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.
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.