The “Black Death selection” finding you mention was subject to a very strong rebuttal preprinted in March 2023 and published yesterday in Nature. The original paper committed some pretty basic methodological errors[1] and, in my opinion, it’s disappointing that Nature did not decide to retract it. None of their claims of selection – neither the headline ERAP2 variant or the “half a dozen others” you refer to – survive the rebuttal’s more rigorous reanalysis. I do some work in ancient DNA and am aware of analyses on other datasets (published and unpublished) that fail to replicate the original paper’s findings.
Some of the most glaring (but not necessarily most consequential): a failure to correctly estimate the allele frequencies underlying the selection analysis; use of a genotyping pipeline poorly suited to ancient DNA which meant that 80% of the genetic variants they “analysed” were likely completely artefactual and did not exist.
use of a genotyping pipeline poorly suited to ancient DNA which meant that 80% of the genetic variants they “analysed” were likely completely artefactual and did not exist.
Brutal!! I didn’t know this gotcha existed. I hope there aren’t too many papers silently gotch’d by it. Sounds like the type of error that could easily be widespread and unnoticed, if the statistical trace it leaves isn’t always obvious.
I don’t think that recent ancient DNA papers are affected by this issue, at least not to the same extent. Every aDNA researcher I know is extremely aware of the many pitfalls associated with sequencing ancient material and the various chemical and computational methods to mitigate them. Checking for signs of systematic artifacts in your aDNA data is very routine and not especially difficult.
To provide some brief speculation, I think a major explanation for this paper’s errors is that aDNA lab that did the sequencing was quite old, under-staffed, and did not have much recent experience with sequencing human nuclear aDNA, so they had not kept fully abreast of the enormous methodological improvements in this area over the past twenty years.
Basically any paper trying to detect signals of natural selection in humans will turn up something plausibly immune-related [1][2][3][4]. Alongside pigmentation and diet-related genes, it’s one of the most robustly detected categories of monogenic selection signal.
While it seems extremely likely that some selection due to pathogenic disease has occurred in humans, I don’t think I’ve seen a paper that convincingly ties a particular selected gene to a particular historical pathogen or pandemic. It would be pretty hard to do so. There’s a many-to-many mapping between immune system genes and pathogenic diseases, and selection generally takes many centuries to detectably alter allele frequencies, during which time there have generally been many epidemics and other changes to the environment – which is responsible for the selection signal?
Regarding autoimmunity in particular: I am in no way an immunologist and have much less insight to offer here, but perhaps it isn’t surprising (almost tautological?) that immune system genes are often implicated in autoimmunity as well. And I’m not sure that inborn immunity due to HLA alleles or similar will be an important tool in the human race’s survival in the face of future pandemics. It’s perhaps telling that when you try to find variants associated with getting critically ill with COVID-19 – an extremely well-powered examination of the effects of genetic variability on response to a pandemic disease! – the very largest effect sizes for individual variants are a doubling/halving of risk. This is a notable difference, but nowhere close to “total immunity” vs “certain death”.
Having said that, I view “robust pathogen defence vs autoimmunity trade-off” as a very plausible just-so story, and likely to be true, but not concretely established at present. Sadly, it’s one of those questions in science where running the right controlled experiment is practically impossible and we have to make do with detective work.
The “Black Death selection” finding you mention was subject to a very strong rebuttal preprinted in March 2023 and published yesterday in Nature. The original paper committed some pretty basic methodological errors[1] and, in my opinion, it’s disappointing that Nature did not decide to retract it. None of their claims of selection – neither the headline ERAP2 variant or the “half a dozen others” you refer to – survive the rebuttal’s more rigorous reanalysis. I do some work in ancient DNA and am aware of analyses on other datasets (published and unpublished) that fail to replicate the original paper’s findings.
Some of the most glaring (but not necessarily most consequential): a failure to correctly estimate the allele frequencies underlying the selection analysis; use of a genotyping pipeline poorly suited to ancient DNA which meant that 80% of the genetic variants they “analysed” were likely completely artefactual and did not exist.
Brutal!! I didn’t know this gotcha existed. I hope there aren’t too many papers silently gotch’d by it. Sounds like the type of error that could easily be widespread and unnoticed, if the statistical trace it leaves isn’t always obvious.
I don’t think that recent ancient DNA papers are affected by this issue, at least not to the same extent. Every aDNA researcher I know is extremely aware of the many pitfalls associated with sequencing ancient material and the various chemical and computational methods to mitigate them. Checking for signs of systematic artifacts in your aDNA data is very routine and not especially difficult.
To provide some brief speculation, I think a major explanation for this paper’s errors is that aDNA lab that did the sequencing was quite old, under-staffed, and did not have much recent experience with sequencing human nuclear aDNA, so they had not kept fully abreast of the enormous methodological improvements in this area over the past twenty years.
Thanks for catching that! I hadn’t heard. I will probably have to rewrite that section of the post.
What’s your impression about the general finding about many autoimmune variants increasing protection against ancient plauges?
Basically any paper trying to detect signals of natural selection in humans will turn up something plausibly immune-related [1] [2] [3] [4]. Alongside pigmentation and diet-related genes, it’s one of the most robustly detected categories of monogenic selection signal.
While it seems extremely likely that some selection due to pathogenic disease has occurred in humans, I don’t think I’ve seen a paper that convincingly ties a particular selected gene to a particular historical pathogen or pandemic. It would be pretty hard to do so. There’s a many-to-many mapping between immune system genes and pathogenic diseases, and selection generally takes many centuries to detectably alter allele frequencies, during which time there have generally been many epidemics and other changes to the environment – which is responsible for the selection signal?
Regarding autoimmunity in particular: I am in no way an immunologist and have much less insight to offer here, but perhaps it isn’t surprising (almost tautological?) that immune system genes are often implicated in autoimmunity as well. And I’m not sure that inborn immunity due to HLA alleles or similar will be an important tool in the human race’s survival in the face of future pandemics. It’s perhaps telling that when you try to find variants associated with getting critically ill with COVID-19 – an extremely well-powered examination of the effects of genetic variability on response to a pandemic disease! – the very largest effect sizes for individual variants are a doubling/halving of risk. This is a notable difference, but nowhere close to “total immunity” vs “certain death”.
Having said that, I view “robust pathogen defence vs autoimmunity trade-off” as a very plausible just-so story, and likely to be true, but not concretely established at present. Sadly, it’s one of those questions in science where running the right controlled experiment is practically impossible and we have to make do with detective work.