The Black Death shaped the evolution of immunity genes, setting the course for how we respond to autoimmune diseases today, researchers find

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Researchers from the Institut Pasteur, McMaster University and the University of Chicago have identified genes that protected some individuals against the devastating bubonic plague pandemic that swept through Europe, Asia and Africa nearly 700 years ago. The same genes that once conferred protection against the Black Death are today associated with an increased susceptibility to autoimmune diseases. Their study was published on Wednesday October 19, 2022, in the journal Nature.

The epidemic known as the "Black Death," which struck in the Middle Ages, remains the single greatest human mortality event in recorded history, killing a large proportion of the people in what were then some of the most densely populated parts of the world. "When a pandemic of this nature – killing 30 to 50 per cent of the population – occurs, there is bound to be selection for protective alleles in humans, which is to say people susceptible to the circulating pathogen will succumb. Even a slight advantage means the difference between surviving or passing. Of course, those survivors who are of breeding age will pass on their genes," explains evolutionary geneticist Hendrik Poinar, joint last author of the paper and director of McMaster's Ancient DNA Centre.

The pathogen responsible for the Black Death is the bacterium Yersinia pestis. "The plague bacillus is one of the most virulent infectious agents that exists on the surface of the earth. We are working to understand the molecular mechanisms involved in the pathogenicity of this microorganism and the immune responses that are triggered after humans are infected with it," comments Javier Pizarro-Cerdá, one of the authors of the study, who is head of the Yersinia Research Unit, director of the World Health Organization Collaborating Center for Plague, and deputy head of the Plague and Yersinioses National Reference Center at the Institut Pasteur.

The scientists wanted to find out whether the plague bacillus led to the selection of protective genes against bubonic plague in humans in the Middle Ages. They screened ancient DNA samples extracted from the remains of individuals who had died before, during or after the Black Death in London, where there are several particularly well preserved, well dated cemeteries. Additional samples were taken from human remains buried in five other locations across Denmark. By comparing centuries-old DNA from victims and survivors of the Black Death pandemic, the scientists identified key genetic differences that determined who lived and who died, and how our immune systems have continued to evolve since that time.

Four genes under selection were identified, all of which are involved in the production of proteins that defend our systems from pathogens. The scientists discovered that versions of those genes, called alleles, either protected or rendered one susceptible to plague. Individuals with two identical copies of a functional gene, known as ERAP2, survived the pandemic at a much higher rate than those with non-functional versions of ERAP2. Researchers estimate that people with the ERAP2 protective functional allele (the good copy of the gene) were 40 to 50 per cent more likely to survive than those who did not.

This genetic variability still exists in our genomes today. "Few teams in the world are capable of studying interactions between cells in the immune system and the Y. pestis bacterium. Our expertise has demonstrated the real effect of the phenotype linked to ERAP2 on the response to a live plague bacterium," explains Christian Demeure, a researcher in the Institut Pasteur's Yersinia Unit. Using human cells, the scientists studied how ERAP2 alleles affected the interaction between the Y. pestis bacterium and immune cells. They analyzed how macrophages neutralized the Y. pestis bacterium. "The results were categorical. The 'good' copies of the ERAP2 gene allowed for more efficient neutralization of Y. pestis by immune cells. Having the right version of ERAP2 seems to have been decisive in giving immune cells the capability to destroy Yersinia pestis bacteria," comments Christian Demeure.

"The selective advantage associated with the selected loci is among the strongest ever reported in humans, showing how a single pathogen can have such a strong impact on the evolution of the immune system," says human geneticist Luis Barreiro, joint last author of the paper, and professor of Genetic Medicine at the University of Chicago.

The same genes that once conferred protection against the Black Death are today associated with an increased susceptibility to autoimmune diseases such as Crohn's and rheumatoid arthritis. This is the balancing act upon which evolution plays with our genome. "The identification of ERAP2 strengthens the idea that what enabled people to survive in one era may have a negative impact on survival in another," concludes Javier Pizarro-Cerda.

The findings, the result of years of work from graduate student Jennifer Klunk, formerly of McMaster's Ancient DNA Centre, and the postdoctoral fellow Tauras Vigylas from the University of Chicago, in association with the Institut Pasteur's Yersinia Research Unit, allowed for an unprecedented look at the immune genes of victims of the Black Death, and their interaction in current human populations with Yersinia pestis.



Source :

Evolution of immune genes is associated with the Black Death, Nature, 19 octobre 2022

Jennifer Klunk1,2 *, Tauras P. Vilgalys3 *, Christian E. Demeure4, Xiaoheng Cheng 5, Mari Shiratori3, Julien Madej4, Rémi Beau4, Derek Elli6, Maria I. Patino3, Rebecca Redfern7, Sharon N. DeWitte8, Julia A. Gamble9, Jesper L. Boldsen10, Ann Carmichael11, Nükhet Varlik12, Katherine Eaton1, Jean-Christophe Grenier13, G. Brian Golding1, Alison Devault2, Jean-Marie Rouillard2,14, Vania Yotova15, Renata Sindeaux15, Chun Jimmie Ye16, 17, Matin Bikaran16, 17, Anne Dumaine3, Jessica F Brinkworth18,19, Dominique Missiakas6, Guy A. Rouleau20, Matthias Steinrücken5,21, Javier Pizarro-Cerdá4, Hendrik N. Poinar1,22,23,#, Luis B. Barreiro3,21,24,25,#

*These authors contributed equally to this work, and are presented in alphabetical order

#These authors jointly supervised this work

1 McMaster Ancient DNA Centre, Departments of Anthropology, Biology and Biochemistry, McMaster
University, Hamilton, Ontario, Canada L8S4L9
2 Daicel Arbor Biosciences, Ann Arbor, MI, USA
3 Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA
4 Yersinia Research Unit, Institut Pasteur, Paris, France
5 Department of Ecology and Evolution, University of Chicago, Chicago, IL, USA
6 Department of Microbiology, Ricketts Laboratory, University of Chicago, Lemont, IL, USA
7 Centre for Human Bioarchaeology, Museum of London, London, UK, EC2Y 5HN
8 Department of Anthropology, University of South Carolina, Columbia, SC, USA
9 Department of Anthropology, University of Manitoba, Winnipeg, Manitoba, R3T2N2
10 Department of Forensic Medicine, Unit of Anthropology (ADBOU), University of Southern Denmark, Odense S, 5260, Denmark
11 History Department, Indiana University, Bloomington, IN, USA
12 Department of History, Rutgers University-Newark, NJ, USA
13 Montreal Heart Institute, Faculty of Medicine, Université de Montréal, Montréal, Quebec, Canada, 31  H1T 1C7
14 Department of Chemical Engineering, University of Michigan Ann Arbor, Ann Arbor, MI, USA
15 Centre Hospitalier Universitaire Sainte-Justine, Montréal, Quebec, Canada, H3T 1C5
16 Division of Rheumatology, Department of Medicine, University of California, San Francisco, CA, USA.
17 Institute for Human Genetics, University of California, San Francisco, CA, USA
18 Department of Anthropology, University of Illinois Urbana-Champaign, Urbana, IL, USA
19 Carl R Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
20 Montreal Neurological Institute-Hospital, McGill University, Montréal, Quebec, Canada, H3A 2B4
21 Department of Human Genetics, University of Chicago, Chicago, IL, USA
22 Michael G. DeGroote Institute of Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada L8S4L9
23 Humans and the Microbiome Program, Canadian Institute for Advanced Research, Toronto, Canada
24 Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL, USA
25 Committee on Immunology, University of Chicago, Chicago, IL, USA

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