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These "two distinct lineages" are separated by exactly two single-nucleotide polymorphisms (SNPs). For comparison, omicron differs from the original Wuhan virus

These "two distinct lineages" are separated by exactly two single-nucleotide polymorphisms (SNPs). For comparison, omicron differs from the original Wuhan virus by more than fifty SNPs. SARS-CoV-2 averages something around a third of an SNP per human-to-human transition. https://mobile.twitter.com/jbloom_lab/status/1534630607220711425 https://mobile.twitter.com/jbloom_lab/status/153463060722071... It's overwhelmingly likely that something around two months of cryptic spread occurred before the market super-spreader event, regardless of whether the origin was natural or research-related. That's plenty of time for these "two distinct lineages" to develop. They could also have developed at the market, either in a single transmission with two mutations, or in two transmissions with an intermediate lineage that died out before it could be sampled. Were you previously aware that the two lineages were just two SNPs apart? It's bizarre to me that the "two lineages" have received so much press as evidence of natural zoonosis, when they could have arisen so easily in human-to-human transmission.

mikeyouse 4y ago
> Were you previously aware. Yes, of course. > It's overwhelmingly likely that something around two months of cryptic spread occurred before the market super-spreader event, regardless of whether the origin was natural or research-related. That's plenty of time for these "two distinct lineages" to develop. They could also have developed at the market, either in a single transmission with two mutations, or in two transmissions with an intermediate lineage that died out before it could be sampled. Two points - if there were months of cryptic spread, that essentially rules out 95% of the lab leak hypotheses and further reduces the importance of the WIV proximity. Secondly, Twitter is an obnoxious interface but Pekar who wrote the paper highlighting the divergent sequences has a good thread explaining why it’s such an important data point: https://mobile.twitter.com/jepekar/status/1499843269500407808 https://mobile.twitter.com/jepekar/status/149984326950040780... Since the multiple lineages were present in the very first patients as compared to say January 2020, it narrows the dates and source of the first virus considerably. The very first identified cases had two distinct viruses and were all present at the market. That’s not at all what you would see if the virus had been spreading for a longer period (we’d have intermediate samples) or if someone from the WIV went to the market and infected people (they’d all show the common lineage that all other transmission chains show).
- tripletao 4y ago
  I've seen the paper, and I don't understand its reasoning. Maybe that's my lack of domain knowledge; but Jesse Bloom is impeccably credentialed and he seems to disagree too. I believe it's possible that: 1. The mutations that separate Lineages A and B occurred in non-human animals, and were introduced to humans in two zoonotic jumps. This is Pekar's argument. 2. Or, the mutations that separate Lineages A and B occurred in humans during cryptic spread, at the market or elsewhere. If the two lineages were separated by a large number of mutations, then option (2) would be very unlikely--the virus couldn't spread in humans for long enough to accumulate that many SNPs without exploding into a large enough cluster with enough sickness and mortality that emergence would have been discovered earlier (and we'd have found evidence of that spread retrospectively in sero-surveillance of stored samples, etc.). But it's just two SNPs--as Jesse Bloom notes, 5-10% of single human-to-human transmissions show at least that much difference, as will many two-transmission chains for which the intermediate never got sampled (or longer chains for which many intermediates never got sampled; the over-dispersed "superspreader" nature of SARS-CoV-2's transmission means almost all chains die out, while a few explode). So what excludes (2)? ETA: I've never found anyone able to explain in their own words why "two lineages" definitely implies two zoonoses despite the tiny genetic distance between them. I strongly suspect that most people making that claim are simply repeating it, and aren't able to understand the paper, and that the reason none of us can understand is that it's nonsense. If anyone believes otherwise then I'd love to hear, though.
