“This is, to my knowledge, the first demonstration that indeed, the Black Death was an important selective pressure to the evolution of the human immune system,” said Barreiro.
The research team zeroed in on one gene with a particularly strong association to susceptibility: ERAP2. Individuals who possessed two copies of one specific genetic variant, dubbed rs2549794, were able to produce full length copies of the ERAP2 RNA transcript, therefore producing more of the functional protein, compared to another variant that led to a truncated and non-functional version of the transcript. Functional ERAP2 plays a role in helping the immune system, and in particular macrophage cells, recognize the presence of an infection.
“When a macrophage encounters a bacterium, it chops it into pieces for them to be presented to other immune cells signaling that there’s an infection,” said Barreiro. “Having the functional version of the gene appears to create an advantage, likely by enhancing the ability of our immune system to sense the invading pathogen. By our estimate, possessing two copies of the rs2549794 variant would have make a person about 40% more likely to survive the Black Death than those who had two copies of the non-functional variant.”
The team even went so far as to test how the rs2549794 variant affected the ability of living human cells to help fight the plague, determining that macrophages expressing two copies of the variant were more efficient at neutralizing Y. pestis compared to those without it.
“Examining the effects of the ERAP2 variants in vitro allows us to functionally test how the different variants affect the behavior of immune cells from modern humans when challenged with living Yersinia pestis,” said Javier Pizarro-Cerda, PhD, head of the Yersinia Research Unit and director of the World Health Organization Collaborating Centre for Plague at Institut Pasteur. “The results support the ancient DNA evidence that rs2549794 is protective against the plague.”
The team further concluded that the selection for rs2549794 is part of the balancing act evolution places upon our genome; while ERAP2 is protective against the Black Death, in modern populations, the same variant is associated with an increased susceptibility to autoimmune diseases, including acting as a known risk factor for Crohn’s disease.
