Black Death may have influenced evolution of genes involved in immune responses, study finds

The phrase “Black Death mass burial site” tends to evoke images of haphazard piles of diseased deceased like the “bring out your dead” Monty Python scene.

But Hendrik Poinar, anthropology professor at McMaster University, said the East Smithfield graveyard in London, a mass burial site that dates back to the height of the bubonic plague pandemic, is the exact opposite. “Each individual is buried very carefully and meticulously and with tremendous care and precision.”

The archaeologists, he added, call it ‘the lasagna of Black Death.’”

Because it has a precise historical date for when it was in use (1348-1349), East Smithfield was ripe for studying the bacterium that caused the Black Death, Yersinia pestis, and how this medieval pandemic shaped our modern immune responses.

In a paper published Wednesday in Nature, Poinar, together with researchers from the University of Chicago and France’s Institut Pasteur, studied DNA samples from individuals at the East Smithfield graveyard as well as people who lived just before and a few decades after the Black Death. The team found that the Black Death not only created selective evolutionary pressure for genes that promote better immune response to Y. pestis but also may have contributed to humans’ current susceptibility to autoimmune diseases like Crohn’s disease.

“This [is the] sort of study that people in my field dream about when we’re doing our Ph.D.s,” said Paul Norman, an associate professor of biomedical informatics at the University of Colorado School of Medicine, who was not involved in the research. “These associations with plague resistance have been talked about for many, many years, and people would say, ‘Oh, you know, if we could just dig up some plague victims, and then we would figure it out.’ We never used to think that that would actually be possible.”

With the advent of ancient DNA sequencing techniques in the last couple of decades, for which Poinar’s former Ph.D. advisor Svante Pääbo won the 2022 Nobel Prize in Medicine, understanding these evolutionary events is now possible.

Studies have estimated that the Black Death killed 30%–50% of Europe’s population between 1347-1351. (For scale, the mortality rate for the Covid pandemic is less than 2.5% for most countries.) The “plague resistance” Norman referred to stems from the hypothesis that this concentrated mass death event could have caused hugely selective pressure on the genetics of the individuals who survived, who would likely have passed down genes that allowed them to survive the plague.

While a few studies have previously looked at the ancient DNA of plague victims, until this point, no studies had shown that genetic variances in people’s DNA before and after the Black Death were connected to the body’s immune response to Y. pestis.

The research team looked at the DNA sequences of immune-related genes from both a London cohort of 318 people and a separate Danish cohort of 198 individuals from before, during, and after the plague. The sample sizes are both bigger than previous studies and allow causal arguments because of their spacing through time. The researchers found 245 variations between the pre- and post-pandemic London samples.

Assuming that genes related to functions that confer greater immunity to Y. pestis infection would be less prevalent in people who died from the Black Death and more prevalent in generations after the Black Death, the researchers looked for genes that followed this pattern and narrowed the list to 35 variations of interest. Comparing this to the results from the Danish cohort, they identified four variations of interest that appeared in both cohorts and thus were likely selected for by the Black Death.

One of these variations was near the ERAP2 gene, which is known for coding a protein that cuts up proteins from invading pathogens. That protein lives inside immune cells called macrophages, which ingest invaders such as Y. pestis. After ingesting the bacteria and slicing up its proteins, the macrophage displays the bits of chopped-up proteins on its surface to create antigen “warning flags” to alert the rest of the immune system. People without this variant have a truncated version of ERAP2 that does not make the Edward Scissorhands protein; thus people can possess either two working copies of ERAP2, one working copy and a non-working copy, or two non-working copies.

To determine if this identified genetic variant does in fact respond to Y. pestis infection, the researchers took modern humans’ blood samples and determined which samples possessed two, one, or zero working copies of the ERAP2 gene. The researchers exposed some of the macrophages from the blood samples to Y. pestis. As hypothesized, the immune cells from people who expressed two working copies of the gene killed the bacteria better than those with two non-working copies, with the single working copy showing an intermediate performance. However, there are other immune responses this variant is associated with, and its other effects on ERAP2 remain to be studied in the future.

Beyond drawing a relationship between the genes Y. pestis survival favored and gene function, the new study also indicates that the Black Death has affected our present-day susceptibility to disease. Because Y. pestis and perhaps other pathogens select for gene variants that increase immune response, those genes are useful in an infectious disease pandemic. However, this comes with a tradeoff: an increased risk of autoimmune diseases — in the case of ERAP2, Crohn’s disease.

“In these processes of selection there is more and more evidence of a relationship between the protection against infectious diseases and a susceptibility to autoimmune diseases,” said Alicia Sanchez-Mazas, head of the Laboratory of Anthropology, Genetics, and People in History at the department of genetics and evolution at the University of Geneva. “The idea is that we have to keep a balance between both effects to survive, actually, and this is really challenging.”

Under selection events like the Black Death, it’s beneficial to express more genes related to immune response. But in times where there’s no longer a pathogen like Y. pestis to fight against, that increased immune sensitivity is a disadvantage, leaving people at a bigger risk for diseases like Crohn’s, rheumatoid arthritis, and lupus, all of which have documented links to genes identified in this study.

Sanchez-Mazas, who was also not involved in the research, said it was surprising that this study didn’t find associations with another group of genes called HLA genes, but that perhaps this stemmed from the fact that HLA is notoriously difficult to study, especially with ancient DNA. Instead, the researchers used a more targeted approach of looking only at immune-related gene regions rather than a genome-wide association study.

HLA proteins are the agents that display the chopped-up proteins as warning-flag antigens on the cell surface, which is related to the role of the proteins from the ERAP2 gene. Norman, who studied victims of a later plague wave in the 16th century and found differences in the expression of the HLA gene between that population and modern humans, said that because of the intertwined function of the HLA and ERAP2 genes, the new study is actually in line with what his research has found.

There’s no clear translational value to this study, said Luis Barreiro, professor of genetic medicine at the University of Chicago, and one of the authors on the study — it won’t result in a new pill. Instead, it answers a fundamental evolutionary question about how pathogens have shaped the human genome.

Norman agreed that this study shows the longstanding hypothesis between past infectious diseases and modern-day humans’ risk for autoimmune diseases is one worth studying further: “Others have hinted at it,” he said. “To my knowledge, this is the first one to really put it all together in one place.”

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