Covid: Summary of lab-origin hypothesis

You're ignoring other data which is counter to the idea of B evolving from A in humans. Pekar's models are not the only evidence.

- Early cases were predominantly B - A shows less generic divergence than B, this is what Pekar is talking about with regards to the discontinuity in the early clock.

When we first started discussing this - I spoke up because I was annoyed by you trashing peer-reviewed papers when it was obvious you weren't even attempting to grok the phylogenetics involved. Still annoyed.

It's been genuinely interesting watching the scientific debate to root the SC2 tree over the past few years because of the involved paradoxes.

"Just a few SNPs" is just such a silly argument when stacked against peer-reviewed phylogenies in high-impact publications.

> because nothing else excludes an earlier (even September) first introduction into humans. With an earlier introduction and thus more extensive unsampled spread, it's much harder to insist that A and B would be first sampled in the same order in which they evolved in humans

The tMRCA clearly excludes an earlier introduction. Because the tMRCA is based on genetic diversity, you cannot calculate a tMRCA based on all the known samples, get a date, and then say "oh, geez- well, there was also wide cryptic spread before that." It just doesn't make sense. Pekar addresses this point directly.

A race between the first A and the first B is a strawman. Rather, it's the predominance of lineage B over A in the early pandemic which is interesting. It would be unexpected for lineage B to dominate if A came first. Much of the modeling is to get a handle on how unlikely that situation would be. It shouldn't be surprising that the models don't support it as being likely. (But, that's not the only evidence.)

If you're willing to actually think about and engage on the phylogeny - stop with the "just a few SNPs" nonsense, and ask yourself what you really think the early origins looked like. If it really was a single introduction - Was lineage A ancestral? Was B ancestral? A C/C ancestor? A T/T ancestor? All these have interesting problems being supported by the data.

Finally, after reading some of your earlier comments, I'm realizing that you're conflating several techniques from Pekar's paper, eg:

> Have you looked at Pekar's full model, as set out mostly in the supplementary materials? This isn't any standard molecular clock approach. It's a byzantine stack of plausible but somewhat arbitrary assumptions, ending in a simulated phylogenetic tree.

His epi simulations are separate from the tree-building, with the possible exception of rooting, which he was using the output of the models to inform. Otherwise, the epi modeling which everyone is hand wringing over is really separate and doesn't end "in a simulated phylogenetic tree."

There /are/ novel methods used in the tree building (eg, non-reversibility of base substitutions), but that's a whole separate technique.

> Essentially Pekar's argument is a "two introductions of the gaps"--that if their model of a single introduction doesn't conform to reality, then it must have been two introductions.

BS. Again - understanding the paradoxes and debate involved in rooting the tree is basically required to understand the importance of this paper. The existing data is confounding and didn't conform to a logical understanding of viral evolution. A separate introduction elegantly explains the existing evidence.

If their modeling isn't strong enough evidence for you, fine. But that's different than throwing everything out because you don't understand how "just a couple SNPs" can still provide sufficient resolution to make phylogenetic inferences possible. If you think that "just a couple SNPs" /don't/ provide enough for experts in the field to inform their phylogenies, at least get to that argument directly instead of throwing ignorant shade at an unrelated portion of the paper.

Thanks for the links to those other threads. Nod's was interesting, but AFAICT, way off-base, starting around "Needless to say, early winter in Wuhan is not the Mardi Gras."

Here's Pekar's earlier thread which I recently reread and found helpful for understanding the significance of the phylogeny (#20 is where he gets into how lineage A breaks the clock):

https://twitter.com/jepekar/status/1499840335349911553

and Worobey re-emphasizing that we're not just talking about a few SNPs, it's the shape of the tree which matters:

https://twitter.com/michaelworobey/status/157050467474223923...

> We simulated SARS-CoV-2–like epidemics (22, 23) with a doubling time of 3.47 days [95% highest density interval (HDI) across simulations, 1.35 to 5.44] (24–26) to account for the rapid spread of SARS-CoV-2 before it was identified as the etiological agent of COVID-19 (figs. S21 and S22, tables S3 and S4, and supplementary text). We then simulated coalescent processes and viral genome evolution across these epidemics to determine how frequently we recapitulated the observed SARS-CoV-2 phylogeny.

Coverage of this paper in the popular press usually said something like "study finds that SARS-CoV-2 arose from two introductions into humans", so I thought the latter was the more important result and started there. Like in your second link, Worobey says:

> [...] We then go on the explain, point by point, that it is not a two-mutation difference that is unexpected. It is a two mutation difference between two large clades like lineage A and lineage B, each displaying a MASSIVE polytomy at their root. This is something that [sic] DO NOT see in ~99.5% of simulations. That is the crux of the paper. Not the idea that two mutations can't happen in a single transmission event.

Are those "simulations" not the SIR-type epi simulations (followed by simulation of the mutations and sampling, then construction of the tree)? I believe his 99.5% is 100% minus the 0.5% from Figure 2C.

Their former model is of course independent of their SIR stuff, and indeed purports to independently establish tMRCA in humans too recent for significant cryptic spread. It carries a different set of plausible but arbitrary assumptions though, again about the stochasticity/overdispersion and sampling rate of early spread, just less directly.

> It carries a different set of plausible but arbitrary assumptions though, again about the stochasticity/overdispersion and sampling rate of early spread, just less directly.

So, you don't only have problems with the modeling of the authors, but their base phylogeny too? Do you reject their tMRCA? Good grief.

I'm still looking forward to discussing the molecular phylogenetics of this paper sometime.

Yeah, pretty much; and it's what other critics, including well-credentialed mathematical biologists, are saying too. There's a continuum of dispersion, with my perfectly-deterministic strawman at the left extreme but extending to infinity. Their power-law network adds some dispersion, but how do we know it's enough? I believe they chose that distribution because it's been shown to fit some real data (including the spread of HIV) reasonably well; but how do we know it fits the early spread of SARS-CoV-2, in the earliest lineages of the virus with unknown biology, in an unknown group of people with unknown behaviors?

I don't know how to root the phylogeny, and I'm mistrustful of anyone who claims they can based on the limited information available. Anyone who's built and attempted to validate mathematical models knows that sometimes, there's simply not enough information to confidently reach any useful conclusions. Absent validation of the approaches used here (e.g. evidence that they've successfully made predictions in the past in similar situations), I believe that's our situation here.