The Black Death produced changes in the human immune system that persist to this day.

O Black Plaguecaused by bacteria Yersinia pestis, spread across Europe, the Middle East and North Africa between 1346 and 1350 and caused the death of between 30% and 50% of the population at the time. In outbreaks over the next 400 years, death rates declined. This may be due to a human genetic adaptation to bacteriaas the authors of a study published this week in Nature.

The work, led by the University of Chicago (USA), found evidence that one of the darkest periods in history exerted significant selective pressure on the population and produced changes in the human immune system that persist today.

As he comments to SINC Luís Barreiro, professor of Genetic Medicine at the American university and co-author of the study, “the Black Death was the greatest mortality event in history; therefore, we set out to test the hypothesis that people who survived this pandemic Genetic variants that have increased their protection against Y. pestis”.

In addition to the University of Chicago, researchers from McMaster University (Canada) and the Pasteur Institute (France) participated in the work.

Using DNA extracted from the teeth of people who died before and during the Black Death pandemic, researchers were able to identify the genetic differences that determined who survived and who died from the virus. / Matt Clarke / McMaster University

Ancient DNA analysis of the bones of over 200 individuals

To explore the evolution of genetic variation in genes related to the immune system, the scientists examined samples of ancient DNA from the bones of more than 200 individuals. from London and Denmark who died before, during and after the plague wiped out 50% of Europe’s population in the late 1340s.

By selectively sequencing a set of 300 immunity-related genes, they identified four genes which, depending on the variant, protected or increased susceptibility to Y. pestis.

Specifically, the team found that having two copies of a specific variant of the ERAP2 gene was strongly associated with pest survival. Those who survived the pandemic passed on this functional genetic variant, called rs2549794to their descendants.

“When a macrophage encounters a bacterium, it cuts it into pieces to present to other bacteria. immune cells signaling that there is an infection”, explains Barreiro. “Having the working version of the gene appears to create an advantage, likely improving our immune system’s ability to detect the invading pathogen. According to our estimates, having two copies of the rs2549794 variant would cause a person to have 40% more chance to survive the Black Death than those who had two copies of the non-functional variant.”

An advantage at a cost to the offspring

However, this advantage that made these people survive the pandemic, in turn, carries a cost: “Having this same variant that we think is protective against the Black Death is today associated with a greater susceptibility to certain autoimmune diseases, such as the Crohn’s disease”, warns Barreiro.

The researcher points out that this work evaluated “in a very direct way the impact that a single pathogen had on human evolution. It has long been speculated that the Black Death may have been a strong cause of selection, but this is difficult to prove when looking at modern populations because humans had to deal with so many other selective pressures. The only way to solve the problem was to reduce the analyzed time window”, he points out.

Having the same variant that we’ve found to be protective against the Black Death is now associated with an increased susceptibility to certain autoimmune diseases, such as Chrohn’s disease.

Luis Barreiro, co-author of the study (UChicago)

“As far as I know,” he adds, “this is the first demonstration that, in fact, the Black Death represented an important selective pressure for the evolution of the human immune system”.

In turn, the co-author Hendrik Poinar, Professor of Anthropology at McMaster University, notes that “what provided enormous protection during hundreds of years of plague epidemics has turned out to be linked to autoimmunity now. An overactive immune system may have been great in the past, but in today’s environment it may not be as helpful.”

The authors plan to expand the project to scan the entire genome, not just a selected set of genes related to immunity. Their next goal is to analyze the genetic variants that affect susceptibility to bacteria in modern humans and compare them with ancient DNA to determine whether these variants were also the result of natural selection.

“There is a lot of talk about how pathogens shaped human evolution, so being able to formally show which pathways and genes were targeted for selection really helps us understand what allowed humans to adapt and exist today,” says Barreiro, who concludes: “This tells us about the mechanisms that allowed us to survive throughout history and why we are still here today.”

General plan of plague pits at East Smithfield (London). / Courtesy of the Museum of Archeology, London (MOLA)