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We recently published two preprints that provide the strongest evidence yet that the COVID-19 pandemic began at a market selling live animals in Wuhan.
An almost mirror-image of SARS just two decades earlier.
https://zenodo.org/record/6291628
https://zenodo.org/record/6299600
Long 
pic.twitter.com/LPr1zblf6r
Why do we believe the Huanan market was the origin?
Precedent
Clustering of hospitalizations, cases, deaths
Not a superspreading event
Two introductions
Susceptible animals sold
Clustering where animals were sold
Animal-associated objects 
Details
Before I dive in, I want to answer the most important question - does this mean we have solved the origin of the pandemic?
No, we have not. It is clear that it began at a market, but most everything upstream remains a black box and there's still a ton to do.
More at the end .
In the first preprint, led by @jepekar we show that:
"SARS-CoV-2 emergence very likely resulted from at least two zoonotic events"https://zenodo.org/record/6291628
In the second preprint, led by @MichaelWorobey we show that:
"The Huanan market was the epicenter of SARS-CoV-2 emergence"https://zenodo.org/record/6299600
Precedent
The emergence of SARS-CoV-2 looks a lot like that of SARS-CoV-1, especially:
Virus similarity (both are sarbecoviruses)
Timing (November 2002 vs November 2019)
Host range (broad)
Association with wet markets
For example, compare...pic.twitter.com/lRicrRxUXH
The emergence of a novel coronavirus isn't exactly news - it happens frequently. Here's a sampling of the ones we know about .
And, of course, since the beginning of the pandemic, many closely related viruses have been found, including BANAL-52:
https://www.nature.com/articles/s41586-022-04532-4 …pic.twitter.com/NaNJUi5yC8
These viruses are widespread all across South-East Asia because their reservoirs - horseshoe bats - are widely distributed, including, yes, in Hubei province. Importantly, virus diversity is massively undersampled.
Excellent paper led by @SpyrosLytras:
https://www.science.org/doi/10.1126/science.abh0117 …pic.twitter.com/LjZCWIuzso
If we go back to SARS1, we know that infected animals were found on farms in Hubei in both 2003 and 2004 - outside Wuhan. In fact, more SARS1 infected animals were found on Hubei farms than anywhere else in China - and Hubei supplied animals to Guangdong.https://twitter.com/K_G_Andersen/status/1488918972003094529?s=20&t=Lc1K_fAPVgT9VdVW8W-aIw …
Interestingly, the SARS1 genomes from Hubei - unlikely those from Guangdong - are significantly closer to the SARS1 genomes from human patients. Were Hubei farms the potential source for SARS1 and SARS2? Maybe, but need much more research. References: https://twitter.com/K_G_Andersen/status/1488718228238974983?s=20&t=j-VcqV9tc-t9wMEEpVHFeg …pic.twitter.com/mUSkdR2rMc
Because SARS-CoV-2 became a pandemic virus and SARS-CoV-1 did not, we would expect to find some 'key' features in this virus. We discussed this in our "Proximal Origin" paper: https://www.nature.com/articles/s41591-020-0820-9 … And this review: https://www.cell.com/cell/fulltext/S0092-8674(21)00991-0 …
I previously did a lengthy thread on one of these features - the furin cleavage site. Some have suggested that the structure of this site is suggestive of engineering - that couldn't be further from the truth (quite the opposite).https://twitter.com/K_G_Andersen/status/1391507230848032772 …
pic.twitter.com/Txc3sQYZSeSo why Wuhan? Another thread from @MichaelWorobey:https://twitter.com/MichaelWorobey/status/1438202006678630404 …
Clustering of hospitalizations, cases, deaths around the Huanan market
@MichaelWorobey wrote an excellent perspective on the clustering of hospitalizations early in the pandemic that showed a *very* clear association to the Huanan market:https://www.science.org/doi/10.1126/science.abm4454 …
I previously talked about the clustering of cases and excess deaths when I did a (rather lengthy...) rundown of the @WHO mission report:https://twitter.com/K_G_Andersen/status/1376954932004196352 …
to follow later today. pic.twitter.com/PziAyiWB4NIn the first part of Worobey et al., we go much deeper on the "clustering" analysis:
Early cases are clearly associated with the market
Association is non-random and not a result of age/demographics
