Marc Johnson Profile picture
Sep 18, 2022 19 tweets 7 min read Read on X
SARS-CoV-2 lineages, Cryptic lineages, and a prediction of what the next dominant VOCs will be.
We sequence SARS-CoV-2 from wastewater using a different approach than most. We sequence smallish fragments of the genome so that we can tell if particular mutations are derived from the same virus. This way we are better able to determine if there is anything new circulating. Image
About a year and a half ago we detected something from a St. Louis sewershed that didn't make sense. SARS-CoV-2 lineages whose sequence did not match anything that had been seen from patients. We called these 'cryptic lineage'. Image
Wanting to know if this kind of thing was common, we started collaborating with @DrJDennehy to see if we could find anything similar in other places. NYC also had cryptic lineages. Not the same lineages, but lineages with similar characteristics.
nature.com/articles/s4146…
By the end of 2021, we had identified 9 sewersheds (out of about 180 that were being routinely surveyed) that contained cryptic lineages, including a lineage from California with @RoseKantor.
medrxiv.org/content/10.110…
My obsession with finding and characterizing these cryptic lineages accelerated in 2022. To date we have screened wastewater from around 700 sewersheds. In total we have found 24 putative lineages. I say putative because some of them we have only seen once.
We still didn't know where these lineages were coming from. I was convinced of an animal reservoir. What changed my mind is when we tracked a lineage in Wisconsin with @dho all the way to a single set of bathrooms. There is no animal contribution. It is from a person. Image
What we think is happening is that cryptic lineages are very long-term infections in people (often >1 year). Perhaps GI infections. The hosts are obviously mounting an immune response, but are not able to clear the infection.
Because there are no genetic bottlenecks from spreading from person-to-person, these viruses basically push the evolutionary fast-forward button.
What can these lineages tell us about circulating viruses? These are the sites in the Spike RBD that are most commonly changed in the cryptic lineages. We had seen lineages with these changes long before they were seen in Omicron. Image
When Omicron arrived (shown in red) it had mutations at many of the same sites. The main exceptions were L452 and N460, which were common in cryptic lineages, but were not in Omicron (BA.1). Image
About six months later we started seeing Omicron lineages with mutations at L452. Highlighted in red are the changes in BA.4/5 (which has L452R), but there were also lineages with L452Q, L452M, and others. These lineages took over, but there were still no changes at N460. Image
Finally, a few months ago N460K appeared in an Omicron lineage (BA.2.75). However, it was not combined with any of the L452 mutations. Nonetheless, BA.2.75 and its derivatives have continued to expand and slowly displace other lineages. Image
A few days ago, a new lineage appeared in a MO wastewater sample. Omicron with L452R+N460K (and K444M). This appears to match a new lineage that was just designated as BU.1 a few days ago. Currently there are only 13 sequences in GISAID with this combination of mutations. Image
However, I recently learned from @CorneliusRoemer that I was behind in my lineages. There is another completely independent lineage that arrived at almost exactly the same combination. This lineage is designated BQ.1.1. This group has L452R+K444T (rather than K444M).
In addition, BQ.1.1 has also picked up R346T (also in BA.4.6). We haven't focused as much on this region of spike, but most cryptic lineages that we have checked also have a mutation at this site. It seems to be pretty critical. BQ.1.1 is new, but it seems to be taking off.
There you have it. BQ and BU. I don't know if they will cause a spike in total cases, but barring something completely new appearing, I predict that they will be the dominant VOCs in the coming months.
Addendum. It seems a few other lineages have hit very similar 'jackpot' combinations very recently. In addition to BU and BQ:

BW.1 (BA.5.6 derivative)
BS.1 (BA.2.3 derivative)
BR.2 (BA.2.75 derivative)
other undesignated

They all have N460K, L452R + other changes.
Real pango experts, please correct me if I botch any of these, or have missed any. @CorneliusRoemer @PeacockFlu @siamosolocani @LongDesertTrain

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More from @SolidEvidence

Nov 22
If anyone wants to follow along with the Maryland variant (or doesn't believe my analysis), have a look for yourself.

