Origin of Multiple Sclerosis And These Common Diseases Lies in Ancient DNA

Around 5,000 years ago, at the dawn of the Bronze Age, a mass migration of peoples from the grasslands of the Eurasian steppe poured into Europe. Called the Yamnaya, these horse herders introduced Europe to the pastoralist way of life, shifting it away from its hunter-gatherer societies. The Yamnaya also left a lasting impression on the genetic landscape, one that endures today and from which chronic autoimmune diseases, like multiple sclerosis (or MS), likely originate.

In a study published Wednesday in the journal Nature, researchers in the UK and Denmark found that when the Yamnaya and their descendants traveled northwest through Europe, they passed along many genes conferring risk for MS. Although MS is considered a debilitating disease today, these genes would have made these ancient people resilient against the everyday onslaught of infectious diseases back 5,000 years ago. The researchers suggest this could be the reason why genetic risk variants for MS remained within circulation down the generations. But as our lifestyles changed with time, these formerly protective genes became more harmful than good.

This paper is among a collection of three other studies investigating how shifts in ancient DNA resulting from mass migrations shaped modern Eurasian genetics. In one of those papers, the same group of researchers also found genes impacting nutritional health, like lactose tolerance, that emerged in Europe around 6,000 years ago before the arrival of the Yamnaya. Genes influencing one’s risk for conditions like Type 2 diabetes and Alzheimer’s disease could be traced back to ancient hunter-gatherer societies in Europe.

“This is early days, of course, for [these findings],” Eske Willerslev, the senior author of all four papers and an evolutionary geneticist both at the University of Cambridge in the UK and the University of Copenhagen in Denmark, told reporters during a press briefing. “But I really do believe that we have a framework — that will improve — for looking at all kinds of diseases and understanding their origins and what has been under [evolutionary] selection, how we are who we are, the good and bad, and so forth.”

Pastoralist ancestry and multiple sclerosis

Multiple sclerosis is an autoimmune condition affecting the central nervous system (or CNS), which is comprised of the brain and spinal cord. It occurs when the immune system mistakenly attacks myelin, a protective sheath of tissue insulating the nerve fibers of the CNS. This leaves nerves damaged and the brain unable to communicate with the rest of the body and vice versa. Common symptoms of MS include fatigue, weakness, cognitive dysfunction, and difficulty walking, among many others.

While the cause of MS is unknown, a variety of environmental and genetic factors have been implicated. Previous infection with the Epstein-Barr virus (or EBV) is also considered a significant risk factor, at least for most individuals, egging the immune system on toward inflammation and autoimmunity.

MS affects most ethnic groups, but it’s disproportionately common among individuals of northern European descent. In order to figure out why that’s the case, Willerslev and his colleagues turned to ancient DNA genomic data they used in their other studies. This included DNA taken from bone and teeth recovered from 317 individuals who lived across Northern and Western Eurasia, mainly during the Mesolithic Period some 8,000 to 10,000 years ago. The researchers already had an existing data set of genetic information taken from more than 1,300 ancient Europeans.

This ancient DNA was compared against the DNA of modern-day self-reported “white British” people taken from the UK Biobank, an open-access database that’s been collecting biomedical data from nearly 500,000 individuals across the UK since 2006. Those who carried more of the Yamnaya genetic legacy — also referred to as pastoralist ancestry by the researchers to differentiate between ancestry from the hunter-gatherers who predate the Yamnaya — on chromosome six appeared to have a higher risk of developing MS. This finding is pretty significant since chromosome six is home to an immune system gene, called HLA-DRB1*15:01, that’s been consistently linked with MS in nearly all populations studied.

Not only that, further analysis suggested something far more surprising. Inheriting genetic risk variants for MS appeared to be Mother Nature-approved, evolutionarily advantageous rather than harmful to the people carrying them, said William Barrie, the study’s first author and a genetics researcher at the University of Cambridge.

“In the past, [these variants] were actually beneficial,” Barrie told reporters during the press briefing. “The people carrying them were able to survive more and pass their genes onto their children, a process called positive selection. These variants were giving the people an advantage of some kind, we think, protecting them against the pathogens they were exposed to through their animals.”

