The fourteenth century was a rough time to be alive. Not so much because of the time itself but because of what was happening: the Black Death. Arguably the deadliest pandemic in human history, the Black Death descended from an ancient bubonic plague that ravaged Rome in the mid-6th century and lingered throughout the centuries by mutating into a form more virulent to humans.

The plague is caused by the bacterium Yersinia pestis, which is transmitted by infected fleas to rats. The second pandemic of the plague exacted a heavy toll, killing an estimated 30 to 50 percent of the world’s population. It also left an indelible mark on its survivors and their descendants, it turns out — an evolutionary struggle encoded deep within our DNA.

In a study published Wednesday in the journal Nature, a group of researchers has found that the Black Death may have shaped the human immune system, specifically by favoring (inadvertently, of course) survivors with robust genes that protected against the vicious germ. Over 600 years later, these Black Death-proof immune genes still circulate within us and may have repercussions today in the 21st century.

“Understanding the dynamics that have shaped the human immune system is key to understanding how past pandemics, like the plague, contribute to our susceptibility to disease in modern times,” Hendrik Poinar, an evolutionary geneticist at McMaster University’s Ancient DNA Centre and co-author of the paper, said in a press release.

How they did it — The researchers — a collaboration of scientists from McMaster, the University of Chicago, the Pasteur Institute in France, and other organizations — took bone samples from three burial sites in London (including the infamous East Smithfield plague pit) and five across Denmark.

To make certain whatever genetic changes they encountered were associated with just the plague and not any other infectious diseases (such as tuberculosis), they sought skeletons within a very narrow, 100-year time window: individuals who died shortly before, during, and soon after the Black Death, which hit London in 1348 and tapered off in 1350. This was achieved by combing through historical death records, radiocarbon dating (a technique that gauges the age something is by how much radioactive carbon it contains), stratigraphy (a dating method based on the soil layers that accumulate on top), and other archaeological approaches.

The researchers managed to extract over 500 DNA samples from the London and Danish skeletons (318 and 198, respectively), a particularly difficult feat since DNA weathers poorly over time and may contain genetic fragments from microbes teeming in the environment.

What they found — Despite the challenges, the scientists discovered hundreds of genetic variants among the London samples that cropped up more frequently, likely in response to Y. pestis. Seeing if these variants were also replicated in the Danish sample, it appeared these genes conglomerated in four regions, or loci, of the human genome. These regions didn’t appear to code for particular immune-related genes themselves but were neighboring some, suggesting they may influence gene expression of specific immune chemicals and proteins, hence the quality and responsiveness of the immune system.

These findings were confirmed by further experiments where the researchers took human cells (from modern-day folks either carrying or not carrying these variants) and infected them with Y. pestis and other disease-causing bacteria Listeria monocytogenes and Salmonella typhimurium, as well as bits of bacterial and viral proteins. In these experiments, human cells with the variants appeared to be better protected against Y. pestis than cells without the genetic survival advantage. These cells also demonstrated varying immune responses to the different pathogens, suggesting that natural selection in response to one event can impact the immune system in more ways than just one.

One immune gene stuck out, in particular: endoplasmic reticulum aminopeptidase 2 (or ERAP2), an enzyme that takes proteins — whether our own or those from foreign invaders — cuts them down to size and presents them to immune cells to get their attention. The researchers found that if an individual inherited two copies of the variant that produces a protective version of ERAP2 (one from mom, the other from dad), they were potentially 40 to 50 percent more likely to survive the plague. The reason? Those immune cells were likely better at recognizing Y. pestis and eliminating it thanks to this vigilant ERAP2 compared to someone who didn’t carry the variant.

“The selective advantage associated with the selected loci are among the strongest ever reported in humans showing how a single pathogen can have such a strong impact to the evolution of the immune system,” Luis Barreiro, a professor in genetic medicine at the University of Chicago and lead researcher of the study, according to the press release.

Why it matters — This isn’t the first study to suggest that the repercussions of the Black Death, while mostly long gone, still reverberate today, impacting our health in a myriad of ways. In 2021, researchers at the University of Colorado and Max Planck Institute in Germany found in DNA samples collected from a mass grave in Ellwangen in southern Germany compared against current living inhabitants the plague likely influenced genes involved in initiating and directing the immune response to infection.

Another study conducted by the National Human Genome Research Institute, part of the National Institutes of Health, found that certain Mediterranean groups — mostly Turkish, Jewish, Armenian, and Arab populations — may be more susceptible to an autoinflammatory disease called familial Mediterranean fever (FMF) because of evolutionary changes in response to the plague.

“Going forward, more studies of ancient DNA could also enable a better understanding of the evolutionary origins of autoimmune diseases,” David Enard, an evolutionary biologist at the University of Arizona, who wasn’t involved in the study, wrote in an accompanying review of the Nature study. “Population migrations can shape the risk of such diseases through ‘founder’ events, in which, by chance, the founders of a given population happen to carry specific disease-associated variants. [This study’s] inferences… indicate that ancient epidemics are also a force to consider.”