The Huanan market was the early epicenter
https://zenodo.org/record/6299600 pic.twitter.com/2N4aQwqsuL
We extracted early case locations from the WHO mission report, later (probable) case locations from Weibo, and created null models based on population density or Jan/Feb cases. No matter how we look at the data, the association is clear and non-random.pic.twitter.com/cZG3abk5QB
Further, the Huanan market is *the only* place in Wuhan where early cases had a clear association - there are no other epidemiological links to any other place in the city. All of that changed as the outbreak spread - then we see clear association based on demographics.pic.twitter.com/DyFNaMpeYb
Not a superspreading event
Some have taken this to mean that the market was "merely a superspreading event". This is very unlikely:
Clustering inside market
Timing + multiple spillovers
Further, the doubling rate in the market was ~3-4 days (estimated from WHO data)pic.twitter.com/ihSx7qEZ8a
Two introductions
Let's hop over to Pekar et al., where we show that it's very likely that SARS-CoV-2 jumped multiple times (like SARS-CoV-1) - with one 'successful' lineage ("B") likely spilling over in late November and lineage "A" 1-2 weeks later.pic.twitter.com/iAehEVxLG1
One quick comment on "multiple spillovers" as some people find this exceedingly unlikely ("one spillover is unlikely, so two spillovers are much more unlikely"). This is not correct. We're dealing with conditional probability - one happens, two (and more) are likely to happen.
As Joel Wertheim put it - "we failed to climb Mount Everest for hundreds of thousands of years. And then, in just one day, two people did".
This is the same. The "(un)likelihoods" are upstream of infected animals - with just the right virus - ending up in a market. Once done,
pic.twitter.com/D9GM3aH9Qg
We have known for a while that two early lineages of SARS-CoV-2 existed - Lineage "A" and Lineage "B", using the PANGO naming convention. These two differ at two sites - 8272 ("A"=T; "B"=C) and 28144 ("A"=C; "B"=T) so "A" is T/C and "B" is C/T.https://zenodo.org/record/6291628
Genomic data show that "intermediates" (C/C; T/T) between A and B may have existed during the early outbreak in Wuhan - suggesting that e.g., A evolved to B or B evolved to A in humans. However, we show that this likely wasn't the case - early intermediates are due to errors.pic.twitter.com/a3Nsnt2Ho2
Lineage A is closer to closely related viruses like RaTG13 and BANAL-52, however, we can't simply say that this means that A is the ancestor of B as some have done previously. E.g.,https://academic.oup.com/mbe/article/38/12/5211/6353034 …
Trying to establish a rooted phylogeny of SARS-CoV-2 requires much more careful analysis than simply performing "outgroup" rooting (like 
).
In Pekar et al., we performed several Bayesian analyses to estimate likely roots and also created a putative "common ancestor".pic.twitter.com/JmD3N8J1PR
Once we obtain proper (posterior) estimates of the early SARS-CoV-2 phylogeny - and incorporate factors such as sampling times and evolutionary models - we can simulate plausible scenarios of early virus diversity and compare to the diversity that was actually observed.
These analyses make it clear that it is *much* more likely that A and B resulted from independent spillovers - one did not evolve into the other in the human population. Further, our timing estimates show that B likely spilled over late-November and A a little after that.pic.twitter.com/bvbBEfxIuk
These findings need to be seen in the context of a clear geographical association of *both* Lineages A and B with the Huanan market.pic.twitter.com/7vtj7u50xX
Further, as we were wrapping up our preprints, Gao et al. posted a preprint showing that Lineage A was indeed present at the Huanan market - in an environmental sample ("A20"), no less.https://www.researchsquare.com/article/rs-1370392/v1 …
We also don't see any evidence of intermediate genomes at the Huanan market in the Gao et al. preprint. We can therefore conclude:
Both Lineage A and B found at Huanan market
Early intermediates likely not real
Very likely two independent spillovers at the Huanan marketpic.twitter.com/Sff11DRw5H
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