Evolution of immune genes is associated with the Black Death

Jennifer Klunk, Tauras P. Vilgalys, Christian E. Demeure, Xiaoheng Cheng, Mari Shiratori, Julien Madej, Rémi Beau, Derek Elli, Maria I. Patino, Rebecca Redfern, Sharon N. DeWitte, Julia A. Gamble, Jesper L. Boldsen, Ann Carmichael, Nükhet Varlik, Katherine Eaton, Jean-Christophe Grenier, G. Brian Golding, Alison Devault, Jean-Marie Rouillard, Vania Yotova, Renata Sindeaux, Chun Jimmie Ye, Matin Bikaran, Anne Dumaine, Jessica F. Brinkworth, Dominique Missiakas, Guy A. Rouleau, Matthias Steinrücken, Javier Pizarro-Cerdá, Hendrik N. Poinar () and Luis B. Barreiro ()
Additional contact information
Jennifer Klunk: McMaster University
Tauras P. Vilgalys: University of Chicago
Christian E. Demeure: Institut Pasteur
Xiaoheng Cheng: University of Chicago
Mari Shiratori: University of Chicago
Julien Madej: Institut Pasteur
Rémi Beau: Institut Pasteur
Derek Elli: University of Chicago
Maria I. Patino: University of Chicago
Rebecca Redfern: Museum of London
Sharon N. DeWitte: University of South Carolina
Julia A. Gamble: University of Manitoba
Jesper L. Boldsen: University of Southern Denmark
Ann Carmichael: Indiana University
Nükhet Varlik: Rutgers University
Katherine Eaton: McMaster University
Jean-Christophe Grenier: Université de Montréal
G. Brian Golding: McMaster University
Alison Devault: Daicel Arbor Biosciences
Jean-Marie Rouillard: Daicel Arbor Biosciences
Vania Yotova: Centre Hospitalier Universitaire Sainte-Justine
Renata Sindeaux: Centre Hospitalier Universitaire Sainte-Justine
Chun Jimmie Ye: University of California
Matin Bikaran: University of California
Anne Dumaine: University of Chicago
Jessica F. Brinkworth: University of Illinois Urbana-Champaign
Dominique Missiakas: University of Chicago
Guy A. Rouleau: McGill University
Matthias Steinrücken: University of Chicago
Javier Pizarro-Cerdá: Institut Pasteur
Hendrik N. Poinar: McMaster University
Luis B. Barreiro: University of Chicago

Nature, 2022, vol. 611, issue 7935, 312-319

Abstract: Abstract Infectious diseases are among the strongest selective pressures driving human evolution1,2. 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 pestis3. This pandemic devastated Afro-Eurasia, killing up to 30–50% of the population4. 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 201 variants that are highly differentiated within the London dataset. Combining evidence from during the Black Death, our replicate population in Denmark, and function evidence, rs2549794 near ERAP2 emerges as the strongest candidate for positive selection. The selected allele at 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.

Date: 2022
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DOI: 10.1038/s41586-022-05349-x

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