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Black Death Sequencing Study Reveals Impacts on Human Immune Evolution, Autoimmune Disease

Yersinia pestis

NEW YORK – New research is revealing ways that the immune system of European individuals was impacted by the Black Death — a Yersinia pestis bacteria-caused bubonic plague pandemic in the 1300s that killed off around one-third to half of individuals in affected sites in Europe, the Middle East, and North Africa.

"Our results provide strong empirical evidence that the Black Death was an important selective force that shaped genetic diversity around some immune loci," co-senior and -corresponding authors Luis Barreiro of the University of Chicago, Hendrik Poinar of McMaster University and the Canadian Institute for Advanced Research, and their colleagues reported in a paper published Wednesday in Nature.

The researchers started by screening more than 500 ancient samples collected at sites in and around London or at several burial sites across Denmark, focusing in on 206 ancient samples spanning time points that preceded the Black Death, fell within the pandemic, or represented a post-plague period.

From there, the team turned to targeted enrichment capture sequencing to profile 356 immune-related genes and nearly 500 sites linked to immune conditions in prior genome-wide association studies, along with 250 parts of the genome that are believed to be immune "neutral."

Among almost 250 loci that were genetically differentiated during the time points considered, the investigators narrowed in on four loci that appeared to be most strongly differentiated in the pre- and post-Black Death samples assessed in London and Denmark — a set that encompassed genes and variants implicated in Crohn's disease, rheumatoid arthritis, or other autoimmune conditions.

"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," Barreiro said in a statement.

In particular, the researchers flagged a version of the ERAP2 gene that appeared to coincide with better odds of survival during the Black Death pandemic. They estimated that ancient individuals carrying two copies of a protective ERAP2 allele called rs2549794 — which coincided with higher-than-usual ERAP2 expression — were up to 40 or 50 percent more likely to survive Y. pestis infections. The same variant has been implicated in enhanced Crohn's disease susceptibility, they noted.

"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," Poinar explained in a statement. "A hyperactive immune system may have been great in the past but in the environment today it might not be as helpful."

The team speculated that that this survival boost stemmed from more effective immune cell recognition and neutralization of the deadly bug — a hypothesis backed up by follow-up cell line experiments in macrophage immune cells that either expressed rs2549794 or alternative variants that produce truncated ERAP2 transcripts.

"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," Barreiro explained. "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."

In a related news and views article in Nature, University of Arizona at Tucson ecology and evolutionary biology researcher David Enard noted that the plague results suggest that "even humans, with their historically small populations and long intervals between generations, can adapt at remarkable speed," although "riding the evolutionary bullet train might come at a cost."

"Going forward, more studies of ancient DNA could also enable a better understanding of the evolutionary origins of autoimmune disease," Enard explained, noting that "[p]opulation 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."