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Bubonic plague may be shaping modern-day immune responses, say scientists

Scientist have suggested that genes that perhaps helped our forefathers survive the Black Death may make us more susceptible to certain diseases today, in a classic example of how germs shape us over time.

The Black Death in the 14th century was the single deadliest event in recorded history, spreading throughout Europe, the Middle East and northern Africa and wiping out up to 30% to 50% of the population.

According to Luis Barreiro, a senior author of recent research: “Our genome today is a reflection of our whole evolutionary history as we adapt to different germs.” Some, like those behind the bubonic plague, have had a big impact on our immune systems.

Barreiro and his colleagues at the University of Chicago, McMaster University in Ontario and the Pasteur Institute in Paris examined ancient DNA samples from the bones of more than 200 people from London and Denmark who died over about 100 years that stretched before, during, and after the Black Death swept through that region.

The Associated Press reports that they identified four genes that, depending on the variant, either protected against or increased susceptibility to the bacteria that causes bubonic plague, mainly transmitted by the bite of an infected flea.

They found that what helped people in mediaeval times led to problems generations later — raising the frequency of mutations detrimental in modern times. Some of the same genetic variants identified as protective against the plague have been linked to certain autoimmune disorders, like Crohn’s disease, rheumatoid arthritis and lupus. In these sorts of diseases, the immune system that defends the body against disease and infection attacks the body’s own healthy tissues.

“A hyperactive immune system might have been great in the past but in the environment today it might not be as helpful,” said Hendrik Poinar, an anthropology professor at McMaster and another senior author.

Past research has also sought to examine how the Black Death affected the human genome. But Barreiro said he believes theirs is the first demonstration that the Black Death was important to the evolution of the human immune system. One unique aspect of the study, he said, was to focus on a narrow time window around the event.

Monica Green, an author and historian of medicine who has studied the Black Death extensively, called the research, published in the journal Nature, “tremendously impressive”, bringing together a wide range of experts.

“It’s extremely sophisticated and addresses important issues, such as how the same version of a gene can protect people from a horrific infection and also put modern people – and generations of their descendants – at risk for other illnesses,” said Green, who was not involved in the study.

Will the COVID-19 pandemic have a big impact on human evolution? Barreiro said he doesn’t think so because the death rate is so much lower and the majority of people who have died had already had children.

In the future, however, he said more deadly pandemics could well continue to shape us at the most basic level. “It’s not going to stop. It’s going to keep going, for sure.”

Study details

Evolution of immune genes is associated with the Black Death

Jennifer Klunk, Tauras Vilgalys, Christian Demeure, Xiaoheng Cheng, Mari Shiratori, Julien Madej, Rémi Beau, Derek Elli, Maria Patino, Rebecca Redfern, Sharon DeWitte, Julia Gamble, Jesper Boldsen, Ann Carmichael, Nükhet Varlik, Katherine Eaton, Jean-Christophe Grenier, Brian Golding, Alison Devault, Jean-Marie Rouillard, Vania Yotova, Renata Sindeaux, Chun Jimmie Ye, Matin Bikaran, Luis Barreiro.

Published in Nature on 19 October 2022

Abstract

Infectious diseases are among the strongest selective pressures driving human evolution. 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. This pandemic devastated Afro-Eurasia, killing up to 30–50% of the population. To identify loci that may have been under selection during the Black Death, we characterised 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.

 

Nature article – Evolution of immune genes is associated with the Black Death (Open access)

 

Associated Press article – Genetic twist: Medieval plague may have molded our immunity (Open access)

 

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