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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
36 subscribers
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
Nov 24, 2024 • 4 tweets • 2 min read
@SolidEvidence There was yet another paper this week describing someone chronically infected, with serious symptoms, but who repeatedly tested negative for everything with nasopharyngeal swabs. On bronchoalveolar lavage (BAL), they were Covid-positive. 1/ ijidonline.com/article/S1201-…Image @SolidEvidence BAL is very rarely performed, yet there must be dozens of documented cases now where NP-swab PRC-negative patients who were very ill tested positive by BAL. This has to be way more common than we realize.

If we had a similar GI test, I imagine we'd find something similar. 2/
Nov 22, 2024 • 6 tweets • 2 min read
Superb thread here by @jbloom_lab that meshes well with what we've seen over the last few months in SARS-CoV-2 spike evolution: not much.

IMO, nothing significant has happened since the NTD-glycan-adding muts (T22N, ∆S31) & Q493E appeared. This 🧵 explains why. 1/6 Read full 🧵for explanation, but the short story is that the best apparent escape mutations all interact w/something else—like a nearby spike protomer or other important AA—making mutations there prohibitively costly.

In short, the virus has mutated itself into a corner. 2/6
Nov 10, 2024 • 15 tweets • 5 min read
It's an interesting thought. I think the evidence is strong that all new, divergent variants have derived from chronic infections. The first wave of such variants—Alpha, Beta, Gamma—IMO involved chronic infections lasting probably ~5-7 months. It's controversial to say.... 1/15 …that Delta originated in a chronic infection, but I think the evidence that it did is strong. One characteristic of chronic-infection branches is a high rate of non-synonymous nucleotide (nuc) substitutions (subs)—i.e. ones that result in an amino acid (AA) change. 2/15 Image
Nov 3, 2024 • 4 tweets • 2 min read
I'd add that XEC's had no noticeable impact on cases & isn't likely to going forward barring a serious change, which we've not seen since S:Q493E & the glycan-adding S:S31-/S:T22N appeared months ago. Next major change seems likely to take the form of an entirely new variant. 1/4 I've been in lockstep with @SolidEvidence and @JPWeiland on this front. Despite the sensational early growth advantages XEC appeared to have, it never seemed likely to me ever to have a noticeable real-world impact. 2/4
Oct 11, 2024 • 6 tweets • 3 min read
Molnupiravir-created mutants still show up intermittently, mostly in Australia and Japan. A remarkable one popped up today: A KP.3.1.1 with 94 private mutations. 1/6 Image The closest related sequences are from the same region and from about 1 month earlier, suggesting these 94 consensus mutations were acquired in about one month, and possibly a shorter period of time. 2/6 Image
Oct 5, 2024 • 5 tweets • 2 min read
There aren't many convergent mutations in ORF1b in chronic-infection sequences. But many of the ones that do show up repeatedly are also highlighted in this study looking at NSP12 mutations that developed in immunocompromised pts treated with remdesivir. 1/4 I've spent hundreds of hours compiling a list of >3500 likely chronic-infection sequences & have created an imperfect, approximate measure for how overrepresented a mutation is in chronic sequences compared to circulating sequences (as measured by independent acquisitions). 2/4
Sep 25, 2024 • 7 tweets • 3 min read
It seems more certain than ever: getting Covid is bad for your brain.

This study, which found cognitive effects at 1 year post Covid to be equivalent to brain aging from age 50 to 70, looked only at hospitalized patients. But as Dr. Topol says.... 1/7 ...another recent study—a controlled experimental one involving young (18-30), healthy volunteers—found significant negative cognitive effects from mild illness 1 year after the challenge trial.
Mild illness. Healthy 18-30-year-olds. 1 yr later. 2/7
Sep 21, 2024 • 20 tweets • 7 min read
I’ve mostly pooh-poohed the rise of XEC for 2 reasons:

#1. Its spike is almost identical to the dominant KP.3.1.1
#2. I don’t think its advantage over KP.3.1.1 is large enough to make a significant real-world impact.

But one aspect of XEC is noteworthy: The demise of N*.
1/20 I’ve talked a lot about nucleocapsid before, mostly in this 120-tweet thread that was too long for anyone to want to read. Nucleocapsid is by far the most abundant SARS-CoV-2 protein. Nothing else comes close. It is very, very important. 2/20
Sep 8, 2024 • 15 tweets • 5 min read
Update on XEC: the weekly growth advantage of XEC relative to KP.3.1.1 has withered to approximately zero in Germany, the country XEC has been in longest and which has by far the highest proportion of XEC sequences. 1/13
Image The country of origin is generally the best place to compare a new variant to others. But globally, most seqs have been collected outside Germany (World: ~225, Germany: ~60), & these deserve some weight.

And globally, it looks like an XEC massacre. 2/13 Image
Sep 1, 2024 • 6 tweets • 2 min read
Lots of talk about the XEC variant lately. It's a fast variant, but I want to emphasize two things.

First, I don't think XEC is much faster than the dominant KP.3.1.1. Germany is the only country w/enough seqs for a reliable growth estimate & it's pretty modest & uncertain. 1/6 Image A variant w/such a small growth advantage (assuming it's accurate) takes months to grow to dominance. And such modest advantages do not result in any noticeable change in case levels, so I don't expect XEC to have any real impact. By the time it would become dominant... 2/6
Jul 17, 2024 • 25 tweets • 9 min read
KP.3, w/the unusual Q493E mutation, now dominant globally. To me, it's the first major spike change—involving real structural/epistatic change as opposed to treadmilling, stepwise antibody-evasion mutations merely keeping pace w/population immunity—since JN.1 emerged. 1/23 Most spike mutations affect ACE2 binding similarly in BA.2, XBB.1.5, & JN.1—e.g., Y453F confers a large incr in ACE2 affinity in all—so the XBB.1.5 deep mutational scanning info from @bdadonaite & @jbloom_lab is still invaluable. But Q493E is different. 2/
Jul 3, 2024 • 4 tweets • 2 min read
AI is a disaster for journalism. Here are a two examples of AI hallucinations on the FLiRT variants of JN.1, which are named after spike mutations F456L & R346T.

This one from @NewstalkFM says FLiRT stands for "F-Type Recombinant Lineage," a term invented from whole cloth. 1/3 When I Googled that name, a clear AI hallucination dutifully copied & pasted by "journalists," I accidentally stumbled on another.

This one, from the Manchester Evening News via Yahoo News, says FLiRT stands for "Fresh Lineage of Rapid Transmission." 2/3 Image