The Black Death that ravaged Eurasia and North Africa in the 14th century had a profound effect on our genetic balance, which, according to a new study, still decides our fate today.
These effects are a mix of good news and bad news. While the genetic variations that helped our ancestors survive the plague continue to offer some protection against similar respiratory illnesses today, they also leave us prone to damaging autoimmune diseases.
Last year, researchers published a comparison of genomes taken from individuals who lived before, during and after epidemics of Yersinia pestis infections that have swept across Europe. They found that those with two identical copies of a gene called ERAP2 were about 40-50% more likely to survive than those with two variants of the gene.
To better understand how the current state of ERAP2 variation in modern populations might still influence our ability to cope with infection, another team of researchers sifted through three large databases of studies: the UK Biobank, FinnGen and GenOMICC. These databases each contain information on hundreds of thousands of participants, allowing study authors to see if ERAP2 combinations are linked to other health conditions.
The team found that the same double-up of identical ERAP2 copies conferred a lower risk of respiratory diseases such as COVID-19. More surprisingly, those who had two copies of the same copy were also at higher risk for autoimmune diseases, Crohn’s disease and type 1 diabetes.
“This gene basically chops up proteins for the immune system,” says infection specialist Fergus Hamilton from the University of Bristol in the UK.
“Although we don’t know the exact mechanism influencing disease risk, carriers of alleles that provide more protection against respiratory disease appear to have an increased risk of autoimmune disease.”
To assess the relationship between ERAP2 and the health conditions we face today, the researchers used a technique called Mendelian randomization: the approach is designed to use the genetics we are born with to take into account the environmental and lifestyle conditions, in order to then more strongly suggest cause and effect.
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There was no relationship between genetic variation and sepsis, the team found – a curious finding given the role sepsis is believed to have played in plague deaths. There was also some association with reduced parental lifespan, possibly due to the link with autoimmune disease. Each discovery will require further research to better understand their role in our immunity.
“This is potentially a great example of a phenomenon called ‘balancing selection’ – where the same allele has different effects on different diseases,” says Hamilton.
This balancing act is also important to keep in mind when developing treatments. Work is already underway to target ERAP2 to treat diseases like Crohn’s disease and cancer, but this research suggests that targeting ERAP2 could have knock-on effects in other diseases.
The study authors say the effects of these genetic variations are likely to change as environmental pressures on us also change – life today is radically different from what it was in the 14th century, which it whether food, exposure to disease or medical care.
This of course extends to medical research: large genetic databases such as those used here were not available to late medieval scientists, and it can also be difficult to identify diseases and infections that were not known or defined in centuries past. .
“It’s a theoretical story of balance – linked to historical and contemporary disease profiles – that reflects our past and is rarely seen in real human examples,” says genetic epidemiologist Nicholas Timpson, of the University of Bristol.
The research was published in the American Journal of Human Genetics.