Evolution of immune genes is associated with the Black Death

Abstract

Infectious diseases are among the strongest selective pressures driving human evolution 1 , 2 . This includes the single greatest mortality event in recorded history, the first outbreak of the second pandemic of plague, commonly called the Black Death, which was caused by the bacterium Yersinia pestis 3 . This pandemic devastated Afro-Eurasia, killing up to 30–50% of the population 4 . To identify loci that may have been under selection during the Black Death, we characterized genetic variation around immune-related genes from 206 ancient DNA extracts, stemming from two different European populations before, during and after the Black Death. Immune loci are strongly enriched for highly differentiated sites relative to a set of non-immune loci, suggesting positive selection. We identify 245 variants that are highly differentiated within the London dataset, four of which were replicated in an independent cohort from Denmark, and represent the strongest candidates for positive selection. The selected allele for one of these variants, rs2549794, is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages. Finally, we show that protective variants overlap with alleles that are today associated with increased susceptibility to autoimmune diseases, providing empirical evidence for the role played by past pandemics in shaping present-day susceptibility to disease.

Variation inERAP2has opposing effects on severe respiratory infection and autoimmune disease

“…In this study, we show that variation at ERAP 2 is associated with susceptibility to respiratory infection in the present day. In line with a recent study using ancient DNA 8 , we show evidence suggesting that the C allele of rs2549794 is protective against respiratory infection, with evidence of increasing protection against severe disease. Although the effect size of the T allele on respiratory infection is modest (OR 1.05-1.1), this plausibly represents a large attenuation of the “wild type” effect of this locus, given modern treatments for respiratory infection (e.g.…”

“…There are three clear implications of the. Firstly, this data confirms the hypotheses raised by other studies: 5–8 there is likely a balancing effect at ERAP2 driven by protection from infection with increased risk of Crohn’s disease and type 1 diabetes. Secondly, therapeutics to target ERAP1 and ERAP2 are in development (to target Crohn’s disease and cancer 33 ).…”

“…Previous work has suggested that important variation (such as at rs2248374) at ERAP2 acts via alternative splicing leading to altered RNA and protein levels. 1,5,8,22 We therefore went on to perform Mendelian randomisation using expression and protein quantitative trait loci (QTL) cis for ERAP2 , to identify if altered levels of ERAP2 transcripts or protein altered the odds of each outcome. We identified independent (r 2 > 0.1, in the European population of 1000 Genomes Project 23 ) SNPs that were associated (p < 5 × 10 −8 )with either a) whole blood RNA expression, b) lung tissue RNA expression, or plasma protein levels of ERAP2.…”

“…5–7 Haplotype A encodes the full ERAP2 protein, whereas Haplotype B has a premature stop codon leading to nonsense mediated decay, and reduced levels of ERAP2 protein. 8…”

Large effect loci have a prominent role in Darwin’s finch evolution

“…In contrast, the data on Darwin’s finches and other natural populations deviating from a solely polygenic model represent long-term responses to intense perturbations by natural selection, introgression, and environmental fluctuations. In humans, large effect alleles are known to affect adaptation to extreme environments at high altitudes (Simonson et al 2010) and diving (Ilardo et al 2018), and following strong selection associated with the Black Death (Klunk et al 2022).…”