Genetic risk for multiple sclerosis (MS) was brought into Europe by sheep and cattle herders migrating from the east approximately 5,000 years ago, DNA profiles from archaeological bones and teeth suggested.
Migration among pastoralists from the Pontic steppe — a region that includes parts of what are now Ukraine, Russia, and Kazakhstan — brought genetic variants that, in a modern environment, raise the risk of MS, reported Lars Fugger, MD, PhD, of Oxford University in England, and co-authors in Nature.
In the past, however, these variants may have served a purpose: they likely protected livestock herders against pathogens from their domesticated animals.
“The situation today is different because the diseases these variants originally provided protection against are no longer as big a problem as they likely were then,” Fugger said in a news briefing. “Because in the intervening millennia, we have antibiotics, vaccinations, and far, far higher standards of hygiene than people had thousands of years ago. The risk genes are now miscast in terms of their original biological role.”
Inherited risk for MS is located within or in close proximity to immune-related genes. Variants tied most strongly with MS are located in the human leukocyte antigen (HLA) region, with the most prominent one — HLA-DRB1*15:01 — tripling the risk of MS for people who carry at least one copy of the allele.
MS prevalence varies throughout the world and is highest in Northern Europe. Why MS develops isn’t clear, but gene-gene or gene-environment interactions are thought to play a role. Collectively, genetic factors are estimated to account for about 30% of disease risk. Environmental factors, like Epstein-Barr virus exposure, also raise the likelihood of developing MS.
To identify patterns in modern genomes, Fugger and co-authors evaluated ancestry at specific loci for 410,000 participants in the U.K. Biobank who self-identified as white British individuals, using a reference panel of 318 ancient DNA samples from the Mesolithic period to the Bronze Age and new Medieval and post-Medieval genomes. They compared the ancestry at each single-nucleotide polymorphism (SNP) to genome-wide ancestry in the U.K. Biobank to determine an anomaly score.
Two regions stood out as having the most extreme ancestry compositions: the LCT/MCM6 region on chromosome 2, which is well established as regulating lactase persistence, and the HLA region on chromosome 6, Fugger and colleagues observed.
“The frequencies of the alleles conferring the highest risk for MS (odds ratio >1.5), all of which are within the HLA class II region, showed striking patterns in our ancient groups,” the researchers wrote.
The tag SNP (rs3135388[T]) for HLA-DRB1*15:01, which carries the highest risk for MS, was first observed in an Italian Neolithic individual and rapidly increased in frequency around the time of the emergence of the Yamnaya culture about 5,300 years ago in steppe and steppe-derived populations, they added.
MS-associated immunogenetic variants underwent positive selection both within the steppe population and in combination with other groups, “probably driven by pathogenic challenges coinciding with changes in diet, lifestyle, and population density,” Fugger and colleagues noted.
“Our interpretation of this history is that co-evolution between a range of pathogens and their human hosts may have resulted in massive and divergent genetic ancestry-specific selection on immune response genes according to lifestyle and environment followed by recombinant-favoring selection after these populations merged,” they added.
From a genetic perspective, the Yamnaya people are thought to be the ancestors of present-day people in much of northwestern Europe, they pointed out. Their genetic footprint in southern Europe, where MS risk is less, is much smaller.
The findings may help demystify MS, Fugger noted.
“We can do away with the conventional perception of MS, which defines the disease in terms of the impairments it causes, and instead understand and seek to treat MS for what it actually is: the result of a genetic adaptation to certain environmental conditions that occurred back in our prehistory and which has endured in our DNA, even though the environmental conditions have changed hugely in the time between then and now,” he said.
The paper is one of four published simultaneously in Nature in which researchers compared modern and ancient human DNA. Other findings showed that the APOE4 gene associated with Alzheimer’s disease could be traced back to early hunter-gatherers. Future work will look at genetic markers of autism, attention deficit-hyperactivity disorder, schizophrenia, bipolar disorder, and depression.
Disclosures
The research was funded by a grant from the Lundbeck Foundation and was conducted at the Lundbeck Foundation GeoGenetics Center at the University of Copenhagen.
Fugger and co-authors had no disclosures.
Primary Source
Nature
Source Reference: Barrie W, et al “Elevated genetic risk for multiple sclerosis originated in steppe pastoralist populations” Nature 2024; DOI: 10.1038/s41586-023-06618-z.
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