Deep Genomic History and the Evolutionary Origins of Multiple Sclerosis Risk
Multiple sclerosis (MS) is a complex neuro-inflammatory and neurodegenerative disease characterized by the immune system attacking the brain and spinal cord. While its prevalence is global, a striking geographical bias exists: Northern Europeans exhibit significantly higher susceptibility compared to other populations. Despite knowing that inherited risk is primarily located near immune-related genes, the historical origins of this risk have remained elusive. Recent genomic research has now traced the emergence of elevated MS genetic risk to ancient pastoralist populations from the Pontic-Caspian steppe.
Deep Genomic Mapping Across 10,000 Years
To uncover these origins, researchers assembled a massive dataset of 1,750 ancient genomes, spanning from the Mesolithic period to the Bronze Age, supplemented by Medieval and post-Medieval samples. This temporal transect allowed for the projection of modern "white British" genomes from the UK Biobank onto a model of European prehistory. By analyzing "local ancestry"—the specific ancestral source of different regions of the genome—the study identified the human leukocyte antigen (HLA) region on chromosome 6 as a primary area of unusual ancestry composition.
The Yamnaya Migration and MS Risk Expansion
The study reveals that genetic risk for MS rose sharply among steppe pastoralists and was introduced into Europe approximately 5,000 years ago via Yamnaya-related migrations. During the Bronze Age, these migrations brought a roughly equal mixture of Eastern hunter-gatherer (EHG) and Caucasus hunter-gatherer (CHG) ancestry to Europe. Specifically, the tag SNP for the allele conferring the highest MS risk, HLA-DRB1*15:01, was found to have rapidly increased in frequency during the formation of the Yamnaya culture.
Positive Selection Driven by Ancient Pathogens
These MS-associated immunogenetic variants did not persist by chance; they underwent positive selection. Evidence suggests that between 5,000 and 2,000 years ago, these risk-associated alleles were selectively favored, likely because they provided a survival advantage against pathogens. This selection coincided with the Neolithic transition and Bronze Age, periods marked by dramatic changes in diet, lifestyle, and increased population density, which facilitated the transmission of infectious diseases from domesticated animals to humans.
Implications for Personalized Risk Prediction
Understanding the ancestry-specific origins of MS risk offers a new pathway for individual risk prediction. By utilizing a new method called HTRX (Haplotype Trend Regression with eXtra flexibility), researchers found that haplotypes and gene-gene interactions explain more variance in MS risk than independent genetic variants alone. These findings highlight how deep historical migrations and lifestyle innovations 5,000 years ago continue to dictate the health outcomes and disease prevalence of modern European populations.
Comparative Evolutionary Profiles: MS vs. Rheumatoid Arthritis
Interestingly, the study found a contrasting evolutionary profile for rheumatoid arthritis (RA), another HLA-associated inflammatory disease. While MS risk is highest in steppe-derived ancestry, RA risk was found to be more prevalent in older Mesolithic hunter-gatherer ancestries (WHG and EHG). Furthermore, while MS variants underwent positive selection, RA-associated risk variants have generally undergone negative selection over the past 15,000 years, decreasing in frequency as human lifestyles evolved.
The "Hygiene Hypothesis" and the Modern Immune Mismatch
The research supports a refined version of the hygiene hypothesis, suggesting that our current environment no longer matches the genetic architecture we inherited. The immune variants that once protected ancient pastoralists from chronic viruses and parasites now predispose modern individuals to autoimmunity in a cleaner, highly sanitized world. This "mismatch" occurs because the fine balance of immune pathways, once honed to combat a broad repertoire of pathogens, now lacks its historical targets, potentially leading the system to harm self-tissue.
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