The researchers also found the higher incidence of MS among Northern versus Southern Europeans is explained by the geographical trend in pastoralist ancestry: the Yamnaya avoided migrating southward, favoring instead northwest to Scandinavia and the surrounding area. In doing so, southern Europeans didn’t inherit nearly as many genes for MS.

The genetic legacy of the hunter-gatherers

In another study, the same group of researchers did a genomic analysis looking at genes related to dietary, physical, and mental health. They traced the ancestry of DNA found in present-day Europeans to DNA from 1,664 skeletons collected from various archaeological sites across the region of Eurasia spanning from Scandinavia to Russia and even the Middle East. These ancient ancestors lived as far back as the Mesolithic Period and some more recently from the Bronze Age, which ended sometime around 1000 B.C.

The researchers specifically homed in on the genetic legacy of hunter-gatherers hailing from different geographical locations across Eurasia (east, west, and the Caucasus) and farmers from West Asia in Anatolia (Turkey today).

The genomic analysis revealed a bunch of interesting findings. For example, having Yamnaya ancestry seemed to be correlated with tallness. Lactose tolerance, or the ability to digest the sugars in milk and other dairy products, emerged in Europe some 6,000 years ago at a time when farming had just taken off but before the migration of pastoralists from the Eurasian steppe. Thriving off a vegetable-rich diet was made possible by genes involved in fatty acid production — a crucial component of various biological processes — introduced by people who migrated to Europe during the Neolithic Period, also known as the New Stone Age.

“So in the hunter-gatherer societies, they probably had more caloric intake from meat and hunting, and as we shift to agriculture, we have more dietary intake of fatty acids from various forms of vegetables,” Rasmus Nielsen, one of the study’s co-authors and a biologist at the University of Copenhagen and the University of California, Berkeley, told reporters during the press briefing. “We see a very strong selection in Europe, after the transition to agriculture, associated with [fatty acid production genes] characteristic for having a diet that’s more vegetarian.”

The researchers also looked at how these ancestries influenced disease risk for conditions like Type 2 diabetes, Alzheimer’s disease, and bipolar disorder. Western hunter-gatherer DNA, which was more abundant among Eastern Europeans, said Willerslev, was associated with a higher risk of diabetes and Alzheimer’s disease. Bipolar disorder, on the other hand, seemed to be associated with ancient farmer DNA.

“We do find the APOE2 [gene], which is protective against Alzheimer’s, being positively selected in the people of the Pontic steppe around Ukraine and Russia, which they then carried into Europe,” Astrid Iversen, one of the study’s co-authors and a professor of virology and immunology at the University of Oxford, told reporters. “During the migrations in the Bronze Age, we did not find any selective footprint for the APOE3 [the gene that doesn’t seem to influence Alzheimer’s risk].”

Further research

For multiple sclerosis, these findings demonstrate how genes, once useful because of their place within a certain lifestyle or environmental niche, can reign chaos as human society evolves.

“This paper is a beautiful example of how changes in lifestyle affect pathogenic challenges and how that again affects what diseases the people who live a certain way [are] exposed to,” said Iversen. “We see that our lifestyle has changed within the last 200 years where we have increased hygiene, a different diet, and we are not loaded up on parasites. Suddenly, we see some of these beneficial immune responses and the fine balance between pro- and anti-inflammatory responses backfire, leading to overactive immune responses that lead to autoimmune diseases like MS.”

In an accompanying editorial, Samira Asgari, an assistant professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai, who was not involved in the study, writes that the positive selection of genetic risk variants of MS sounds valid but needs cementing with further research.

“Some of this evidence could be provided by further studies of ancient genomes, which would help scientists to better understand the extent to which pathogens exerted selective forces on the human genome, and the resulting effects on genetic diversity and disease risks in present-day humans,” she writes.

Infectious pathogens molding our genomes isn’t exactly a new idea. Studies have found that events like the Black Death, a devastating epidemic of bubonic plague striking Europe and Asia for centuries, may have shaped our immune systems, specifically by favoring survivors with immune resiliency.

But delving into ancient DNA to inform our present-day health and well-being will require a more nuanced scientific undertaking, particularly among non-white, non-European populations.

“Although human biology is shared,” writes Asgari, “each population has a unique history, and focusing on a single population limits opportunities for discoveries that can bring insights that advance medicine.”