Ancient Steppe Ancestry and the Evolutionary Origins of Multiple Sclerosis Risk
Multiple sclerosis is a chronic neuro-inflammatory and neurodegenerative disease whose prevalence is particularly high in Northern Europe. The article “Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations” investigates a long-standing question in human genetics: why alleles that increase susceptibility to autoimmune disease remain common in modern populations. By integrating ancient DNA, modern biobank data, and evolutionary modelling, the authors propose that part of the contemporary genetic risk for multiple sclerosis originated in Bronze Age steppe pastoralist populations and was later introduced into Europe through Yamnaya-related migrations approximately 5,000 years ago.
The Evolutionary Puzzle of Autoimmune Risk
The persistence of multiple sclerosis risk alleles is biologically paradoxical because autoimmune disease is not expected to confer a direct reproductive advantage. The study addresses this paradox by distinguishing between the modern pathological effects of these alleles and their possible historical benefits. The authors argue that variants now associated with multiple sclerosis may once have enhanced immune defence against infectious disease. In this interpretation, modern autoimmunity represents a consequence of evolutionary trade-offs: genetic variants that improved survival under ancient pathogen pressures may become harmful when environments, lifestyles, hygiene conditions, and infectious exposures change.
Steppe Ancestry as a Major Contributor to MS Risk
A central finding of the article is that genetic ancestry derived from Pontic-Caspian steppe pastoralists contributes disproportionately to modern multiple sclerosis risk. The authors compare ancient ancestries, including western hunter-gatherers, eastern hunter-gatherers, Caucasus hunter-gatherers, early farmers, and steppe pastoralists. Their analyses show that steppe ancestry carries the highest aggregate risk for multiple sclerosis, especially in the human leukocyte antigen region of chromosome 6. This region is critical for immune recognition, and it contains the strongest known genetic risk factors for multiple sclerosis, including the HLA-DRB1*15:01 haplotype.
HLA-DRB1*15:01 and the Rise of Immunogenetic Risk
The study pays particular attention to HLA-DRB1*15:01, a major multiple sclerosis risk allele that substantially increases disease susceptibility in carriers. Ancient DNA evidence suggests that this allele was rare before the Bronze Age but increased in frequency around the period associated with the formation and expansion of Yamnaya-related steppe populations. In modern Europe, its distribution broadly corresponds with regions that have higher proportions of steppe ancestry, including parts of Northern Europe. This pattern supports the authors’ conclusion that the modern north–south gradient in multiple sclerosis prevalence is partly shaped by ancient demographic history.
Methodological Integration of Ancient and Modern Genomics
The strength of the study lies in its integration of several analytical frameworks. The authors used ancient genomes spanning thousands of years, newly sequenced Medieval and post-Medieval Danish genomes, and data from hundreds of thousands of UK Biobank participants. They applied local ancestry inference to identify which ancient ancestral components were present at specific genomic loci, rather than relying only on genome-wide ancestry proportions. They also used ancestral risk scores, haplotype-based modelling, and selection analyses to determine whether multiple sclerosis risk alleles increased through neutral demographic processes or through positive selection.
Pathogen Pressure and Immune Adaptation
The authors propose that positive selection on multiple sclerosis-associated alleles was probably driven by infectious disease pressures linked to changing subsistence strategies. Pastoralism, animal domestication, increasing population density, and altered diet would have intensified human exposure to pathogens. Under such conditions, immune variants that improved resistance to bacterial, viral, or parasitic infections may have been advantageous. The article therefore frames multiple sclerosis risk not as an isolated genetic anomaly, but as a legacy of immune adaptation during a period of profound ecological and cultural transformation in Eurasian prehistory.
Implications for Human Disease and Evolutionary Medicine
This study has important implications for evolutionary medicine. It demonstrates that present-day disease risk cannot be fully understood without considering ancient population movements, historical pathogen landscapes, and gene–environment interactions. The findings do not imply that ancestry alone determines multiple sclerosis, since environmental factors such as Epstein–Barr virus infection, smoking, vitamin D exposure, obesity, and other lifestyle variables remain highly relevant. Rather, the article shows how ancient selection may have shaped the immunological architecture upon which modern environmental triggers act. Multiple sclerosis, in this framework, is partly a modern expression of ancient immune adaptations that were once beneficial but now contribute to disease susceptibility in a radically altered environment.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Barrie, W., Yang, Y., Irving-Pease, E.K. et al. Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations. Nature 625, 321–328 (2024). https://doi.org/10.1038/s41586-023-06618-z
