The Black Death killed more people in Medieval Europe than any other pandemic in recorded history.
Up to 50 per cent of the European population was wiped out by the Black Death — the bubonic plague — in just five years in the middle of the 14th century.
"It is unimaginable how the world would be after an event like that," said geneticist Luis Barreiro of the University of Chicago.
The catastrophic pandemic sent so many people to an early grave in Europe, it rapidly shaped the evolution of immune system genes in future generations related to the survivors, according to an analysis of ancient DNA by Professor Barreiro and colleagues.
Their new study, published today in the journal Nature, found that people who survived the ravages of the disease were more likely to carry a version of a gene that protected them against the plague.
But this gene may have also made today's descendants of Black Death survivors more susceptible to autoimmune disorders such as Crohn's disease and rheumatoid arthritis.
"We speculate that there's been some evolutionary trade-off where a particular [variation] in a gene that protects you against a pathogen might also today lead to an over-reactive immune system," Professor Barreiro said.
The evolution of plague
The Black Death, aka the pestilence, is caused by the bacterium Yersinia pestis.
The bubonic form of the disease, typified by large weeping pustules known as buboes followed by fever and vomiting blood, was spread to humans by bites from rat fleas.
Most people afflicted with it died within a week of being infected.
Ancient DNA suggests the Black Death began in Kyrgyzstan, but it soon spread throughout Asia, Africa and Europe, landing in London a decade later in 1348.
To find out if some people were more genetically protected against the disease than others, the researchers studied DNA from bodies buried in three cemeteries in London.
Two cemeteries contained the remains of people without plague who died up to 50 years before or after the Black Death.
The Black Death victims were all buried in the East Smithfield plague pit, specially built in 1348 because there was no room in the city to accommodate the dead.
The researchers initially found 245 gene variants or alleles associated with the immune system that became more common post-pandemic.
After cross-checking DNA data with samples from nearly 200 people exhumed from five sites in Denmark, they identified versions of four genes that changed more than by chance.
A genetic trade-off
In particular, the team decided to look at variations of one gene called ERAP 2, which regulates proteins.
This gene is involved with a type of white blood cell known as a macrophage, which is on the look out for anything suspicious.
After these garbage trucks of the innate immune system eat an intruder, the ERAP 2 gene chops the protein in the pathogen up into fragments which the macrophage spits back out onto its surface so other cells can identify it and mount a widescale inflammatory response.
"[The process] alerts the immune system that something is wrong and it needs to fight this pathogen," Professor Barreiro said.
But, he said, some people have a version of the gene that doesn't cut the protein up correctly for other cells to identify.
To see how that might affect someone's vulnerability to the plague, the researchers placed macrophages that had either the protective or non-working version of the gene in petri dishes with the pathogen.
"What we saw is that macrophages derived from individuals with the protective allele killed the bacteria faster than macrophages that didn't have the protective ability," Professor Barreiro said.
People with two copies of this allele were 40 per cent more likely to have survived the plague.
As those without the gene were picked off, the protective gene became more common in the population and may explain why waves of the plague over the next 400 years didn't kill as many people.
The downside, however, is that the functioning variant of the gene is associated with Crohn's disease.
Considering the majority of people who were buried in the East Smithfield plague pit died before they were 35, this would have been a small evolutionary trade-off at the time.
Learning from the past
The study provided clear evidence of the pandemic before, during and after, said Yassine Souilmi of the Australian Centre for Ancient DNA, who was not involved in the research.
"We are learning fundamental things about how the ERAP 2 gene is involved in the immune response," Dr Souilmi said.
"This is fascinating because this teaches us something ... which we weren't able to learn without looking back at the past."
It was not unusual to see evolutionary trade-offs throughout time that were once beneficial but may be deleterious today, he added.
We can see this in the genetic signature of a coronavirus-like epidemic thought to have occurred 20,000 years ago.
"We have found the variants that helped the South-east Asian populations respond to [a coronavirus-like epidemic] have a role today in shaping the susceptibility and the risk for a person to get severe COVID today.
"Our research was not as strong as [the Black Death study], simply because we only had circumstantial evidence of the existence of that epidemic."
Studies of Neanderthals also demonstrate that genes that many of us inherited from our ancient cousins also increased the risk to coronaviruses.
So could the COVID-19 pandemic eventually shape our immune system genes?
"Will we see effects? Very likely. Will the effects be as bad as what we are looking at here? No. Absolutely not," Dr Souilmi said.
"We are far better shielded from effects like these [seen in the Black Death] because we have modern medicine on our side."
