The 14th-century global outbreak of bubonic plague, known as the Black Death, was the deadliest disease outbreak in recorded history, killing up to half of the European, Asian, and African populations. Among the scars left by this mass mortality event are those in the genomes of modern humans, including the prevalence of gene variants that may have protected against the causative bacterium Yersinia pestis but which today are associated with an increased risk of developing an autoimmune disease, according to a study published yesterday (October 19) in Nature.
The results show “how these studies on ancient DNA can help actually understand diseases even now,” Mihai Netea, an infectious disease specialist at Radboud University Medical Center in the Netherlands who did not participate in the research, tells Science News. “And the trade-off is also very clear.”
For the study, University of Chicago population geneticist Luis Barreiro and his colleagues examined DNA samples from the remains of more than 200 Europeans who lived before, during, or shortly after the 14th-century pandemic, including 42 of its victims. Focusing on immune-related genes, they identified four mutations that appear to have rapidly increased in frequency after the event, suggesting they were selected for and may have improved survival.
One of these mutations stood out. It falls in a gene called ERAP2, which is expressed in macrophages and is involved in the cutting and displaying of bacterial proteins on the immune cells’ surfaces. Lab experiments suggested that individuals carrying two copies of the mutation, which yielded a longer RNA transcript than the nonmutated variant, were 40 percent more likely to survive the Black Death, according to the study. Barreiro tells The New York Times that it’s the largest evolutionary advantage for a variant ever identified in people. “It’s actually shocking,” University of Arizona evolutionary biologist David Enard, who was not involved in the research, tells the newspaper.
The downside of this protective ERAP2 variant, however, is that it’s a known risk factor for Crohn’s disease, an autoimmune disorder that affects the gastrointestinal tract. Similarly, the team identified another gene variant that became more common in the human population after the Black Death and is linked to two other autoimmune conditions, rheumatoid arthritis and systemic lupus erythematosus.
“A hyperactive immune system may have been great in the past but in the environment today it might not be as helpful,” study coauthor Hendrik Poinar, an anthropology professor at McMaster University in Ontario, tells the Associated Press.
This study is not the first to show that the adaptive response to the plague may lead to increased risk of autoimmunity. In 2014, for example, a genetic analysis of Europeans and Rroma yielded a similar result, as did a 2021 study of 16th-century German plague victims.
University of Pennsylvania population geneticist Ziyue Gao, who was not involved in the study, tells Nature there are likely more variants associated with plague immunity—and possibly with autoimmune conditions—that have yet to be discovered. “I’m wondering how many variants were missed,” she says. “Does that mean they’re only detecting the tip of the iceberg?”