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Ryan Hisner Profile picture
@LongDesertTrain
Jan 23, 2022 • 16 tweets • 7 min read • Read on X
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No one seems to know what BA.2 means for the world. I'm not aware of any studies on it, but I hope they come out soon. It seems apparent BA.2 will become dominant everywhere before long—as it already has in Denmark.

🧵 of graphs comparing BA.1 & BA.2 in various countries
1/16
Of all the countries with decent genetic surveillance, Denmark has the highest proportion of BA.2. 2/16
According to the Outbreak numbers compiled using @GISAID data, January 12 was when BA.2 surpassed 50% of all cases in Denmark, with 480/955 cases. 3/16
A similar conclusion was reached by @JosetteSchoenma, who's assiduously tracked BA.2 prevalence in Denmark (and elsewhere) and was pointing out its significance before anyone else. 4/16
The fact that Denmark has the highest level of Covid cases per 100,000 of any country in the world and the highest percentage of BA.2 of any country with decent sequencing data is probably not a coincidence. 5/16
The UK BA.2 numbers are far lower than in Denmark at the moment but are clearly on an exponentially increasing trajectory. It's only a matter of time before BA.2 becomes dominant there. 6/16
According to @OliasDave, BA.2 is doubling every 4 days (as a percentage of all cases) in the UK, meaning it could become dominant there in about three weeks. 7/16
Genetic surveillance outside of Denmark & the UK is far less comprehensive. The graphs therefore noisier & the trends less consistent. Still exponential increase in the proportion of BA.2 seems universal. Sweden and Norway are in the 10-15% range & exhibit similar trends. 8/16
Belgium and the Netherlands are both around 5% BA.2 with exponential increases underway. 9/16
Germany's data is pretty sparse after January 7, but there are hints of an early exponential increase in BA.2 there. 10/16
Finally, there have only been 47 sequences of BA.2 detected in the US, 17 of them in Arizona. But there can hardly be any doubt we'll see large increases in BA.2 prevalence throughout the US in the coming weeks. 11/16
Some have claimed that BA.2 is no different than BA.1 and nothing to worry about. It could turn out that way, but it seems far from certain. BA.2 has 70 mutations significantly more than the 53 of BA.1. 12/16
BA.1 and BA.2 share a set of mutations, but their mutations differ a great deal as well, both spike and non-spike. outbreak.info/compare-lineag… 13/16
One Denmark report said there was "no evidence" of increased severity from BA.2. This may turn out to be right, but it reminds me of the early declarations that there was "no evidence" Alpha or Delta were more severe. Evidence takes time to accumulate. 14/16
We can hope BA.2 won't seriously change things for the worse, but to assume it is nothing to worry about seems extremely unwise. Similar assumptions have not worked out well for us in this pandemic.

Interesting tidbit from @bicidiario here. 15/16
See this great thread by @PeacockFlu for more info on BA.2. 16/16

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More from @LongDesertTrain

Ryan Hisner Profile picture
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
Ryan Hisner Profile picture
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
Ryan Hisner Profile picture
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
Ryan Hisner Profile picture
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
Ryan Hisner Profile picture
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
Ryan Hisner Profile picture
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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