How the Black Death shaped human evolution

The East Smithfield plague pit, where people who died were buried during the Black Death from 1348 to 1349. McMaster University

The fourteenth-century bubonic plague pandemic is known as the Black Death. Caused by the bacterium Yersinia pestis, it killed up to half the population in Europe, the Middle East, and North Africa. Such a deadly disease may have selected for genetic variants that protected against infection. People with protective versions of certain genes would be more likely to survive and pass on those variants to future generations. Yet pinpointing such variants has been a challenge.

An NIH-funded team of researchers, led by Drs. Hendrik Poinar at McMaster University in Canada and Luis Barreiro at the University of Chicago, used ancient DNA samples to search for variants enhanced by the Black Death. The team sampled DNA from the remains of more than 500 people who died before, during, and after the Black Death. Most samples came from three cemeteries in London and from five locations throughout Denmark. Others came from people buried in a well-dated plague cemetery in London, all of whom died during the Black Death, from 1348 to 1349. In all, the researchers were able include samples from more than 200 people in their analysis. Results appeared in Nature on October 19, 2022.

The researchers focused on regions of the genome known to be related to the immune system and immune disorders. They looked for genetic variants that became much more or less common after the Black Death. Four variants were strong candidates for further investigation.

Of the four candidate variants, one stood out as being especially protective. Individuals carrying two copies of this variant were about 40% more likely to survive the Black Death than those without it. The variant was near the gene ERAP2. ERAP2 encodes a protein that breaks pathogen proteins into smaller pieces to help the immune system detect infections. Human immune cells with the protective variant produced the full-length, functional protein. Those lacking this variant produced a shortened, non-functional protein. Cells possessing two copies of the protective variant produced more functional protein than those with just one copy.

The team went on to test how the protective variant affected the function of human immune system cells called macrophages in culture. The protective variant altered the levels of various signaling molecules, called cytokines, released upon infection with Y. pestis. Macrophages carrying the protective variant were more effective at killing Y. pestis bacteria.

These results suggest that the Black Death influenced the evolution of the human immune system. “When a pandemic of this nature—killing 30 to 50% of the population—occurs, there is bound to be selection for protective alleles in humans,” Poinar says. “Even a slight advantage means the difference between surviving or passing. Of course, those survivors who are of breeding age will pass on their genes.” 

However, the protection against plague conferred by these variants appears to have come at a cost. The protective ERAP2 variant is also a known risk factor for Crohn’s disease. Another protective variant has been associated with an increased risk of two autoimmune diseases. Thus, the Black Death and other past pandemics may have shaped humans’ immune systems in ways both good and bad. While we acquired better protection against infections, we became more susceptible to autoimmune diseases.

—by Brian Doctrow, Ph.D.