Yersinia pestis under the microscope. (Image by NIAID)

By Celeste Cohen

Pandemics have shaped our history and present, changing the way we consider disease and hygiene. They have also shaped pathogens, which evolve to increase their transmission and resistance. But what about us? Have we evolved as a result of pandemics? The answer is likely yes, and has been shown by studying one of the most famous and deadly pandemics: the Black Death.

Researchers have studied ancient DNA from British and Danish populations who died before, during and after the Black Death to identify genetic differences that may have been caused by the pandemic. They found that at least 4 genetic regions, and potentially up to 245 more, had evolved because of the pandemic. In particular, a gene called ERAP2 (Endoplasmic reticulum aminopeptidase 2) showed strong evidence of selection. ERAP2 is involved in antigen presentation, which allows the immune system to recognise and destroy pathogens or infected cells. Two variants of the gene were identified: a protective variant, associated with increased expression and subsequent translation of the gene, and a deleterious variant which shows no such phenotype. Individuals that were homozygous for the protective variant of ERAP2 were estimated to have a 40% increased chance of surviving the Black Death compared to those homozygous for the deleterious allele. Not only this, but experiments using immune cells of individuals with the protective allele showed improved response and resistance to Yersinia pestis infection, the bacteria causing the bubonic plague or Black Death.

So why is this relevant today? Although the bubonic plague is now treatable with modern antibiotics, the effects of ERAP2 variants likely extend to other pathogens beyond Y. pestis. But if ERAP2 underwent selection during the Black Death and possibly in response to other pathogens, why does the deleterious variant still exist? This improved immune response to pathogens may actually increase our susceptibility to autoimmune disorders. The protective variant of ERAP2 is a known risk factor for Crohn’s disease, and protective variants of other genes under selection are associated with increased risk of rheumatoid arthritis and systemic lupus erythematosus. All three of these diseases are autoimmune disorders, causing over-inflammation of healthy tissues in the body. 

The natural selection our genome undergoes during pandemics such as the Black Death may thus be in part responsible for increasing incidence of autoinflammatory diseases. This in turn would cause balancing selection that maintains variants which are disadvantageous against pathogens. So did populations pre-Black Death experience less autoimmune diseases? Probably, but we will likely never know for sure.


Klunk J, Vilgalys TP, Demeure CE, Cheng X, Shiratori M, Madej J, Beau R, Elli D, Patino MI, Redfern R, DeWitte SN, Gamble JA, Boldsen JL, Carmichael A, Varlik N, Eaton K, Grenier JC, Golding GB, Devault A, Rouillard JM, Yotova V, Sindeaux R, Ye CJ, Bikaran M, Dumaine A, Brinkworth JF, Missiakas D, Rouleau GA, Steinrücken M, Pizarro-Cerdá J, Poinar HN, Barreiro LB. Evolution of immune genes is associated with the Black Death. Nature. 2022 Nov;611(7935):312-319. doi: 10.1038/s41586-022-05349-x. Epub 2022 Oct 19. PMID: 36261521; PMCID: PMC9580435.

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