Friday, December 9, 2022

Black Death left risky and ‘mind-boggling’ legacy in our genes

Genes that gave our ancestors a life-saving advantage during the Black Death are responsible for higher rates of autoimmune diseases such as Crohn’s and rheumatoid arthritis today, scientists say.

Their study has identified specific gene variants that gave certain people significantly better odds of surviving the bubonic plague (Yersinia pestis) pandemic that killed upwards of half the population in large parts of Europe, Asia and Africa during the 1340s and 1350s.

The researchers said that, in revealing that these variants became far more prevalent as a result of the pandemic, the study was the first hard evidence that the Black Death played an important role in the evolution of the human immune system through natural selection.

The research, published in the journal Nature, draws on analysis of DNA from remains of more than 500 people who died before the Black Death, died of it, or survived it, in London. This includes individuals buried at plague pits at East Smithfield that were used for mass burials in 1348-9. Additional samples were taken from remains buried at locations across Denmark.

Illustration from the Toggenburg Bible of 1411, from Switzerland, depicting bubonic plague or smallpox. Photo: Niday Picture Library/Alamy

Most notably, the researchers found that people with the protective variant of a gene known as ERAP2 survived the pandemic at much higher rates than those with the alternative variant. The protective variant allowed for more efficient neutralisation of Yersinia pestis by immune cells, ensuring that its carriers were 40-50 per cent more likely to survive than others.

Professor Hendrik Poinar, director of McMaster University’s Ancient DNA Centre in Ontario and an author of the paper, said this variant was found in about 40 per cent of the English population before the Black Death and 60 per cent of the UK population today. He said the scale of the shift in frequencies of the variant over three generations around the mid-14th century was “mind-boggling” and the largest such shift observed to date.

Although the variant was highly beneficial in the context of bubonic plague, Poinar said that, today, it was associated with autoimmune and inflammatory disease. The strongest association is with Crohn’s, but other studies have linked the gene to psoriasis and ankylosing spondylitis. Poinar said this disadvantage had a balancing effect that explained why the variant wasn’t even more prevalent now.

Explaining the double-edged nature of the variant, he said: “These genes have the tremendous capability to cut any invading pathogens up into tiny pieces, and they provide that as a smorgasbord meal to the immune cells. So the people that survived had really good scissors, and the people that died had a version of this gene which is like a scissor with a single blade. So you can still knock the pathogen, but you don’t get a smorgasbord display, which means that when you present those to the immune cells, they’re like, ‘Well, I can’t mount an effective response to this, but interesting, right?’

The researchers used DNA extracted from teeth of people who died before, during and during the Black Death. Photo: Matt Clarke/McMaster University

“Fast forward into modern times when there’s increased sanitation, pathogen identification, antibiotics, different treatments. Most of us living in Western countries or developed economies don’t have the infectious disease burden that we used to during the Middle Ages. The smallpox, tuberculosis, leprosy, cholera — you name it. And so what do your really hyperactive, super-good scissors do? They start targeting your own system, your own body. And this is this is what leads to autoimmune disorders.”

The team didn’t only infer the variant’s attributes but performed lab tests using living human immune cells and living Yersinia pestis to confirm its effectiveness in fighting plague. Poinar said the variant was not only more effective in clearing out the plague bacterium but would also have prevented cytokine storms — a dangerous inflammatory response — from occurring in infected carriers.

The scientists identified a total of four genetic variants that would have been advantageous during the Black Death and that went through a process of selection as a result. Another of these variants, which are more prevalent today due to the medieval pandemic, is associated with increased risk of rheumatoid arthritis and lupus. The team believe that future research will reveal the role of the Black Death in altering the prevalence of further variants.

“It’s horrific to think it was down to the luck of your alleles”

Professor Hendrik Poinar

Poinar said that, during the Black Death, there would have been carriers of both the protective and non-protective variants within the same families. “You’ll have heard the stories of the Black Death where everyone in a family except one member would die. Or parents in complete pain and horror, saying, ‘Why take them? Why not me?’ It’s a horrific thing to think that it was down to the luck of your alleles [variants] — something completely out of your control.”

The team believe the study raises questions about the enduring effects of other historic and current pandemics on human health. Poinar explained: “For example, I think it’s natural to ask how is Covid modulating our genome? And can we, by understanding these things in the past, get a better understanding of targets for new medicines?”

The findings are the result of seven years of work from graduate student Jennifer Klunk, formerly of McMaster’s, and postdoctoral fellow Tauras Vigylas, of the University of Chicago, along with Poinar and researchers from the Museum of London, the Institut Pasteur in Paris and other institutions.

In addition to driving the genetic changes identified by the scientists, the Black Death has long been recognised as a catalyst for social change. In England, this included higher wages and greater mobility for the peasantry.

Nevertheless, the cost was terrible. Symptoms of plague included nausea, high fever, painful swollen lymph nodes and dark skin blotches. Many victims died within a week of infection. The contemporary Rochester Chronicle recorded that: “This mortality devoured such a multitude of both sexes that no one could be found to carry the bodies of the dead to burial, but men and women carried the bodies of their own little ones to church on their shoulders and threw them into mass graves, from which arose such a stink that it was barely possible for anyone to go past a churchyard.”

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