Natural Selection Driven by the Black Death Linked to Modern-Day Autoimmune Disease

The Black Death, a pandemic of bubonic plague that blighted Europe, North Africa and Asia during the 14^th century, left an indelible mark on the continent’s cultural consciousness. A new study suggests the pandemic might have also had an enduring effect on the European genome, stoking an incredibly rapid evolution of the immune system that could have health impacts even today.

Natural selection through a pandemic

In slightly less than five years, the Black Death – a virulent strain of plague driven by the bacterium Yersinia pestis – forever changed humanity. The pandemic killed 30–50% of the population in the North African and Eurasian cities it affected. New research published in Nature by researchers at the University of Chicago, McMaster University and the Institut Pasteur used an innovative sampling technique to explore how the plague interacted with the human immune system.

“People have speculated for a long time that the Black Death might be a strong cause of selection, but it’s hard to demonstrate that when looking at modern populations, because humans had to face many other selective pressures between then and now. The only way to address the question is to narrow the time window we’re looking at,” said Luis Barreiro, PhD, professor of genetic medicine at the University of Chicago and co-senior author on the study, in a press release.

To do so, Barreiro and colleagues took DNA samples from 206 medieval skeletons dug up across London and several burial sites in Denmark. The remains represented individuals who had perished before, during and after the pandemic. The authors took a narrow focus, looking at a pre-selected set of 300 immune-related genes.

Looking first at data taken from three digs across central London, the researchers identified 245 variant genomic regions, called loci, that were substantially different in samples taken from before and after the Black Death.

After also looking at the variability seen in the Danish population, the researchers were able to whittle that list down to four loci that were the strongest candidates for influencing selection during the plague.

These loci contained genomic variants that influenced an individual’s chance of surviving the Black Death by up to 40% - some of the strongest selection influences, say the authors, ever detected in human studies.

To unravel how these variants may have contributed to varying chances of surviving the Black Death, the authors conducted a series of in vitro studies using samples of Yersinia pestis and human cells. They first showed that the expression of the genes analyzed was robustly altered in immune cells called macrophages that were exposed to weakened forms of the bacteria. This suggested that the genes are involved in the body’s immune response to the plague.

The strongest association noted was between a loci called rs2549794 and the expression of a gene called ERAP2. The team showed that people whose genomes contained only one of the variant forms, the so-called A allele, expressed greater levels of functional ERAP2 protein, which can help the immune system identify threats.

Unintended consequences of protection

Javier Pizarro-Cerda, PhD, head of the Yersinia Research Unit and director of the World Health Organization Collaborating Centre for Plague at Institut Pasteur, commented, “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. The results support the ancient DNA evidence that rs2549794 is protective against the plague.”

Finally, the authors suggested that the boost given by the protective variant of ERAP2 might have also resulted in negative impacts to the health of modern-day European populations. This variant, they note, is also a risk factor for autoimmune diseases such as Crohn’s disease.

"These genes are under balancing selection — what provided tremendous protection during hundreds of years of plague epidemics has turned out to be autoimmune related now. A hyperactive immune system may have been great in the past but in the environment today it might not be as helpful,” said Hendrik Poinar, PhD, Professor of Anthropology at McMaster University and co-senior author on the study.

Reference: Klunk J, Vilgalys TP, Demaure CE et al. Evolution of immune genes is associated with the Black Death. Nature. 2022. Doi: 10.1038/s41586-022-05349-x