Evolutionary Origins of Multiple Sclerosis: How Ancient Migrations Shaped Modern Disease Risk
Multiple sclerosis (MS) is a complex immune-mediated and neurodegenerative disease affecting over 2.5 million individuals globally, with a notably higher prevalence in Northern Europe. Despite extensive genomic research identifying over 200 susceptibility loci—particularly within the human leukocyte antigen (HLA) region—the evolutionary origins of these risk variants have remained unclear. The study presented in Nature (2024) provides compelling evidence that the genetic predisposition to MS is deeply rooted in ancient human migrations and adaptive processes. By integrating ancient DNA with modern genomic datasets, the authors reconstruct how evolutionary pressures shaped immune-related genetic variation long before the emergence of modern disease patterns .
Ancient Genomes and the Reconstruction of European Ancestry
The study leverages a comprehensive dataset of ancient genomes spanning approximately 10,000 years, from the Mesolithic to post-Medieval periods. These genomes were analyzed alongside modern data from the UK Biobank to infer ancestry components across Europe. The researchers identified key ancestral groups—western and eastern hunter-gatherers, early farmers, and steppe pastoralists—and quantified their contributions to present-day populations. This approach enabled a fine-scale mapping of genetic variation across time and geography, revealing how major demographic transitions, particularly the Neolithic transition and Bronze Age migrations, reshaped the European gene pool .
Steppe Pastoralists and the Emergence of MS Risk
A central finding of the study is that genetic variants associated with MS risk increased significantly in frequency among steppe pastoralist populations originating from the Pontic-Caspian steppe. These populations, linked to the Yamnaya culture, migrated into Europe approximately 5,000 years ago, introducing a distinct genetic component. Notably, the HLA-DRB1*15:01 allele—the strongest known genetic risk factor for MS—rose sharply during this period. Ancient allele frequency trajectories demonstrate that while this variant appeared earlier, it became widespread during and after steppe expansions, particularly in populations with high steppe ancestry .
Positive Selection and Immune Adaptation
The increase in MS-associated variants was not a neutral process but rather driven by positive selection. The study identifies a significant polygenic selection signal between 5,000 and 2,000 years ago, suggesting that these alleles conferred adaptive advantages. Importantly, these advantages were likely related to immune function rather than MS itself. The selected variants are enriched in genes involved in pathogen recognition and immune response, indicating that ancient populations experienced strong selective pressures from infectious diseases. Thus, alleles that now predispose individuals to autoimmune disease were historically beneficial in combating pathogens .
Recombinant-Favouring Selection in the HLA Region
An innovative aspect of the study is the identification of “recombinant-favouring selection” within the HLA region. Unlike classical selection models, this mechanism favors genetic diversity arising from recombination between ancestries. The authors demonstrate that haplotypes combining different ancestral origins were selectively advantageous, likely because they enhanced immune versatility against diverse pathogens. This finding underscores the complexity of immune system evolution and highlights how admixture between populations can generate novel adaptive combinations of alleles .
Pathogen-Driven Evolution and Pleiotropic Effects
Further analyses reveal that many MS-associated variants under selection are also linked to resistance against infectious diseases, including viruses such as Epstein–Barr virus and pathogens like Mycobacterium tuberculosis. This supports a model of pleiotropy, where alleles beneficial in one context (infection resistance) have detrimental effects in another (autoimmunity). The study also contrasts MS with rheumatoid arthritis, showing divergent evolutionary trajectories: while MS risk increased over time, rheumatoid arthritis risk decreased, reflecting different selective pressures across ancestral populations .
Conclusion: Evolutionary Trade-offs and Modern Disease
This research fundamentally reframes MS as a disease shaped by evolutionary trade-offs. The genetic variants that increase MS risk today were likely selected for their protective effects in ancient environments characterized by high pathogen burden and changing lifestyles. The transition to modern environments—with reduced infectious exposure and altered immune challenges—has unmasked these variants as risk factors for autoimmunity. Ultimately, the study highlights how ancient population movements, lifestyle shifts, and pathogen interactions continue to influence contemporary human health, offering a powerful example of how evolutionary history informs modern disease biology .
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
