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Five thousand years ago, sheep and cattle herders migrated westward from Asia to Europe, bringing with them their pastoral way of life — and higher genetic risk for multiple sclerosis, according to a new <a href="https://www.nature.com/articles/s41586-023-06618-z" target=_blank>study</a> of DNA from thousands of ancient and present-day people.

The finding answers a long-standing conundrum in medical science: Why is this debilitating autoimmune disease most common in people from northern Europe? The research also recasts the modern-day illness, suggesting it is rooted in an evolutionary trade-off.

Multiple sclerosis is a neurological disease in which a person’s normally protective immune system turns on their nervous system. Thousands of years ago, when people began living in proximity to livestock and their germs, variants of genes related to immunity began to give people an evolutionary edge, possibly because they helped bolster defenses against an onslaught of infections and parasites carried by their animals.

But genes don’t do just one thing. In a prehistoric world filled with infectious perils, a potent immune response could mean the difference between life and death. Thousands of years later, those same gene variants also happen to increase their descendants’ risk of the haywire immune response in MS.

For years, researchers have debated the “<a href="https://www.washingtonpost.com/business/2023/09/08/real-reasons-food-allergies-are-rise/" target=_blank>hygiene hypothesis</a>,” the idea that asthma or allergies may be a consequence of modern life being too clean to allow the immune system to develop. The new paper unpacks in detail how variants of specific immune-related genes instead became more common because they gave people an evolutionary advantage thousands of years ago.

“What has been honed for 5,000 years and refined in our evolution — that’s basically what we are trying to battle today,” said Lars Fugger, a professor of neuroimmunology at the University of Oxford who cares for MS patients, and one of the authors of the paper. “So it’s no mystery that it’s difficult to treat.”

How 10,000 years of plagues left their mark on our DNA

The study, one of four published in the journal <a href="https://www.nature.com/articles/s41586-023-06865-0" target=_blank>Nature</a> on Wednesday, is part of a larger effort to analyze DNA recovered from ancient human remains and unravel the origin and evolution of various traits and disease risks. The authors also found, for example, that a version of a gene called APOE4 that increases risk for <a href="https://www.washingtonpost.com/science/2023/05/15/alzheimers-disease-treatments/" target=_blank>Alzheimer’s disease</a> was probably introduced into the European population from hunter-gatherers.

“Processes that were occurring many thousands of years ago are having these really pronounced and profound effects on the health and longevity of people in the present,” said Evan Irving-Pease, a study author and assistant professor of population genetics at the University of Copenhagen.

The Danish National Museum

Analysis of <a href="https://www.nature.com/articles/nature14317" target=_blank>ancient DNA</a> extracted from bones or teeth has rewritten our understanding of human prehistory, yielding new insights into the waves of migrations that led to modern populations. Researchers already knew, for instance, that the modern-day European population was shaped by three key waves of migration: hunter-gatherers who moved into the region 45,000 years ago, farmers who came from the Middle East about 11,000 years ago and animal herders who migrated from the Pontic Steppe, grasslands that extend from Central Europe to Central Asia, about 5,000 years ago.

But ancient DNA’s potential to transform understanding of human biology has been limited, so far, by the lack of DNA from enough samples, said David Reich, a geneticist who studies ancient DNA at Harvard University and was not involved in the new studies.

Nobel awarded to Swedish scientist who deciphered the Neanderthal genome

For their latest work, the scientists analyzed DNA from more than 300 individuals, a third of them from Denmark, who lived between 25,700 years ago and 1,200 years ago. They included a father buried next to his infant son, a hunter-gatherer called Dragsholm Man, who had adopted the diet of immigrant farmers, and the <a href="https://en.natmus.dk/historical-knowledge/denmark/prehistoric-period-until-1050-ad/the-neolithic-period/polished-axes-of-flint/weapons-violence-and-death-in-the-neolitic-period/" target=_blank>Porsmose Man</a>, discovered in a bog with an arrow through his nose and breastbone. Combining that data with previously sequenced ancient samples, they created a database of 1,600 ancient genomes from across Eurasia.

The goal is to create a database of 5,000 ancient genomes that will help scientists look for the roots and spread of disease risk, said Eske Willerslev, an evolutionary geneticist at the University of Cambridge and a leader of the project.

So far, the ancient DNA reveals that key traits such as height, and disease risks, evolved first outside Europe and were imported into the population by those multiple waves of migration.

“In terms of our disease susceptibility and in terms of how we look, are very much created through these migration events,” Willerslev said.

Multiple sclerosis is a complex disease, caused by a combination of <a href="https://www.washingtonpost.com/health/2022/01/14/epstein-barr-virus-multiple-sclerosis-mononucleosis/" target=_blank>environmental</a> and genetic factors that are still only partly understood. But Lawrence Steinman, a neurologist at Stanford Medicine who was not involved in the research, said that the new paper presents a fascinating and provocative line of evidence tracing genetic risk back to ancient populations.

“MS is generally not going to affect you until you’re a young adult, so you would have been able to propagate and increase the population and have offspring before you have the manifestations of MS — and those genes may give an advantage against certain infections,” Steinman said.

The idea that infectious diseases helped shape human evolution is not new, but the researchers said they were still surprised to observe such a clear signal that the MS risk genes had been “positively selected” — meaning that they increased in frequency because they provided an evolutionary advantage.

But Samira Asgari, a computational biologist at Icahn School of Medicine at Mount Sinai who is focused on understanding the human genetics of infection and immunity, said the specific advantage the papers propose — greater protection against infection — is a reasonable explanation, but still a hypothesis.

“That’s the part more research is needed to prove,” Asgari said.

The researchers have another paper that is <a href="https://www.biorxiv.org/content/10.1101/2023.10.06.561165v1" target=_blank>not yet peer-reviewed</a> showing an explosion in pathogens that jump from animals to humans around 5,000 years ago, which they say could bolster the case that the pathogens surrounding early Europeans shaped their genetics.

“What we see consistently in the immune system is genes are being selected according to the pathogen challenges the populations are encountering, throughout time,” said Astrid Iversen, a professor of virology and immunology at the University of Oxford.

Multiple experts cautioned that getting a deeper understanding of the genetic roots of human illnesses won’t lead directly to new treatments, but they couldn’t it rule out, either.

“Understanding biology from different angles,” Asgari said, “can accelerate the move toward better drugs.”

Finalist for the 2013 Pulitzer Prize in national reporting, as part of a team

Amherst College, BA in Physics and English

MIT, MS in Science Writing

Carolyn Johnson is a science reporter. She previously covered the business of health and the affordability of health care to consumers. 