  - mikeyouse 4y ago
    > I've never found anyone able to explain in their own words why "two lineages" definitely implies two zoonoses despite the tiny genetic distance between them. I strongly suspect that most people making that claim are simply repeating it, and aren't able to understand the paper, and that the reason none of us can understand is that it's nonsense. If anyone believes otherwise then I'd love to hear, though. Plenty of us understand - even Bloom, who I generally respect (aside from some sloppy work at the beginning of the pandemic) understands but thinks it's slightly less likely than the theory you're implying. I (and many others!) disagree. Pekar does a lot of complicated testing and statistics to shore up his case, but "in my own words", it all comes down to timing. We know in which direction the genetic drift of SC2 occurs, which lets us know that Lineage A is the closer than Lineage B to the ancestral bat coronavirus. So Lineage A could mutate into Lineage B, but the opposite is very unlikely. However, the very first cases reported to the Chinese government - e.g. the very first patients actually were infected with Lineage B. It was several days later until patients began showing up with Lineage A infections. They've reconstructed the phylo trees to the extent possible with the genomes from those first patients and they just don't leave any real possibility that B came from A. The timing just doesn't work. Pekar estimates that Lineage B infections precede Lineage A ones by ~7 days. This is further buoyed by the rate of divergence in both Lineages being almost exactly the same even though the basic characteristics of each virus are identical. For that to be true, Lineage A. would've had to quietly spread without being IDed, would need to quickly mutate to Lineage B in order for the first sicknesses to be IDed as Lineage B, and then greatly slow down the rate of mutation to maintain the same divergence as B. This doesn't "disprove" that a single infection could have sparked both lineages - though it's extremely unlikely to have caused two viable viruses and left no trail whatsoever before them in the genetics. It's all a matter or probabilities and IMO, this shows it's far more likely to have had two jumps (similar to how SARS1 and MERS spread) than some hidden ancestor that was extremely similar to SC2 but wasn't noticeably pathogenic. At very least, this greatly narrows the timeframe and the location of the very first infection. If various vendors at the market were infected with viruses of different lineage within a handful of days of each other, it's completely obvious that this was the site of the first spread. That may seem like an anodyne observation but unfortunately there are still a lot of people who dispute even that much. I think Bloom is missing something here that would further change his odds in favor of the multiple zoonosis; https://mobile.twitter.com/jbloom_lab/status/1534663705060773888 https://mobile.twitter.com/jbloom_lab/status/153466370506077... > Agreed & one scenario under "not seeded by lineage B at market" is seeded by lineage A at market which then evolved into lineage B in humans. Alternatively could have been seeded by lineage A elsewhere & superspreading of derived lineage B at market. Guo found environmental samples of both Lineage A and Lineage B at the market -- so both were present there -- his second hypothetical would then be highly unlikely.

