Ryan Hisner Profile picture
Jan 28, 2022 10 tweets 4 min read Read on X
A thread of BA.2 updates.

BA.2 continues to do its thing in Denmark. The two most recent days of sequencing (January 20 & 21) recorded 74.2% BA.2 (285 of 384 cases). 1/9
The exponential increase in the proportion of BA.2 cases continues in the UK.

The apparent slowdown in growth in the past several days is entirely due to 0 of 8 sequences being BA.2 over the past four days & should therefore be ignored. 2/9
Similar exponential increase in the percentage of BA.2 cases in the US.

Again, the illusory plunge over the last five days is entirely due to a very small number of sequences and should be ignored. 3/9
My home state of Indiana had recorded zero BA.2 cases before last night's update, when six cases were recorded in the most recent week of sequencing, indicating a substantial percentage of BA.2. Major caveat: sample size very small. 4/9
Germany's BA.2 path is similar to what Denmark's was early on. A recent report found that 30% of cases in Berlin were BA.2, so as has been the case elsewhere, large cities with lots of international travelers are leading the way. 5/9
Japan finally has enough BA.2 to provide a decent indication of it's path. Surprise!—it's upward.

(Once again, the tiny sample sizes in recent days mean the illusory plunge at the end should be ignored.) 6/9
Not much sequencing in Portugal, but in the most recent day of sequencing, which was two weeks ago, all eight cases sequenced were BA.2. 7/9
Spain, like Portugal, has poor genetic surveillance, but is seeing a similarly steep rise in BA.2.

Small sample size makes this a pretty unreliable estimate, however. 8/9
Most of the other countries whose graphs I posted in a previous BA.2 update have seen little change. Not much has changed in Sweden, but I'll include it here since it has among the highest level of BA.2 among countries with decent sequencing. 9/9
I was rushed when putting together this thread and made a mistake in the number of BA.2 cases recorded in Indiana. There have actually been 12 BA.2 sequences in the most recent 8 days of sequencing, not 6. This gives Indiana the highest percentage of BA.2 of any US state.

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More from @LongDesertTrain

Jun 29
@suprion_verlag @dfocosi @yunlong_cao @RajlabN @BenjMurrell @SystemsVirology @SimonLoriereLab @EricTopol @TRyanGregory @tylernstarr @JPWeiland @siamosolocani @CorneliusRoemer The basic pattern has been that we occasionally see huge evolutionary jumps with no intermediate sequences (BA.1, BA.2, BA.5, BJ.1/XBB, BA.2.3.20, BA.2.86, & many others), which in reality evolved stepwise within a single, chronically infected individual.
@suprion_verlag @dfocosi @yunlong_cao @RajlabN @BenjMurrell @SystemsVirology @SimonLoriereLab @EricTopol @TRyanGregory @tylernstarr @JPWeiland @siamosolocani @CorneliusRoemer Then, after such a variant begins circulating, it begins to pick up mutations, primarily in the spike protein, which evade antibodies that are widespread in the population. The specific mutations vary somewhat with each new variant, but there's a lot of common ground as well...
@suprion_verlag @dfocosi @yunlong_cao @RajlabN @BenjMurrell @SystemsVirology @SimonLoriereLab @EricTopol @TRyanGregory @tylernstarr @JPWeiland @siamosolocani @CorneliusRoemer R346T, for example, has been acquired again and again. Various mutations at E484 and F486 have been common as well, and there are many others that could be mentioned. In some cases, these mutations seem to have arrived at a quasi-endpoint (for now)—∆Y144 or F486P, for example.
Read 5 tweets
Jun 18
. @BenjMurrell is doing the best variant growth modeling in the world, & his latest results confirm most of what we've thought: KP.3 is the fastest large variant, & its sublineage KP.3.1.1—w/the highly advantageous, glycan-creating S:∆S31—is easily the fastest in the world. 1/15
It can be a difficult to decipher the meaning of these graphs if you don't have an encyclopedic knowledge of the latest variants—which I think only @siamosolocani possesses—so I tried to add some context to Ben's graph, which I'll explain below. 2/15 Image
I divide key mutations into 4 categories, from most to least impactful, IMO.

#1. Q493E (KP.3 exclusive), F456L (~universal)
#2. T22N, ∆S31 (glycan-adding)
#3. R346T, T572I
#4. F59S/L, S60P, K182N, Q183H

Lowest row of boxes on the graph is group #1, above it #2, & so on. 3/15 Image
Read 16 tweets
May 8
KP.3 (w/the rare Q493E) has been my pick since I first noticed it emerging from numerous travel seqs from India. F456L & R346T are the typical stepwise immune-evasion mutations that, as @shay_fleishon noted, very likely impose a fitness cost. Q493E may be different. 1/
Q493E involves the rarest of all nucleotide mutations, C->G, and occurs at a key residue that we've seen very little action from of late. 493 mutations, however, are common in the Cryptics, usually Q493K I believe. (@SolidEvidence can correct me if I'm wrong on that). 2/8 Image
493 is also one of the few residues where mutations—on BA.1/BA.2 backgrounds—can confer large increases in ACE2 affinity—see @jbloom_lab data below. The 2-nuc Q493A & Q493V appeared in a handful of remarkable chronic-infection seqs, for example. 3/8 Image
Read 8 tweets
May 1
We have a new record for mutations in a non-molnupiravir sequence. It's a BA.2.12.1 with >100 private mutations. There are 4 seqs from early April, all from the same patient. I'll discuss four interesting features it has in this 🧵. 1/23 Image
#1) Reversions
Reversions are extremely rare. They almost never appear in circulating lineages. There are, however, a large number of reversions that are convergent in chronic-infection sequences. This one has more than usual. 2/23 Image
Let's start with my favorite.
• ORF1b:L314P (NSP12_L323P)
The extraordinarily rare yet hugely significant ORF1b:L314P reversion is an enigma. ORF1b:P314L was one of the very first SARS-CoV-2 mutations. It quickly dominated & has been universal ever since. 3/23
Read 23 tweets
Apr 19
What connects two regions on opposite ends of NSP12, a narrow slice of an obscure NSP3 region (DPUP/SUD-C), & a 3-AA sliver of nucleocapsid (N)? I have no idea, but I’m convinced there’s a link that could help reveal the inner workings of SARS-CoV-2. 1/120
Image
Image
I previously wrote a thread about the strange connection between ORF1a:4395-4398 and ORF1b:820-824 (NSP12_3-6 & NSP12_829-833). There is no known connection between these regions, & they are not close to each other in the NSP12 protein structure. 2/120
Mutations in both regions are rare, yet they arise in the same sequences again and again, at rates that cannot be coincidental. Furthermore, there have never been any circulating lineages with these paired mutations—they are a chronic-infection specialty. 3/120 Image
Read 124 tweets
Apr 13
Always nice to run across a possible function of a rare mutation that's shown up in multiple chronic-infection SARS-CoV-2 seqs. Thanks to an excellent paper by @TheMenacheryLab & @J_Paul_Taylor, I think I now know why N:L13P (a reversion) shows up. 1/6
They proved that the N:1-25 region, esp. the ITFG AA motif from N:15-18, is the essential element in N's ability to suppress the formation of stress granules (SGs) in cells, which capture & disable long viral RNAs & help organizing innate antiviral immune responses. 2/6
Image
Image
All variants retain the ability to suppress SGs, but Omicron's N:P13L weakens N's binding to G3BP1/2—the master cellular regulators of SGs—by about 2.3-fold. That's pretty slight, & almost certainly not enough selection pressure to result in reversions in circulation... 3/6 Image
Read 7 tweets

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