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> They're just two single-nucleotide polymorphisms apart The problem with that argument, is that it doesn't explain the polytomies and is misleading, as you ac

> They're just two single-nucleotide polymorphisms apart The problem with that argument, is that it doesn't explain the polytomies and is misleading, as you accuse Worobey of being. "Just a few SNPs" is disingenuous and glosses over the usefulness of this evidence that almost everyone agrees on - eg, that it's highly unlikely that lineage B evolved from lineage A. (Even Jesse Bloom agrees on this.) It may take a bit to find consensus on the dual-zoonosis theory and related phylogenetics, but the eagerness with which people dismiss this issue drives me nuts. https://twitter.com/jepekar/status/1499840349807656960 https://twitter.com/jepekar/status/1499840349807656960

tripletao 4y ago
You're correct that it's highly unlikely that B evolved from A, but why do you think that's significant? We know the spread of SARS-CoV-2 is highly stochastic, with most lineages dying out and a few exploding, and we know the IFR in humans is small enough that considerable cryptic spread is possible before enough people die to raise the alarm. So why do you take the two lineages as conclusive evidence of two zoonotic events (as Worobey has repeatedly claimed in the media, even though his papers are more cautious)? Given the above, I don't see how we can exclude that the two lineages evolved in early human cryptic spread, before we started sampling enough to draw a perfect phylogenetic tree.
- oasisbob 4y ago
  I don't take two lineages to be conclusive evidence of multiple zoonotic events. However, the multiple polytomies for each are not easy to explain away. Have you read Pekar's most recent paper in Science? I raise this in earnest, I'm reading it now. A lot of it follows the preprint, but the update more directly addresses many of the points we're discussing. https://www.science.org/doi/10.1126/science.abp8337 https://www.science.org/doi/10.1126/science.abp8337 My problem with the "just a couple mutations" deniers is that that viewpoint doesn't speak to any of the real phylogenic questions here.
  - tripletao 4y ago
    I led with "just two mutations" because as far as I can tell, all of Worobey's or Pekar's reasoning starts from the assumption that there was no significant cryptic (unsampled) human spread. If the two lineages were tens of SNPs apart, then I believe that would be a reasonable assumption--it would be hard to explain how the virus could spread in humans long enough to accumulate that many mutations without causing enough sickness and mortality for someone to notice. But with just two SNPs, I believe that assumption is invalid. So while I believe those authors have correctly observed that we're missing part of the evolutionary history of SARS-CoV-2, I don't see how they decided whether that's unsampled spread in animals vs. unsampled spread in humans, except under that incorrect assumption. I hadn't read the final paper, but I'm looking at it now. I don't see any new points that don't depend on that assumption yet, though. Do you?
    - oasisbob 4y ago
      > all of Worobey's or Pekar's reasoning starts from the assumption that there was no significant cryptic (unsampled) human spread. They don't assume that. See the discussion in Pekar. ("The high extinction rate [...] Failed introductions of intermediate haplotypes are also possible.") The whole point of their epidemiological modeling is to disentangle the likelihood of this happening. (See: "Separate introductions of lineages A and B") The tMRCA doesn't allow enough time for any deep cryptic spread. The authors show this. It's not assumed. > We show that it is highly unlikely that SARS-CoV-2 circulated widely in humans earlier than November 2019 and that there was limited cryptic spread, with, at most, dozens of SARS-CoV-2 infections in the weeks leading up to the inferred tMRCA, but likely far fewer.
      - tripletao 4y ago
        The details of that epidemiological model start around page 7 of https://www.science.org/doi/suppl/10.1126/science.abp8337/suppl_file/science.abp8337_sm.pdf https://www.science.org/doi/suppl/10.1126/science.abp8337/su... I haven't fully studied all the layers yet, but as far as I can tell it's numerical sludge, in the same general direction as econometrics, with so many free parameters or arbitrary choices in the model that you could plausibly get almost any result you wanted. Similar models got their chance to make falsifiable predictions of the case count in the actual pandemic, and they failed repeatedly, often by huge margins, in both directions. For a specific criticism, the authors report that they're robust against variation in doubling time, but nothing about robustness to the extent of the overdispersion of SARS-CoV-2's spread (i.e., the superspreader characteristic, where most patients infect very few people but a minority infect a lot). They appear to model that only through the connectivity of the infection network, which appears to be fixed. All other things being equal, more stochastic early spread will make it harder to confidently reach any conclusion. I'm not saying this work isn't interesting at all, or that I could do better; but it's many layers of stacked uncertainty. I believe the confidence that the authors express in this paper is already excessive, and Worobey's statements to the media go considerably beyond that.

