Ryan Hisner Profile picture
Feb 5, 2024 5 tweets 2 min read Read on X
A dozen more sequences of this JN.1 + K444R + Y453F just dropped. All from Brazil, all collected in 2024. 12/13 are from the Brazilian state of Bahia, but those 12 sequences come from 11 different cities. This has the potential to be a big deal.
BA.2.86 had extremely high ACE2 affinity, but as you can see in @yunlong_cao's tweet below, JN.1's S:L455S, while a crucial antibody-evasion mutation, squandered pretty much all the extra ACE2 affinity of BA.2.86 (higher = weaker ACE2 binding). 2/4
By itself, lower ACE2 binding probably isn't a huge detriment, but it left JN.1 with little room to evolve further RBD mutations, which nearly always reduce ACE2. This is probably why JN.1's RBD has remained virtually unchanged since its emergence. 3/4
Y453F has granted huge increases in ACE2 binding in previous variants, so it likely will do the same for JN.1. This could give JN.1 the mutational flexibility it has so far lacked, opening the door to further spike mutations. Stay tuned. 4/4 github.com/cov-lineages/p…
@yousitonmyspot I think the bigger story is the possibility of further RBD mutations due to the incr. ACE2 binding from Y453F. That probably gives JN.1 much more room to maneuver.

OTOH, Y453F has caused instability in some previous lineages, so it may impose a cost as well. Too soon to say.

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More from @LongDesertTrain

Apr 25
About 1 month after this monster BQ.1.1 appeared, an even more extreme sequence has shown up in Alberta. Like the BQ, it has 50 private spike mutations, but it also has >40 AA mutations elsewhere in the genome. 1/6 Image
They include the full panoply of NSP3, NSP12, & N muts I've written about previously. ORF1a:S4398L is the most common mutation in the 4395-4398 region, this has ∆S4398, a rarity also seen in a few other extremely divergent seqs w/this constellation. 2/6 Image
In a theme that's become familiar, it's added two spike NTD glycans, N30 (via F32S) and N155 (via S155N+F157S).
Another chronic-infection leitmotif (first noted by @SolidEvidence): reversions to common or consensus residues in related Bat-CoVs, including SARS-1. 3/6 Image
Read 6 tweets
Apr 10
A fascinating SARS-CoV-2 sequence was recently uploaded—collected from a dog in Kazakhstan in July 2022.

Usher places the seq 1 nuc mut from the Wuhan ref seq—C21846T/S:T95I—i.e. pre-D614G. Could this seq somehow have a close connection to the first days of the pandemic?
1/19 Image
Of the sequences near this one on the tree, all are low-quality & clearly bad BA.1 or Delta sequences. The only genuine one is from the UK, collected April 2020. So it's likely even S:T95I was not inherited.

This sequence has several fascinating aspects. 2/ Image
(This all assumes the sequence is accurate and that C241T & C14408T (ORF1b:P314L) are genuinely absent. Its mutational characteristics make me certain this is a good sequence, though it's not impossible there's dropout not indicated hiding C241T and/or C14408T.) 3/
Read 19 tweets
Mar 12
Do you remember BA.3—the weakling cousin of BA.1 & BA.2 that seemed to take the worst from each & had weaker ACE2 binding than even the ancestral Wuhan Virus?

After 3 years, BA.3 is back.

And it is transmitting.

Who saw this coming?
1/13 Image
While the full extent of the new BA.3’s spread is not known, it’s been detected in 2 different South African regions through regular (not targeted) surveillance by @Dikeled61970012, @Tuliodna, & the invaluable South African virology community.
2/13
github.com/cov-lineages/p…
After nearly 3 years of intrahost evolution in a chronically infected person, the new BA.3 is almost unrecognizable. It has ~41 spike AA substitutions (4 of which are 2-nuc muts) to go with 14 AA deletions (∆136-147+∆243-244). We’ve seen nothing like this since 2023.
3/13 Image
Read 13 tweets
Jan 2
Two quick notes on the state of chronic-infection SARS-CoV-2 seqs

#1) ~3 years after its peak, BA.1 is still showing up in nasal swab seqs—despite reduced surveillance—most recently a mid-late Dec BA.1 from Nebraska.

#2) Chronic JN.1 seqs now more common, w/1 peculiarity

1/12
While BA.1 still show up semi-regularly, pre-Omicron seqs are much rarer. Why? I think there are four major reasons, two obvious & two less obvious.

A) Time.
This one’s obvious: Over time, some chronic infections are cleared, while in other cases, the host dies.

2/12
B) Number of infections.

BA.1 infected more people, more quickly than any previous variant. More infections = more chances to establish long-term infection.
3/12 Image
Read 12 tweets
Dec 23, 2024
Fantastic review on chronic SARS-CoV-2 infections by virological superstars Richard Neher & Alex Sigal in Nature Microbiology. I’ll do a short overview, outline a couple minor quibbles, & defend the honor of ORF9b w/some stats & 3 striking sequences from the past week.
1/64 Image
First, let me say that this is well-written, extremely readable, and accessible to non-experts, so you should go read the full paper yourself, if you can find a way to access it. (Just realized it’s paywalled, ugh.) 2/64nature.com/articles/s4157…
Neher & Sigal focus on the 2 most important aspects of SARS-CoV-2 persistence: its relationship to Long Covid (including increased risk of adverse health events) & its vital importance to the evolution of SARS-CoV-2 variants. I’ll focus on the evolutionary aspects.
3/64 Image
Read 64 tweets
Dec 6, 2024
In SARS-2 evolution, amino acid (AA) mutations get the lion’s share of attention—& rightfully so, as noncoding & synonymous nucleotide muts—which cause no AA change‚ are mostly inconsequential. But there are many exceptions, including a possible new one I find intriguing. 1/30
I’ll discuss four categories of such “silent” mutations, two of which might be involved in the recent growth of one synonymous mutation.

#1. Kozak sequence changes
#2. Secondary RNA structure
#3. TRS destruction/improvement
#4. TRS creation 2/30
Maybe the single most remarkable example of convergent evolution in SARS-CoV-2 involves noncoding mutations: the multitude of muts in major variants that have pulverized the nucleocapsid (N) Kozak sequence.
I wrote about this below & a few other 🧵s 3/
Read 33 tweets

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