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Ryan Hisner Profile picture
Ryan Hisner
@LongDesertTrain
Teacher "Be ruthless with systems and be kind to people." Michael Brooks, 1983-2020
37 subscribers
Nov 5 • 4 tweets • 2 min read
Slovenia gets its first BA.3.2. Its (slow) geographic spread continues.

Also, 2/4 sequences uploaded from Western Australia (WA) today are BA.3.2.2.

If you're not familiar with BA.3.2, see posts 3 & 4 below for an introduction. 1/4 @StuartTurville has pointed out that WA delayed Covid spread longer than elsewhere in Australia. China has a somewhat similar immune history (as do other SE Asian countries). Perhaps BA.3.2 will do well in China once it arrives there? 2/4
Oct 22 • 12 tweets • 5 min read
I beg to differ! If it is not a sequencing mistake—and it looks clean—one of these BA.3.2 has something completely novel in SARS-CoV-2 evolution: an FCS-adjacent deletion!

One of the two QT repeats appears to have been deleted. I've never seen anything like this before. Image Work by @TheMenacheryLab looked at a similar, more extensive, deletion. They deleted both QT repeats plus the next AA (∆QTQTN). In Vero cells (monkey kidney cells), it produced extra-large plaques & outcompeted WT virus—similar to furin cleavage site (FCS)-deletion mutants. 2/12 Image
Oct 13 • 7 tweets • 3 min read
There's a new BA.3.2.2 from South Africa today. For the most part, there's been little substantial change in BA.3.2 over the past few months—mostly synonymous mutations & very little happening in spike.

But this new one has 3 spike mutations & looks quite interesting. 1/7 Image For those not following closely, here's a 🧵 I made about BA.3.2 (not yet designated at the time) that I made some months ago, when it first burst upon the scene. 2/7
Sep 26 • 4 tweets • 2 min read
Attenuation of the SARS-2 furin-cleavage site (FCS) continues apace. It's beginning to look as if some form of FCS-weakening mutation might well become fixed in the near future. Collectively, they are at ~12% globally—a totally unprecedented level—& rising quickly. 1/4 Image In South America, this may have already happened. Recent sequences are scarce, but they nearly all have some sort of FCS-weakening mutation, mostly S:S680P in XFG.3.4.1, but with several others (S680F, S680Y, R683Q, R683W) contributing as well. 2/4 Image
Sep 4 • 10 tweets • 4 min read
There's been some speculation about why, despite persistent immune activation, germinal center activity, & overall elevated Ab levels, LC patients here had very low anti-spike Ab titers. I want to highlight one interesting speculative hypothesis & offer another possibility. 1/10 The ever-fertile mind of @Nucleocapsoid proffers the possibility that exosomes could be responsible for viral spread in some tissue reservoirs. I don't know much about this topic and so don't have much to say at the moment, but I'm trying to l learn. 2/
Sep 2 • 33 tweets • 10 min read
A fascinating new preprint w/one very unexpected finding suggests, I believe, that a large proportion of Long Covid may be due to chronic infection in a particular bodily niche, which could be crucial for finding effective LC treatments. It requires some explaining. 🧵 1/33 Image First, a brief summary of the relevant parts of the preprint. They examined 30 people (from NIH RECOVER cohort) for 6 months after they had Covid, taking detailed blood immunological markers at 3 time points. 20 had Long Covid (PASC), 10 did not (CONV). 2/ biorxiv.org/content/10.110…Image
Jul 30 • 4 tweets • 2 min read
Wow, BA.3.2 hits its 4th continent with a new sequence from Western Australia.

Reminder: BA.3.2 is a saltation variant resulting from a ~3-year chronic infection. It is very different from and more immune-evasive than all other current variants. 1/4 Image It was collected July 15, & is most closely related to the recent S African seqs from May & June.

It has an NSP5 mutation known to be beneficial (ORF1a:K3353R) & 2 new NSP12 mutations, which is unusual. Its 9 synonymous mutations indicate it has been circulating somewhere. 2/4 Image
Jul 7 • 9 tweets • 4 min read
BA.3.2 update: another sequence from the Netherlands, June 18 collection.

It belongs on the same branch as the GBW travel seq (tree gets confused by ORF7-8 deletion). Also, there are 3 artifactual muts in the GBW sequence (as usual), so the branch is shorter than it looks. Image Bottom line, in my view: BA.3.2 has spread internationally & is likely growing, but very slowly. If nothing changes, its advantage vs circulating lineages, which seem stuck in an evolutionary rut, will likely gradually grow as immunity to dominant variants solidifies... 2/9
Jul 2 • 5 tweets • 2 min read
Quick BA.3.2 update. Another BA.3.2.2 (S:K356T+S:A575S branch) from South Africa via pneumonia surveillance.