tripletao 4y ago

You're correct that it's highly unlikely that B evolved from A, but why do you think that's significant? We know the spread of SARS-CoV-2 is highly stochastic, with most lineages dying out and a few exploding, and we know the IFR in humans is small enough that considerable cryptic spread is possible before enough people die to raise the alarm. So why do you take the two lineages as conclusive evidence of two zoonotic events (as Worobey has repeatedly claimed in the media, even though his papers are more cautious)? Given the above, I don't see how we can exclude that the two lineages evolved in early human cryptic spread, before we started sampling enough to draw a perfect phylogenetic tree.

oasisbob 4y ago
I don't take two lineages to be conclusive evidence of multiple zoonotic events. However, the multiple polytomies for each are not easy to explain away. Have you read Pekar's most recent paper in Science? I raise this in earnest, I'm reading it now. A lot of it follows the preprint, but the update more directly addresses many of the points we're discussing. https://www.science.org/doi/10.1126/science.abp8337 https://www.science.org/doi/10.1126/science.abp8337 My problem with the "just a couple mutations" deniers is that that viewpoint doesn't speak to any of the real phylogenic questions here.
- tripletao 4y ago
  I led with "just two mutations" because as far as I can tell, all of Worobey's or Pekar's reasoning starts from the assumption that there was no significant cryptic (unsampled) human spread. If the two lineages were tens of SNPs apart, then I believe that would be a reasonable assumption--it would be hard to explain how the virus could spread in humans long enough to accumulate that many mutations without causing enough sickness and mortality for someone to notice. But with just two SNPs, I believe that assumption is invalid. So while I believe those authors have correctly observed that we're missing part of the evolutionary history of SARS-CoV-2, I don't see how they decided whether that's unsampled spread in animals vs. unsampled spread in humans, except under that incorrect assumption. I hadn't read the final paper, but I'm looking at it now. I don't see any new points that don't depend on that assumption yet, though. Do you?
  - oasisbob 4y ago
    > all of Worobey's or Pekar's reasoning starts from the assumption that there was no significant cryptic (unsampled) human spread. They don't assume that. See the discussion in Pekar. ("The high extinction rate [...] Failed introductions of intermediate haplotypes are also possible.") The whole point of their epidemiological modeling is to disentangle the likelihood of this happening. (See: "Separate introductions of lineages A and B") The tMRCA doesn't allow enough time for any deep cryptic spread. The authors show this. It's not assumed. > We show that it is highly unlikely that SARS-CoV-2 circulated widely in humans earlier than November 2019 and that there was limited cryptic spread, with, at most, dozens of SARS-CoV-2 infections in the weeks leading up to the inferred tMRCA, but likely far fewer.
    - tripletao 4y ago
      The details of that epidemiological model start around page 7 of https://www.science.org/doi/suppl/10.1126/science.abp8337/suppl_file/science.abp8337_sm.pdf https://www.science.org/doi/suppl/10.1126/science.abp8337/su... I haven't fully studied all the layers yet, but as far as I can tell it's numerical sludge, in the same general direction as econometrics, with so many free parameters or arbitrary choices in the model that you could plausibly get almost any result you wanted. Similar models got their chance to make falsifiable predictions of the case count in the actual pandemic, and they failed repeatedly, often by huge margins, in both directions. For a specific criticism, the authors report that they're robust against variation in doubling time, but nothing about robustness to the extent of the overdispersion of SARS-CoV-2's spread (i.e., the superspreader characteristic, where most patients infect very few people but a minority infect a lot). They appear to model that only through the connectivity of the infection network, which appears to be fixed. All other things being equal, more stochastic early spread will make it harder to confidently reach any conclusion. I'm not saying this work isn't interesting at all, or that I could do better; but it's many layers of stacked uncertainty. I believe the confidence that the authors express in this paper is already excessive, and Worobey's statements to the media go considerably beyond that.