since you faked RaTG13, why haven't you faked a closely related ancestral strain from a random intermediate host?"
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Has anyone tried translating it out of frame? Perhaps it says "MADEINCHINA"?
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"FUNGFLUPATENTPENDING"
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```Sars-Cov-2, the authors concluded, was likely to have gained its unique efficiency through a long, undetected period of circulation in humans or animals of a natural and milder precursor virus that eventually evolved into thepotent, deadly form first detected in Wuhan in 2019.```Eh?
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5.1 million reads though
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Vince is loosing the plot: http://www.microbe.tv/twiv/
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I can't stand to listen to him - he's disqualified from all further discussions (the worst thing is - he NEVER listens toANYBODY. It's all about him and only about him - and only he knows). He got Ebola wrong, he got Zika wrong, and he's now once again getting another virus wrong.I have no idea what he actually knows about - because even his virology knowledge (let alone genomics/epi/immunology, etc) is shockingly poor.
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Well, at least Butt Lesion actually knows what he's talking about - at least sometimes.
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He definitely know a thing or two about arseholes.