This means that 40% of SARS-CoV-2 sequences from SA collected since April 1 (2/5) and 50% collected after May 1 (1/2) are BA.3.2. Its foothold seems strong there. 1/3 2 interesting aspects of the new BA.3.2:
1. ORF1b:R1315C (NSP13_R392C)—This mut is in all Omicron *except* BA.3. So this may well be adaptive.

2. S:Q183H—First known antigenic spike mut seen in BA.3.2, not a major one, but one we've seen before—eg, LB.1/JN.1.9.2.1 2/3 Image
Jun 29 • 11 tweets • 4 min read
BA.3.2 update, Chapter: "I'm Not Quite Dead, Sir"

A new sequence from a traveler to the USA from the Netherlands was uploaded yesterday, with a collection date of June 17. 1/10 Image This was a BA.3.2.1, the branch with S:H681R + S:P1162R (not S:K356T + S:A575S).

An updated, annotated version of the BA.3.2 Usher tree pictured below.

This sequence has the first new spike mutation since BA.3.2 emerged in November 2024—S:V227L. 2/10 Image
Jun 27 • 7 tweets • 2 min read
@yaem98684142 @TBM4_JP This analysis is extremely flawed.

There is nothing abnormal about BA.2.86 appearing in multiple countries shortly after discovery. This has been the norm lately w/reduced surveillance. 1/ @yaem98684142 @TBM4_JP The mutational spectrum analysis is poorly done. It cites a single study looking at the mutational spectrum in *three* immunocompromised individuals. Needless to say, this sample size is WAY too small. 3/
Jun 19 • 11 tweets • 4 min read
Interesting recombinant showed up today from Texas. It's a mixture of B.1.595, BA.1, and some flavor of JN.1. Most of the genome is from B.1.595. The ancestry of this one is clear: it directly descends from a B.1.595 sequence collected in January 2023, also in Texas. 1/11 Image When the B.1.595 was collected this infection was >1 yr old, w/no sign of Omicron. BA.1 ceased circulating ~1 year prior.
Now a BA.1 spike appears w/just 5 changes from baseline BA.1, none in the RBD—S12F, T76I, Q271K, R765H, S939F.

This is a zombie BA.1 spike. 2/ Image
May 31 • 35 tweets • 12 min read
An awesome preprint on the novel, unsung SARS-CoV-2 N* protein came out recently, authored by @corcoran_lab & Rory Mulloy. I’ve previously written on N*’s demise in XEC, the top variant in late 2024/early 2025. But…
1/34 …this preprint, along with another great study by the @DavidLVBauer, @theosanderson, @PeacockFlu & others prompted me to take a closer look...
2/34biorxiv.org/content/10.110…
May 15 • 4 tweets • 1 min read
@DameSunshine @SharonBurnabyBC B.1.1.529 wasn't/isn't a real variant; it's a placeholder that represents a putative ancestor of BA.1/BA.2/BA.3.

Bad sequences and/or coinfections tend to get categorized as B.1.1.529:—they have enough Omicron muts to be ID'd as Omicron but so much dropout/mixed signals...
1/ @DameSunshine @SharonBurnabyBC ...that a specific designation isn't possible. Travel sequencing in the US is done by Ginkgo Bioworks. Their sequences are generally poor quality & they upload *pooled* sequences—against database guidelines. The B.1.1.529 here are likely low-quality/pooled sequences from GBW.
2/
May 2 • 9 tweets • 4 min read
Incredible how quickly @yunlong_cao & co provide us w/info on the latest emerging SARS-CoV-2 variants.

Already, we have great data on BA.3.2 (the divergent saltation lineage detected in South Africa & the Netherlands & NB.1.8.1, an emerging contender for global dominance. 1/9 Image
Image BA.3.2 is a clear outlier on the antigenic cartography map—as expected given the enormous differences between its spike protein & every other circulating variant. 2/9
Image
Apr 25 • 6 tweets • 3 min read
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
Apr 10 • 19 tweets • 6 min read
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
Mar 12 • 13 tweets • 5 min read
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…
Jan 2 • 12 tweets • 3 min read
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
Dec 23, 2024 • 64 tweets • 20 min read
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…
Dec 6, 2024 • 33 tweets • 9 min read
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