Bubonic plague left a mark on our genomes and it may have a link to disorders

A recently published paper in Nature suggests that marks of the bubonic plague can still be found in genes that are involved in the immune system

October 26, 2022 by Sandipan Talukdar
Bubonic plague
(Photo: Flickr)

The ‘Black Death’ was the most lethal pandemic that humanity has suffered to date. This bubonic plague pandemic swept northern Africa and Eurasia in the middle of the fourteenth century (1346-1353), killing almost half the human populations in these regions and changing the course of history and evolution.

Caused by the bacterium Yersinia pestis, this disastrous pandemic left its mark on the genome we carry today. The genome is the totality of the DNA found in a cell.

A recently published paper in Nature suggests that marks of the bubonic plague can still be found in genes that are involved in the immune system (the defense that our body uses as a means of protection from invading agents and also from other diseases like cancer). It says that four gene variants appeared to become more common after the pandemic. These gene variants may have contributed to the survival against the plague.

Well, that was a great deal. However, these genes exacted a price in terms of our health as well – two of the four gene variants are associated with an increased risk of some autoimmune disorders, including rheumatoid arthritis and Crohn’s disease. Experts have lauded the findings of the paper titled “Evolution of immune genes is associated with the Black Death”. They believe it has unveiled some crucial aspects of human genetics related to the deadliest pandemic. Ziyue Gao, a population geneticist at the University of Pennsylvania commented, “It’s very innovative work. We always wonder what the forces are that drive population evolution.”

For geneticists, the origin of the Black Death and how it impacted human immunity have been intriguing topics. Along with his colleagues, Luis Barreiro of the University of Chicago, the author of the study, began his work with the hypothesis that an event as massive as the Black Death should have left its mark on the human immune system and did so essentially through genes.

To begin with, Barreiro and his co-researchers studied the genetic variation in more than 200 DNA samples. These samples had been isolated from the bones or teeth of individuals living before the bubonic plague pandemic started, who suffered it and died from it, or could survive one or two generations later.

For the genetic analyses, the team kept its focus on genes that are related to immunity. They found four DNA variants that probably had been beneficial to survival during the pandemic. In nature, the genetic variations that provide an edge for survival at a particular space and time are selected over other variations and are carried forward. Barreiro’s team found those four variants in samples of pandemic survivors from the UK and the USA.

Among the four variants, one affected the expression of the gene named ERAP2. Those carrying this variant could produce a full-length mRNA that encodes the ERAP2 protein and those who lack the variant produce a trumpeted version of the mRNA. At this point, it is worth remembering the basis of genetics, or specifically, the ‘Central dogma of Molecular Biology’. It basically explains how genetic information is carried in a biological system. The portion of the DNA which can direct the production of a protein is called a gene. In fact, a gene contains the code based upon which a particular protein is produced. Again, a gene encodes a protein via another molecule known as the mRNA (messenger RNA).

Importantly, the ERAP2 protein is produced by a specialized immune cell known as the macrophage. Our immune system contains a variety of cell types, each having specific tasks. The macrophages can engulf invading bacteria and digest them by cutting the bacterial protein into pieces.

Barreiro and his team hypothesized that a full-length and fully functional ERAP2 protein could provide better protection during the bubonic plague pandemic. In their laboratory analyses, the team of researchers found that macrophages containing the fully functional ERAP2 protein could obstruct the replication of Yersinia pestis in comparison to the macrophages that contain the truncated version of the protein.

Up to this point, it all seems good. But the gene variant responsible for producing a fully protective ERAP2 protein is known to be a risk factor for Crohn’s disease. Similar to the ERAP2 variant, the researchers found another variant that appeared helpful during the pandemic and is linked to rheumatoid arthritis. Both Crohn’s disease and rheumatoid arthritis are autoimmune diseases. Autoimmune diseases cause the immune system to attack our own organs mistakenly.