In a recent publication in the journal Nature, scientists explored the factors influencing the varying prevalence of multiple sclerosis (MS) across different geographical regions. The study delved into the role of genetic and environmental factors in the development of the disease.
Most commonly found in Northern Europe, multiple sclerosis is a neurological condition with a relatively unclear hereditary risk. This condition impacts the brain and spinal cord, and its prevalence shows variations based on ethnicity and geographical location. Scientists hypothesize that multiple sclerosis is triggered by interactions between gene-gene, and gene-environment, where external triggers initiate a cascade of reactions in individuals genetically predisposed to the condition.
The risk of illness is significantly influenced by environmental and lifestyle factors, contributing to approximately 30% of the overall disease risk. The European genetic background might offer insights into the global differences in multiple sclerosis prevalence observed among diverse populations.
In this study, researchers utilized an extensive ancient genomic dataset spanning from the Mesolithic and Bronze Ages to Medieval and post-Medieval Ages. They aimed to calculate current European ancestry relative to ancestral populations. They investigated whether polymorphisms associated with increased risks of multiple sclerosis (MS) underwent positive selections and lifestyle-specificity of the selection targets.
The study delved into environmental factors that might have influenced the selection of risk variations, including pathogen exposure and human subsistence practices. The team assessed the ancestry at specific loci (local ancestry) for 410,000 white British individuals registered with the United Kingdom Biobank (UKBB), using reference panels of 318 DNA samples from the Neolithic and Mesolithic periods, which included steppe pastoralists.
Anomaly scores were calculated by comparing ancestry at single-nucleotide polymorphisms (SNPs) to genome-level ancestries in the UKBB. The study focused on the human leukocyte antigen (HLA) site, which is significantly related to autoimmune disorders such as multiple sclerosis and rheumatoid-type arthritis (RA), characterized by systemic inflammation that predominantly affects body joints.
The dataset included 1,750 imputed diploid shotgun-sequenced ancient genomes, with 1,509 belonging to Eurasia. Combining this data with current information created a comprehensive transect spanning approximately 10,000 years.
Researchers investigated whether ancestry could predict phenotypes, introducing a new summary measure termed linkage disequilibrium of ancestry (LDA). They explored LD-pruned MS-associated SNPs that shows statistically significant evidence for selection in one or more ancestries using CLUES (n = 32) and had a genome-wide meaningful trait relationship. Findings were compared between MS and RA - a systemic inflammatory disease known for distinctive joint abnormalities - through a thorough literature search for pleiotropic effects of LD-pruned SNPs that exhibit statistically significant evidence of selection. They did this in order to understand the factors underlying the higher genetic risk in hunter-gatherer groups and subsequent negative-type selection.
The result of the study pointed that the genetic risk for multiple sclerosis originated among pastoralists from the Pontic Steppe around 5,000 years ago, and introduced to Europe via Yamnaya-related migration. Positive selection of MS-associated immunogenetic variations occurred within the steppe population and subsequently in Europe, likely due to pathogenetic difficulties coinciding with altered nutrition, lifestyle, and population density. Notably, the LCT/MCM6 area on the second chromosome, recognized as controlling lactase persistence, and the HLA region on the sixth chromosome showed the most extreme ancestry compositions.
Steppe ancestry exhibited the highest risk ratio at all HLA SNPs for MS. The farmer and outgroup ancestries were often the most protective, indicating that a steppe-derived haplotype at these sites increases MS risk. The study revealed that steppe ancestry had the highest ARS for MS, followed by Caucasus hunter-gatherers (CHG), western hunter-gatherers (WHG), and eastern hunter-gatherers (EHG) ancestry. The farmer and outgroup ancestry had the lowest ARS. This means that the steppe ancestry has the highest risk for MS across related SNPs.
The study population, consisting of self-identified white British individuals, was somewhat underpowered concerning MS (1,949 cases and 398,049 controls; 0.49% prevalence). However, MS associations were observed in the HLA region with steppe and farmer ancestry. Local ancestry explained more variance than genotypes in three out of four main LD blocks within the HLA region.
Evidence suggested that disease risk was selectively higher between 5,000 and 2,000 years ago, with significant selection signals in the WHG, EHG, and CHG routes but not in the ANA path. This finding was closely linked to the steppe's pastoralist population with approximately equal amounts of EHG and CHG ancestry.
The study identified a specific ancestral risk profile for RA, with HLA-DRB1*04:01 being a significant genetic risk factor. WHG and EHG ancestry often presented the highest risk at SNPs related to RA, contributing the most risk overall. Most selected SNPs showed associations with protection against specific pathogens and infectious diseases across all pathways.
In summary, the study highlighted the substantial impact of the Neolithic and Bronze Age periods on current immune responses and the likelihood of developing MS in a changing environment. Extreme lifestyle changes over 10,000 years contributed to a diverse genetic lineage, resulting in the highest genetic risk for MS in current times. Positive selection coincided with pastoralist lifestyles in the Pontic-Caspian steppe, and continued selection in admixed populations in Europe shaped this heritage.
The study addressed the dispute over the north-south gradient in MS incidence in Europe, proposing that pathogen-human co-evolution led to high and varied genetic ancestry-specific selection on immune response genes.