mikeyouse 4y ago

> Were you previously aware. Yes, of course. > It's overwhelmingly likely that something around two months of cryptic spread occurred before the market super-spreader event, regardless of whether the origin was natural or research-related. That's plenty of time for these "two distinct lineages" to develop. They could also have developed at the market, either in a single transmission with two mutations, or in two transmissions with an intermediate lineage that died out before it could be sampled. Two points - if there were months of cryptic spread, that essentially rules out 95% of the lab leak hypotheses and further reduces the importance of the WIV proximity. Secondly, Twitter is an obnoxious interface but Pekar who wrote the paper highlighting the divergent sequences has a good thread explaining why it’s such an important data point: https://mobile.twitter.com/jepekar/status/1499843269500407808 https://mobile.twitter.com/jepekar/status/149984326950040780... Since the multiple lineages were present in the very first patients as compared to say January 2020, it narrows the dates and source of the first virus considerably. The very first identified cases had two distinct viruses and were all present at the market. That’s not at all what you would see if the virus had been spreading for a longer period (we’d have intermediate samples) or if someone from the WIV went to the market and infected people (they’d all show the common lineage that all other transmission chains show).

tripletao 4y ago
I've seen the paper, and I don't understand its reasoning. Maybe that's my lack of domain knowledge; but Jesse Bloom is impeccably credentialed and he seems to disagree too. I believe it's possible that: 1. The mutations that separate Lineages A and B occurred in non-human animals, and were introduced to humans in two zoonotic jumps. This is Pekar's argument. 2. Or, the mutations that separate Lineages A and B occurred in humans during cryptic spread, at the market or elsewhere. If the two lineages were separated by a large number of mutations, then option (2) would be very unlikely--the virus couldn't spread in humans for long enough to accumulate that many SNPs without exploding into a large enough cluster with enough sickness and mortality that emergence would have been discovered earlier (and we'd have found evidence of that spread retrospectively in sero-surveillance of stored samples, etc.). But it's just two SNPs--as Jesse Bloom notes, 5-10% of single human-to-human transmissions show at least that much difference, as will many two-transmission chains for which the intermediate never got sampled (or longer chains for which many intermediates never got sampled; the over-dispersed "superspreader" nature of SARS-CoV-2's transmission means almost all chains die out, while a few explode). So what excludes (2)? ETA: I've never found anyone able to explain in their own words why "two lineages" definitely implies two zoonoses despite the tiny genetic distance between them. I strongly suspect that most people making that claim are simply repeating it, and aren't able to understand the paper, and that the reason none of us can understand is that it's nonsense. If anyone believes otherwise then I'd love to hear, though.
- mikeyouse 4y ago
  > I've never found anyone able to explain in their own words why "two lineages" definitely implies two zoonoses despite the tiny genetic distance between them. I strongly suspect that most people making that claim are simply repeating it, and aren't able to understand the paper, and that the reason none of us can understand is that it's nonsense. If anyone believes otherwise then I'd love to hear, though. Plenty of us understand - even Bloom, who I generally respect (aside from some sloppy work at the beginning of the pandemic) understands but thinks it's slightly less likely than the theory you're implying. I (and many others!) disagree. Pekar does a lot of complicated testing and statistics to shore up his case, but "in my own words", it all comes down to timing. We know in which direction the genetic drift of SC2 occurs, which lets us know that Lineage A is the closer than Lineage B to the ancestral bat coronavirus. So Lineage A could mutate into Lineage B, but the opposite is very unlikely. However, the very first cases reported to the Chinese government - e.g. the very first patients actually were infected with Lineage B. It was several days later until patients began showing up with Lineage A infections. They've reconstructed the phylo trees to the extent possible with the genomes from those first patients and they just don't leave any real possibility that B came from A. The timing just doesn't work. Pekar estimates that Lineage B infections precede Lineage A ones by ~7 days. This is further buoyed by the rate of divergence in both Lineages being almost exactly the same even though the basic characteristics of each virus are identical. For that to be true, Lineage A. would've had to quietly spread without being IDed, would need to quickly mutate to Lineage B in order for the first sicknesses to be IDed as Lineage B, and then greatly slow down the rate of mutation to maintain the same divergence as B. This doesn't "disprove" that a single infection could have sparked both lineages - though it's extremely unlikely to have caused two viable viruses and left no trail whatsoever before them in the genetics. It's all a matter or probabilities and IMO, this shows it's far more likely to have had two jumps (similar to how SARS1 and MERS spread) than some hidden ancestor that was extremely similar to SC2 but wasn't noticeably pathogenic. At very least, this greatly narrows the timeframe and the location of the very first infection. If various vendors at the market were infected with viruses of different lineage within a handful of days of each other, it's completely obvious that this was the site of the first spread. That may seem like an anodyne observation but unfortunately there are still a lot of people who dispute even that much. I think Bloom is missing something here that would further change his odds in favor of the multiple zoonosis; https://mobile.twitter.com/jbloom_lab/status/1534663705060773888 https://mobile.twitter.com/jbloom_lab/status/153466370506077... > Agreed & one scenario under "not seeded by lineage B at market" is seeded by lineage A at market which then evolved into lineage B in humans. Alternatively could have been seeded by lineage A elsewhere & superspreading of derived lineage B at market. Guo found environmental samples of both Lineage A and Lineage B at the market -- so both were present there -- his second hypothetical would then be highly unlikely.