SCIENCE

How the Black Death changed our immune systems

On a drizzly April morning in 2006, a geneticist had the sobering task of helping sort 50 boxes of bones in the Museum of London’s basement into two stacks. One contained the remains of people who died 700 years ago during the Black Death. In the other were bones from survivors of the plague who had been buried a year or more later in the same medieval cemetery near the Tower of London.

As Jennifer Klunk, then a graduate student at McMaster University, examined the remains, she wondered what made the two groups different. “Why did some people die during the Black Death and others didn’t?” Klunk, now at Daicel Arbor Biosciences, remembers thinking.

Other scholars have been pondering that mystery for centuries. But now, by analyzing DNA from those old bones and others from London and Denmark, Klunk and her colleagues have found an answer: The survivors were much more likely to carry gene variants that boosted their immune response to Yersinia pestis, the flea-borne bacterium that causes the plague. One variant alone appears to have increased the chance of surviving the plague by 40%, they reported today in Nature. “We were blown away. … It’s not a small effect,” says Hendrik Poinar, an evolutionary geneticist at McMaster and co–lead author of the study (and Klunk’s Ph.D. adviser).

The findings also indicate the Black Death caused a dramatic jump in the proportion of people carrying the protective variant; it is the strongest surge of natural selection on the human genome documented so far. But the improved immunity came at a cost: Today, the variant is also associated with higher risk of autoimmune diseases.

“This is a truly impressive paper,” says population geneticist David Enard at the University of Arizona, who is not part of the study. “The implications of the potential speed and power of natural selection in immune genes are wild.”

The Black Death is the deadliest pandemic recorded in human history. In the mid–14th century, it killed 30% to 50% of all people living in Europe, the Middle East, and Africa. Researchers have long thought the catastrophe must have left a mark on the genome of survivors, giving future generations some immunity against resurgences of the plague. But identifying that mark has proved difficult, in part because genes involved in immunity rapidly change in frequency as new pathogens arrive. It is “not feasible” to detect the plague’s genomic signature in living humans, says molecular anthropologist Anne Stone of Arizona State University, Tempe, who is not part of the study.

Over the past decade, new techniques for analyzing ancient DNA made it possible to search for the legacies of pathogens in the genomes of people who died long ago. But researchers studying the plague struggled to find enough well-dated samples from victims and survivors to reveal real differences in the frequency of immune genes.

Poinar found an answer to that problem in the East Smithfield Cemetery in London, on land that King Edward III bought for a plague pit. Its thousands of burials represent a well-dated time capsule. Plague victims who died in 1348 and 1349, when the disease first ravaged the city, are buried in mass graves at the bottom; survivors who died in 1350 or later are above them. The team extracted bone samples from 318 skeletons from this cemetery and two others in London, as well as from 198 remains found at five sites in Denmark.

This gave them well-dated samples from some 500 people who lived during a 100-year window before, during, and after the plague.

After Klunk extracted and sequenced DNA from the bones, a team co-led by human geneticists Luis Barreiro and Tauras Vilgalys of the University of Chicago used the highest quality DNA from 206 individuals to examine 356 genes associated with immune responses. The team identified an astonishing 245 gene variants that rose or fell in frequency before and after the Black Death in people in London, four of which were also found in samples from Denmark.

Changes in the code for one gene stood out: ERAP2, which encodes a protein called endoplasmic reticulum aminopeptidase 2. Previous work had shown ERAP2 helps immune cells recognize and fight threatening viruses. The team confirmed it also can suppress Y. pestis bacteria by measuring how the genes of cultured human immune cells responded to the pathogen.

The researchers found two variants, or alleles, of ERAP2 in their samples. They differ by just one letter in the genetic code. But that difference—which determines whether the gene produces a full-size or truncated protein—had a big impact on immunity. People who inherited two copies of the allele for the full protein were twice as likely to have survived the plague as those who inherited the variant making the truncated version.

An analysis of 143 samples from London also indicated that, before the Black Death, 40% of Londoners carried one or two copies of the protective variant. But only 35% of plague victims carried it. And after the plague, the share of Londoners carrying the protective variant rose to more than 50% within just a few generations. In Denmark, where the sample size was smaller, the proportion of people carrying the protective variant rose from 45% before the Black Death to 70% after.

Although the 10-percentage-point increase seen in London might not seem like a lot, researchers have never before documented such a rapid surge in a human genetic variant, Barreiro says. “Given the fairly large size of the population [of London] at the time, a 10% change in allele frequency in only three or four generations is highly unusual,” he says. It is among the fastest examples of natural selection ever detected in humans, says population geneticist Monty Slatkin of the University of California, Berkeley, who is not part of the study.

Today, the protective variant is still found in about 45% of British people in the 1000 Genomes database, a catalog of genetic variation. That is surprisingly high, because the protective variant has a downside. Earlier work has shown it comes with a higher risk of developing autoimmune disorders, such as Crohn disease and rheumatoid arthritis. “Once the pandemic is gone, this cost becomes apparent,” Enard says. The variant’s high proportion suggests natural selection continued to favor it until recently, presumably because the plague remained endemic in Europe and Asia into the 19th century.

Researchers are now checking to see whether the protective variant and three other potential plague-resistance variants identified by the Nature study are present and show frequency shifts in other ancient populations, especially in Africa. One recent study from Norway, which analyzed DNA from 54 people who lived before, during, and after the Black Death in Trondheim, found no big swings in the four genes, says Tom Gilbert, an evolutionary biologist at the University of Copenhagen who co-led the work. But Gilbert and population geneticist Ziyue Gao of the University of Pennsylvania say that if researchers can confirm such gene surges in more populations, that could help rule out the possibility that the new findings were skewed, for example by the way researchers commonly reconstruct degraded DNA sequences.

Still, Gilbert expects the results to hold up. And they have led him to wonder whether genetic shifts—and not better pest control or improved cleanliness—explain why Y. pestis is less dangerous today than it was in the 14th century. “We have assumed that the plague went away because we’ve become cleverer at cleaning our houses and keeping rats out,” Gilbert says. “But wouldn’t it be awesome if it went away because we became immune, not just because we have better hygiene?”

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