This photo courtesy of the Museum of London Archaeology, provided in October, 2022, shows excavation of the East Smithfield plague pits in London, which were used for mass burials in 1348 and 1349.The Associated Press
When the Black Death swept across Europe, North Africa and the Middle East almost 700 years ago, it wiped out an estimated one-third to one-half of the population – the worst pandemic in history.
The sheer magnitude of the loss upended society and changed the course of world events. Now scientists have discovered that it rattled the human genome as well.
In a study published Wednesday in the journal Nature, an international team has identified a set of genetic variations that helped some people survive bubonic plague, a bacterial disease whose fateful appearance in the 14th century drove the Black Death.
The widespread presence of those variations today, inherited from those who survived and passed them on, offers a stark case of evolution at work. But the protection they offered came with a trade-off: One of the genes the team found to be most strongly associated with resistance to plague is also implicated in various autoimmune disorders, including Crohn’s disease.
“We’re still living in the shadow of the Black Death,” said Hendrik Poinar, an evolutionary geneticist at McMaster University in Hamilton and a senior author on the study.
Dr. Poinar’s lab was previously involved in rebuilding the genome of an earlier strain of Yersinia pestis, the bacteria that causes bubonic plague, based on fragments of bacterial DNA found in the bones of plague victims from the sixth century.
For the new study, the goal was to look instead at how the genes that regulate the human immune system were affected by the version of the plague that ravaged Europe between 1347 and 1351, when the Black Death was at its height.
“If anything is going to cause selective pressure on the human genome, that’s probably a great place to look,” said Jennifer Klunk, a lead product scientist at Daicel Arbor Biosciences in Ann Arbor, Mich., and the first author on the study.
In 2016, Dr. Klunk, who was then a graduate student in Dr. Poinar’s lab, travelled to England to collect samples from excavated burial pits that date back to the period when people were dying of plague by the thousands.
One site, known as East Smithfield, is located just a few hundred metres from the Tower of London. It proved especially useful for the study because of medieval records that pinpoint precisely when the site was active. Dr. Klunk was able to obtain samples from 50 individuals, using a portion of the skull known as the petrus bone that surrounds the inner ear and is known to be a place were DNA is well preserved in human skeletons.
She was then able to compare samples from people who died during the Black Death and people who were buried some time later and likely died of other causes. To narrow the search, the study focused on areas of the human genome that are linked to the innate immune system, the body’s initial line of defence against infection.
For comparison, samples from the same period were also obtained from a burial site in Denmark.
Further analysis of the samples by researchers at the University of Chicago revealed about 200 changes reflected in the DNA of those who survived the Black Death. The researchers then focused on four immune-related genes that appeared to be under higher selection pressure – meaning there was a distinct shift in which versions of the genes were present before and after the pandemic. The change was especially pronounced in one of the genes, ERAP2.
“It’s like a flashing light bulb,” Dr. Poinar said. “There’s no possible way that could have happened by chance.”
To determine if the change was truly related to protection from plague, a second part of the study was conducted at the Pasteur Institute in Paris, where researchers tested immune cells donated from individuals with different versions of the ERAP2 gene. The donated cells fell into three categories: those from individuals who had inherited the genetic variation from both parents and so had two copies of the gene, those who had the gene from one parent and those who did not have it at all.
“The results we obtained were striking,” said Javier Pizarro-Cerda, a research director at the institute who led the lab work. “The cells that carried both versions of the ‘protective’ variant killed Yersinia pestis efficiently.”
In comparison, cells without the protective gene had little effect against the bacteria, while those with one copy of the gene only exhibited an intermediate effect.
Dr. Pizarro-Cerda said the link between plague and the ERAP2 gene was unexpected but makes sense. ERAP2 functions as a kind of genetic conductor that helps the immune cells chop up invaders.
The more protective version of the gene makes the immune system efficient enough to destroy Yersinia pestis – so much so that those who carried the gene at the time of the Black Death probably had a 50-per-cent greater chance of surviving an infection.
The downside is that this “superefficient” version of the immune system can also react too much, “which is what happens in autoimmune disorders, when the immune system reacts against ourselves,” Dr. Pizarro-Cerda said.
In an accompanying commentary, David Enard, an evolutionary biologist at the University of Arizona who studies ancient epidemics, said further studies could shed light on the ancient origins of autoimmune diseases.
He added that such strong selection pressure on human evolution is unlikely to have occurred for reasons other than a major pandemic. Prior to the advent of vaccines, there was no greater influence on who lived and who died.
This was especially true of the Black Death, which was devastating for the young, Dr. Poinar said.
In comparison, no such effect would be expected from COVID-19, even among the unvaccinated, since those who are most vulnerable to the current pandemic are often older individuals who, if they have children, have already passed on their DNA to the next generation.