Many Europeans carry genetic mutations that protected their ancestors from bubonic plague, scientists reported Wednesday in the journal Nature.
When the Black Death hit Europe in 1348, the bacterial infection killed large swathes of people across the continent, driving the strongest push of natural selection ever measured in humans, according to the new study.
It turns out that certain genetic variants made people much more likely to survive the plague. But that protection comes at a price: People who inherit plague-resistant mutations are at higher risk for immune disorders such as Crohn’s disease.
“These are the unfortunate side effects of long-term selection for protection,” said Hendrik Poinar, a geneticist at McMaster University in Canada and author of the new study.
Bubonic plague is caused by Yersinia pestis, a species of bacteria spread by fleas. Although the plague has been infecting people for thousands of years, it struck medieval Europe with an intense ferocity that led scientists to wonder if the Black Death changed Europe’s genetic makeup.
“We would expect to see a major change,” Dr. Poinar said.
The idea has a fundamental evolutionary meaning: when many organisms die, the survivors pass on mutations that protected them from death. During the industrial revolution, for example, pepper moths changed from a slightly speckled coloration to a dark coloration. This change was caused by coal smoke blackening the trees where the butterflies were resting. Dusky butterflies were better able to hide from birds and survived to pass on their genes.
When the Black Death hit, there were no evolutionary biologists to document its impact. In the 1990s, some scientists searched for clues by studying the DNA of living Europeans. A mutation in a gene, called CCR5, is present in 10% of Europeans but rare in other people. In 1998, researchers proposed that the gene may have offered protection during the Black Death.
But later research showed that it was impossible to rule out that the CCR5 mutation had spread in response to another disease at another time in history. “It’s something that a lot of people talk about but it’s very difficult to demonstrate,” said Luis Barreiro, a population geneticist at the University of Chicago and author of the new study.
Instead of studying living people, Dr Barreiro, Dr Poinar and their colleagues examined the DNA of people who lived centuries ago, extracting genetic material from human remains buried in three London cemeteries. They found DNA fragments in 318 skeletons that had lived between 1000 and 1500. The remains included 42 Black Death victims.
By comparing bones from before and after the plague, scientists discovered a striking difference in DNA: Hundreds of mutations in genes involved in immunity became more common after the outbreak.
This change was not in itself proof that the mutations conferred an evolutionary advantage. Biologists have long known that mutations can become more common in a population through the vagaries of history – a process called genetic drift.
It can be difficult to determine whether a common mutation arose due to genetic drift or natural selection. One way to tell the difference is speed: under extreme conditions, natural selection can spread a mutation much faster than genetic drift.
To compare natural selection and genetic drift, Dr Berreiro and his colleagues returned to the DNA of Londoners for another look. They took advantage of the fact that large portions of our DNA contain no active genes. Mutations that hit these stretches are unlikely to cause harm. They are also unlikely to bring benefits. They only spread through genetic drift.
Dr. Barreiro and his colleagues found that some of these neutral mutations became more common after the Black Death. But 35 of the mutations in immune genes spread much faster than neutral genes – so fast that only natural selection could explain their success.
For another test, the scientists repeated their experiment, this time in Denmark.
They found DNA in the skeletons of 198 Danes who lived between 850 and 1800. Mutations in immune genes also spread rapidly in Denmark after the Black Death, they found. When the scientists aligned the mutations from the samples from London and Denmark, they found four that had spread through both populations. These four mutations spread so quickly in London and Denmark that they must have provided impressive protection against the plague.
Researchers found that carrying two protective versions of a gene called ERAP2, for example, made people 40% more likely to survive the Black Death – the biggest evolutionary advantage ever found in humans, said Dr. Barreiro.
“It’s actually shocking,” said David Enard, an evolutionary biologist at the University of Arizona who was not involved in the new study.
Dr Enard said the study was particularly compelling thanks to the way the scientists ruled out genetic drift. “What really gives this study its power has to do with this whole approach of designing careful comparisons,” he said.
ERAP2 makes a protein involved in the immune response to invading bacteria and viruses. When an immune cell swallows a pathogen, it presents the invader’s proteins on its surface. They serve as an alarm to the rest of the immune system. ERAP2’s job is to cut pieces of foreign proteins to prepare them for display.
Billions of people have a version of the ERAP2 gene with a mutation that prevents cells from making its protein. But people with this version of the gene do not suffer major harm. This is likely because humans have many other genes that help present foreign proteins to the immune system.
During the Black Death, Dr. Barreiro and his colleagues discovered that natural selection favored the working version of ERAP2. To better understand why, they mixed Yersinia bacteria with immune cells from people with both versions of the gene.
The researchers found that two working copies of ERAP2 allowed immune cells to eliminate bacteria. Without it, the cells did a much worse job.
But this version of the gene also increases the risk of Crohn’s disease, a disorder in which the immune system attacks friendly bacteria in the gut and causes damaging inflammation. Dr Berreiro said it was possible ERAP2 was too good at its job, sounding the alarm against friend and foe alike. The other mutations he and his colleagues have identified from ancient DNA have also been linked to immune disorders.
Dr. Berreiro and his colleagues continue to study the genes that evolution favored during the Black Death, not only to understand this chapter in history, but also to understand the genes themselves. The fact that they have undergone such strong natural selection most likely means that they are important in the fight against disease – and perhaps not just plague.
“It was important in the past, and it’s most likely going to be important today,” Dr. Berreiro said.
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