So the following four multi-A->G mutation patterns have shown up in sequences collected July 30 or later. These are all in the spike NTD. In each case, all the mutations were acquired in one step. The bottom one has appeared in numerous US states. What's going on here? 1/3
To be clear, I have no idea. I can't recall ever seeing clusters of A->G mutations like this before. There's a human enzyme called ADAR that can causes A->G mutations. Is there something in the JN.1 secondary RNA structure in this region that attracts ADAR? 2/3
These are not the only multi-A->G mutation clusters in this area. A 2-nuc version of K150R has appeared many times, sometimes w/K147E, & two sequences seem to have acquired K150R via recombination with NSP15.
Just throwing this out there to see if anyone has ideas. 3/3
Nothing in particular stands out about their location in the WT secondary RNA structure. But it looks like an area of low-confidence structure prediction, & there have been a lot of mutations/deletions in this region of the genome. So the real structure may be entirely different.
...to the extent that there is a "true" structure anyway. I know it tends to fluctuate and switch between different structures, probably influenced by a bunch of hard-to-account-for factors in the cellular environment.
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@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
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.
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
But in human lung cancer (Calu3) cells, the ∆QTQTN-mutant replication was dramatically reduced (2.5 orders of magnitude), and in infected hamsters disease was much milder. 3/12
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
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
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
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
The enigmatic anti-correlation between S:∆S31 & FCS ablaters—clear since summer 2024—is strong as ever. Here are the recent CovSpectrum stats for T22N & ∆S31 among all seqs & seqs w/FCS weakeners.
How exactly a 1-AA deletion in a distant region affects the FCS is unknown. 3/4
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/
I'll offer one other possibility: the deep lung environment (or some other tissue reservoir) favors either an extreme RBD-up or extreme RBD-down conformation.
Background: The receptor-binding domain (RBD) of the spike trimer can be up or down. It has to be up to bind ACE2... 3/
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
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…
The PASC group showed signs of persistent, pro-inflammatory immune activation over the 6-month time period that suggested ongoing mucosal immune responses, including elevated levels of mucosa-associated invariant T cells (MAIT). 3/