1/
Go to
Type in SRR31400336 and start alignment.

This is a sample from the Maryland sewershed collected on November 7 of this year.
2/deeperseq.genomium.org
This is the RBD region of the Maryland sewershed, below is a normal sewershed.

It doesn't take a molecular virologist to see that one doesn't look like the other.

3/ Image
Read 4 tweets
Nov 20
Maryland folks, I need another favor.
There is a person from Anne Arundel county that has been infected with SARS-CoV-2 for about 3 years (Delta infection).

They probably don’t even know they are infected, but they are shedding a ton of viral material in wastewater
1/ Image
I’m trying to find this person without invading their privacy, if they are willing to be found.

Here are a few threads I’ve written about this variant if you want to read up.

x.com/SolidEvidence/…
x.com/SolidEvidence/…
x.com/SolidEvidence/…
2/
We figured out that the signal is from the Patuxent sewershed (78k people). We’ve been detecting the variant there since this Spring.

Interestingly, the COVID WW spikes were dates when the cryptic sequence was highly prevalent.

Those spikes were driven by one person!

3/ Image
Read 8 tweets
Nov 17
Need a little help.

Does anyone know someone that works at the Patuxent Water Reclamation Facility in Crofton, MD that they could put me in touch with?

Here's why.
1/ Image
There is a cryptic lineage (unique, evolutionarily advanced SARS-CoV-2 lineage detected in wastewater) that we have been detecting from a Maryland sewershed all year.

The lineage is derived from Delta, so it's from a person that was first infected about 3 years ago.

2/ Image
Please don't ask me how we know this isn't coming from an animal.

That's what I thought at first too, but at this point we are all but certain that the sequences are coming from individual people. Here's one of many threads I've written about this.
3/
Read 12 tweets
Nov 15
Postmortem.

Thanks for all of the retweets!

Late last night the twitter/x account was suspended and I also can't view the ResearchGate account anymore.

Here's a summary of some of the discussion/findings.

1/
I was going to post the full exchange I had with 'Julia', but I can't view it anymore. It was ~three exchanges and they were very benign. I stopped when I decided she was probably fake, but then she tried to reengage a few days later, which is when I investigated.
2/
For those who think I'm naive.

I have had numerous 'weird' messages from people that found me on this platform that turned out to be EXTREMELY beneficial both personally and professionally.

If something isn't obviously fraud, I take it at face value (with skepticism).
3/
Read 12 tweets
Nov 14
I knew there were a lot of fake accounts on this platform, but they are usually obvious. I had no idea how intricate and complex the ruse could be.

Get a load of this story.
1/
About a week ago I got a DM from an account asking me a benign but specific question about my research.

This happens to me all the time. I’ve met some interesting people this way.

Sometimes people even look up my number and call my office. It happens.
2/ Image
The account looked legitimate. They are a paying account (I’ve never seen a bot that pays).
They’ve been on the platform for over 2 years.
They have 52 followers, some of whom I recognize, and they compulsively repost interesting science posts (including some of mine).
3/ Image
Read 16 tweets
Nov 5
I'm doubling down on MV.1*

This lineage has been growing rapidly recently, but it's been hard to tell if it would be a real contender since most of the infections were from Singapore.

In North America its growth has been more questionable.

But I have new data.
1/ Image
You probably know that our team screens all of the wastewater sequences submitted to SRA for cryptic lineages.

One of the 'cryptic-specific' changes we look for is S:F456V, which is common in cryptic, but hadn't been seen much in circulation until recently.
2/
MV.1* has a reversion at S:478 back to T, which is right next door to 456V, so its easy for me to check if the 456V sequences are in fact MV.1*

3/ Image
Read 5 tweets

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