The Black Death struck Cambridge, England, in 1349. The bodies piled up so fast — up to six in ten people died in Europe — that gravediggers struggled to keep up, and many remains wound up in mass burials.
Despite its heavy toll, this wave of bubonic plague doesn’t seem to have had a lasting impact on the genomes of the people of Cambridge, suggests a 17 January study in Science Advances1. The findings contradict a high-profile 2022 Nature paper2 that identified variants in immune genes that were enriched in people who survived the Black Death, suggesting that the variants might have had a protective effect.
Bubonic plague left lingering scars on the human genome
“Because it’s such a devastating event, people naturally expect it will leave some genetic signature,” says Ruoyun Hui, a population geneticist at the University of Cambridge, UK, who co-led the latest study. “We didn’t find much evidence supporting adaptation of immune responses.”
Scarred genomes
Table of Contents
The human genome is littered with scars of ancient disease outbreaks, and there is good evidence that gene variants common in different populations helped their ancestors to survive infections — and pass those helpful variants onto their children3.
But connecting such changes to specific disease outbreaks, such as the Black Death, has been difficult. Natural selection tends to act over many generations, and the influence of one disease outbreak can be especially hard to see in the small numbers of ancient human genomes typically available, says Luis Barreiro, a human-population geneticist at the University of Chicago in Illinois.
In the 2022 study2, Barreiro’s team looked at hundreds of ancient genomes of people from London and Denmark. The researchers identified more than 200 immune gene variants that became either more or less common in d people who survived the Black Death, compared with people died before or during the plague years. In laboratory studies, variants in one gene, called ERAP2, helped immune cells to control the plague-causing bacterium Yersinia pestis.
Ancient DNA traces origin of Black Death
To see how the Black Death might have shaped people’s genomes in other regions, a team led by Hui and her University of Cambridge colleague population geneticist Toomas Kivisild sequenced the genomes of 275 people from medieval and post-medieval Cambridge and surrounding villages.
However, in a subset of 70 most complete genomes the researchers found few signs of natural selection after the Black Death. About 10% of the 245 immune variants that Barreiro’s team had found in Londoners changed in frequency in the Cambridge cohort. But out of 22 gene variants, 10 that seemed to help people to survive the Black Death in Cambridge became less common in London, or vice versa.
Hui and Kivisild’s team detected no shift in the frequency of the plague-protecting ERAP2 variants. A version of another gene that protects against leprosy became slightly more common after the Black Death, but this association did not meet a statistical threshold typically applied to genomic studies. Kivisild says that it’s still possible that the Black Death influenced the evolution of immune genes in ways his team’s study could not detect. “But it is a little bit premature to make far-reaching conclusions at this stage.”
Question of scales
Iain Mathieson, a population geneticist at the University of Pennsylvania in Philadelphia, isn’t surprised that the Black Death didn’t seem to alter the genomes of people in Cambridge. In a 2023 preprint4, Mathieson and his colleagues identified what they say are analytical flaws in Barreiro’s study. When they corrected for these issues, they found that the variants identified no longer met a statistical threshold used in genome-wide studies to avoid spurious associations.
Barreiro stands by his team’s findings, particularly their interpretation of ERAP2’s role5. A separate epidemiological study showed that variants in the gene protect against respiratory infections6. And in another 2023 preprint7, researchers trained a deep-learning model to identify natural selection in ancient-genome data and found hints that two of the ERAP2 variants had been under selection in the past 2,000 years — a period that includes not only the Black Death but also other plague epidemics. “Once you start having these pieces coming together, I think you can build a strong case for selection,” Barreiro says.
Ultimately, the debate is about timescales. “Personally, I think that a single epidemic is unlikely to make much difference,” says Mathieson, “but repeated epidemics and pandemics certainly could.”
Firm answers on the Black Death’s impact — or that of any past disease outbreak — will require thousands of ancient-human genomes and maybe more, researchers agree. “I don’t think it’s going to be resolved in a definitive manner that pleases everyone one until we reach much, much larger sample sizes,” says Barreiro.