Closed FedeGueli closed 1 year ago
I used to look for changes to the various Omicron S2/near-S2 mutations, but I've stopped looking. It's become clear that those mutations—H655Y, N679K, N764K, D796Y, Q954H, & N969K—aren't going anywhere and that changes to any one of them are clearly deleterious. I don't know enough to say how these S2 mutations are connected or function together, but it seems to me like the only way they are going to change—if they ever change—is via wholesale replacement, which is probably only possible through either emergence of an orthogonal variant from a chronic infection or recombination with such a variant. The fact that all the Omicron-Delta recombinants retain the entire Omicron S2 has to mean something, maybe that there are allosteric interactions between some of the Omicron S2 and NTD/RBD mutations that are an essential part of its S2 machinery?
There was that Gupta Lab study that showed Delta and Kappa's NTDs had a large effect on S2 function, and also an earlier one positing a mechanism whereby the NTD could affect S2. If I remember right, the latter involved residues around 735-737, and its interesting to note that a few of the most highly mutated chronic Delta sequences have had mutations at S:735 and S:737. https://www.cell.com/cell-reports/fulltext/S2211-1247(22)01037-3 https://www.sciencedirect.com/science/article/pii/S2211124722005538
At least Y796H is not uncommon. D796Y/D796H showed up in lineages prior to Omicron and it is not uncommon for Delta to gain them. I recall that one study showed that D796H results in lesser infectivity and better immune escape for reasons not very clear. Also there are mutations nearby like T883I and 701-706 mutations. I also noticed that some interesting sequences have T791I/T791P.
The evidence I've seen about N764K seems to suggest that it is a pure gain. It was in B.1.634. It showed up in some highly mutated Delta and Lambda sequences. Unlike N969K, it does not have the altered entry pathway effect. https://www.biorxiv.org/content/biorxiv/early/2022/05/13/2021.12.31.474653/F4.large.jpg?width=800&height=600&carousel=1
For the furin sites, A688V happens quite often and H681R is seen in some chronic sequences.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9542985/ This paper shows that H655Y decreases TMPRSS2 usage and increases cathepsin L usage and suggests that H655Y might be the reason behind the altered entry mechanism. However, the mutation was seen in many lineages prior to Omicron, including Gamma, and none of them was reported to have this type of the altered entry. I think the reason might be in this paper: https://www.nature.com/articles/s41421-022-00419-w It shows two cathepsin L cleavage sites, T259|A260 and Y636|S637 (elaborated by https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455558/) and it shows that the cleavages at both sites may assist both entry routes. Therefore increased cathepsin L usage does not necessarily mean that the entry mechanism is altered. H655Y is near the Y636|S637 site. (By the way, H69 and V70 are near the T259|A260 site and the paper (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9542985/) claims that 69-70del increases cathepsin L usage). H655Y may be fixed now, but there are some interesting mutations not far from the Y636|S637 site, including E619Q, P621S/H, I666V. There is also V642G. https://jbloomlab.github.io/SARS2-mut-fitness/S.html gives it fitness of 3.52. It's at the R346T level. Will it be the next R346T? Not sure. It appeared in many highly mutated sequences recently. V642G is just beside F643, which forms π–π interaction with H655/Y655.
For N969K and Q954H, they are rare aside from Omicrons and Deltacrons. I wonder whether they enable each other. For now, both of them and nearby residues do not mutate often. D950N/D950H became rare since Q954H took over.
Back to the topic. V642G: 11
@oobb45729, that is all super interesting. Thank you for the information and links. On the H655Y topic, I've noticed V642G becoming more common as well, but also deletions in the same area that I'd never seen before. They are always three- or six-nucleotide deletions. The different deletions seem to come in the four flavors depicted below.
For the most part these are not monophyletic, but almost all the recent in-frame ∆F643 have been in BQ.1.3, which also has E619Q. The first BQ.1.3 + ∆F643 sequence showed up on Dec 23 in Switzerland. There seem to be two different lineages: a four-sequence lineage in Switzerland, Austria, and Moldova, and a 38-sequence lineage in Ontario, Canada.
Six-nucleotide deletions in the 620-622 region are also popping up now and then, along with the occasional ∆Q675. And of course, P621S has been on a roll lately and shows up pretty frequently in highly mutated, chronic-infection sequences. I'm not entirely sure what it all means, but it seems like the first inkling of possibly changing selection pressure in that region.
Note that in GISAID query, the branch of XBB.1+T23018C (S:F486P) +S:Y200C has 22 seqs, while XBB.1.5(T17124C, T23018C) +S:Y200C has 11(as mentioned in table). I wonder whether the first one is worth proposing an issue.
@FedeGueli Thanks to reply! I try to propose an issue for discussion in #1704
Just raised: XBB.1.5 cases in China #1717
Yes, that's the 5th one from the US Midwest. with T284I, R403K, L513F, ORF3a:A31V, ORF3a:T269M, and ORF1a:P309S. I've got a proposal mostly written for that one, and if another sequence shows up, I'll probably post it.
I don't think I've ever seen this S2 deletion before: S:∆859-860. It's in an XBB.1.5 from Georgia, USA, which also has another very rare S2 mutation with S:C1236Y, which has only ever been in ~160 sequences worldwide. EPI_ISL_17128969
XBB.1.5 w/ Spike_V83P [ 5 California & 1 Mexico] : A 2-Nuc change
Two cases of XBB.1.5 were reported today in Guangdong, China.
The serial numbers are EPI_ISL_17170853 and EPI _ISL _17170852
Two cases of XBB.1.5 were reported today in Guangdong, China.
The serial numbers are EPI_ISL_17170853 and EPI _ISL _17170852
The pedigree of 17170852 was identified as EM.1, a descendant of XBB.1.5.7. In Zhanjiang, Guangdong, China.
Yesterday's two came from Yichang, Hubei, serial numbers 17182661 and 17182662.
This last update has been very time expending. I m not sure if this could be kept updated anymore. Please write down here if you spot any lineage rising.
i suggest @corneliusroemer to take a look at lineages growing with YYY, likely they are the most fit.
XBB.1.5 in Haikou, Hainan, China, available at 17175998.It has S: S254F
@Mike-Honey just proposed one with S:I666V
S:T478I got designated XBB.1.5.40
XBB.1.5 seems to get outcompeted by a number of parallel XBB lineages - there's already a lot of sublineages due to early spread in high-sampling-geographies (US, Europe) so I think we can slow down here.
Closed indeed
@corneliusroemer , happy new year first!, then here the new XBB.1.5 Spike Diversity Issue: (last update 12/03/23)
XBB.1.5 query : T17124C,T23018C +
Legenda: N or n= not growing = zero new sequences blank = growing little but different from 0seqs y= growing around 15% since last update yy = growing more than 20% since last update yyy = growing more than 50% since last update (Designated lineages are out of the game , no updates for them) Lineages with less than 10 sequences now will not be updated.