Those with genetic resistance had better chances of survival. A study shows that the Black Death, through its strong "selection function", led to the spread of certain immune-related gene variants in the population. However, people may still pay a price for the increased resistance of their ancestors to the plague: Genetic variants that confer protection appear to be associated with an increased susceptibility to autoimmune diseases, the scientists report.
The horror has burned itself deep into the memory of mankind: the devastating wave of plague that spread across the Middle East, North Africa and Europe from 1346 to 1350 is considered the worst death event in history. It is estimated that the Black Death killed up to 50 percent of the European population in just about five years. The high mortality rate indicates that the immune system of the people at that time could muster little resistance against the responsible bacterium Yersinia pestis.
However, this may have changed due to the terrible selection pressure exerted by the infectious disease. An indication of this is that in subsequent outbreaks of plague over the next 400 years, the mortality rate fell significantly. This could be due, among other things, to a genetic adaptation of humans to the pathogen. "It has long been speculated that the Black Death may have been a strong cause of selection, but it is difficult to prove this when looking at modern populations because people were also subject to other selection processes between then and now." says senior author Luis Barreiro of McMaster University in Hamilton.
On the trail of the effect of selective pressure
Barreiro and his colleagues have therefore now investigated the possible genetic effects of the plague using a focused approach: For their study, they analyzed 516 DNA samples from people who died before, during or shortly after the Black Death epidemic in London and Denmark . These assignments were possible based on historical records and dating. The samples also included people who, according to the information, had fallen victim to the plague between 1348 and 1349. In the genetic studies, the scientists concentrated on regions in the genome of the three groups that are known to be important for the human immune system.
When comparing the genetic traits, the researchers encountered numerous genetic variants, the frequency of which was apparently increased in the population by the selection pressure of the Black Death. They were therefore possibly associated with an increased probability of survival. In the end, four genes and their variants came to the scientists' particular attention. With them it seems particularly clear that, depending on their version, they could have conveyed either increased susceptibility or resistance to the plague pathogen. The researchers then carried out more detailed investigations in the case of the gene called ERAP2. As they explain, it plays a role in how the immune system recognizes pathogens. Individuals who have two copies of a particular genetic variant of ERAP2, called rs2549794, can produce comparatively large amounts of the protein that mediates this function.
Increased defenses with shadow side
"When a macrophage encounters a bacterium, it breaks it up into pieces to present to other immune cells, signaling that an infection is present," explains Barreiro. "Having the productive version of the gene appears to confer an advantage, likely by enhancing our immune system's ability to recognize the invading pathogen." As the study results suggest, this was particularly the case with the plague. "By our estimate, owning two copies of the rs2549794 variant would have increased the likelihood of surviving the Black Death by about 40 percent compared to those owning two copies of the non-functional variant," says Barreiro. The team even went so far as to investigate in laboratory tests how the rs2549794 variant affects the resistance of living human cell cultures to the plague pathogen. It was found that macrophages expressing two copies of the variant neutralize Yersinia pestis more efficiently than those without this variant.
However, as the scientists further report, the increased resistance could have been associated with a disadvantage: There is evidence that the genetic predisposition that protects against the plague is associated with an increased susceptibility to autoimmune diseases in modern populations. "An overactive immune system might have been great in the past, but it might not be that helpful in today's conditions," says co-author Hendrik Poinar of McMaster University. "As it turns out, insights are possible into how past pandemics, like the plague, contribute to our present-day susceptibility to disease," says the researcher.
He and his colleagues now want to stay on the ball and continue investigating the effects of infectious diseases on human genetic evolution. In conclusion, Barriereo says: "If we can show which signaling pathways and genes were affected, this could help to understand what made it possible for humans to adapt and still exist today," says the scientist.
Source: University of Chicago Medical Center, McMaster University, Article: Nature, doi: 10.1038/s41586-022-05349-x