Unraveling the Genetic Origins of Multiple Sclerosis: Insights from Ancient Steppe Pastoralists

Multiple Sclerosis (MS), a complex immune-mediated and neurodegenerative disease, primarily affects the brain and spinal cord. Although it has a global presence, its prevalence is particularly high in Northern Europe, raising questions about the genetic and environmental factors contributing to this geographical bias. A recent groundbreaking study published in Nature sheds light on the ancient origins of genetic susceptibility to MS, revealing how these risk factors emerged and evolved in steppe pastoralist populations during the Bronze Age. This blog post delves into the findings of this study and their implications for our understanding of MS and its historical context.

The Genetic Landscape of MS
MS is known to have a complex etiology, involving both genetic predispositions and environmental triggers. Genome-wide association studies (GWAS) have identified over 230 genetic variants associated with MS, with the strongest associations located in the human leukocyte antigen (HLA) region. Among these, the HLA-DRB1*15:01 allele stands out, increasing the risk of MS by approximately threefold in carriers. However, the origins of these risk alleles and their distribution across populations remained largely unexplored until now.

Ancient Genomes and the Rise of MS Risk
The study in question utilized a vast dataset of ancient genomes spanning from the Mesolithic period to the post-Medieval era. By analyzing these genomes, the researchers traced the rise of MS-associated immunogenetic variants to the Pontic steppe pastoralist populations, specifically linked to the Yamnaya culture. Around 5,000 years ago, these pastoralists migrated into Europe, carrying with them genetic variants that would later be associated with a higher risk of developing MS.

Positive Selection and Pathogenic Challenges
Interestingly, the study found that these MS-associated variants underwent positive selection both in the steppe populations and later in Europe. The driving forces behind this selection likely included changes in diet, lifestyle, and increased population density, all of which brought new pathogenic challenges. The transition from a hunter-gatherer lifestyle to one centered on pastoralism and farming introduced new environmental pressures, which, in turn, shaped the genetic landscape of these populations.

The Role of Steppe Ancestry in Modern MS Prevalence
The researchers also explored the modern-day implications of these ancient genetic shifts. By examining the genomes of approximately 410,000 self-identified white British individuals from the UK Biobank, they found that regions with a high proportion of steppe ancestry, particularly those carrying the HLA-DRB1*15:01 allele, exhibited the highest genetic risk for MS. This correlation suggests that the north-south gradient of MS prevalence in Europe may be partly due to the distribution of steppe ancestry across the continent.

Implications for Understanding MS Today
The findings of this study underscore the importance of considering ancient population dynamics and environmental factors in understanding modern diseases like MS. The genetic predispositions to MS that we observe today may be the result of historical processes that began thousands of years ago. As such, these insights offer new avenues for research into MS, particularly in exploring how historical lifestyle changes and pathogenic pressures have shaped the disease's genetic underpinnings.

Conclusion
This study represents a significant advance in our understanding of the genetic origins of MS. By tracing the emergence and evolution of MS-associated genetic variants back to ancient steppe pastoralists, the researchers have provided valuable insights into how the disease's risk factors developed and spread across Europe. These findings not only enhance our knowledge of MS but also highlight the broader impact of ancient migrations and environmental changes on the genetic architecture of modern populations.

Reference:
Barrie, W., Yang, Y., Irving-Pease, E. K., et al. (2024). Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations. Nature, 625, 321-328.