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What were the origins of the genetic mutations that cause Multiple Sclerosis? Were they advantageous in the past? I have been working on these questions for the past year, and am delighted to share our new preprint! A short 🧵: bit.ly/3DWfP5r
This work began when we noticed that the modern distributions of MS and 'Steppe' ancestry (more on this soon) showed strikingly similar patterns - high in northern Europe, decreasing further south. 
To investigate, we used DNA from ~1500 ancient human skeletons combined with 'local ancestry' scores for ~410,000 individuals in the UK Biobank - i.e. an estimate of the ancestry of each genetic position in each modern individual.
Europeans are descended from genetically distinct populations or “ancestries” that existed in the last ~15,000 years: Eastern/Western/Caucasus Hunter-Gatherers, Neolithic Farmers, and Steppe. This last one is important! 
The first thing we did was simple: plotting the frequency of DRB1*15:01 in various populations back in time. This allele carries the single highest risk for MS (OR ~3). The outcome was surprising: from being almost non-existent, it rose sharply during the Bronze Age and later. 
We then calculated the risk of having a particular ancestry at sites in the genome we already know are associated with MS. The results were again striking: Steppe ancestry increased risk while the other ancestries often decreased it. Work by PhD student @Donny69994464 
This means that if you inherit these parts of your genome from the ancient Steppe population, you have an increased risk of developing MS. We showed that this was often a better predictor than genotypes.
We also calculated an aggregate risk score for each ancestry: if a modern individual consisted entirely of one ancestry, what would their risk for MS look like? Again, the pattern was clear. 
So, we had established a clear link between Steppe ancestry in modern people and MS risk. But what was driving this signal? Had these genetic variants been advantageous in the past? To investigate this, we looked at evidence for natural selection.
This involves reconstructing allele frequency trajectories backwards in time in different 'ancestral paths' while controlling for admixture. There are some amazing technical details under the hood that I won't go into here. This work was done by @EvanIrvingPease. 
For example, the four tag SNPs for DRB1*15:01 show that it rose in frequency, mainly in the Caucasus-Hunter Gatherer ancestry path. This ancestry constitutes about 50% of Steppe ancestry, confirming what we suspected: selection for DBR1*1501 occurred in the Steppe. 
When we tested all the SNPs together, we found a clear signal that MS risk was selectively increased 5,000-2,000 years ago. We can plot how the total risk changes over time, which shows this very nicely: 
Something was going on in this period causing selection for these genetic variants that now increase the risk of MS. Many of these are located in or next to immune-related genes, suggesting that novel exposure to pathogens and other environmental pressures drove this.
The Early Bronze Age was a time of massively increased infectious diseases, due to increased population density and contact with domesticated animals. Many diseases trace their origins to this period, such as tuberculosis (TB), bubonic plague, herpes, and chickenpox.
We systematically documented the associations that these selected variants had with specific pathogens (virus, bacteria, fungi and parasites) and/or infectious diseases. 82% had such an association. 
The Steppe population was the first truly pastoralist population in Europe, and would have had massively increased exposure to domestic animals like cows and horses, dairy products and meat consumption. Each would have been accompanied by increased novel pathogen exposure.
We suggest that co-evolution between pathogens and humans resulted in divergent ancestry-specific selection on immune genes, which inadvertently drove an increase in genetic risk for MS. This has left a legacy of heterogeneity in MS risk observed across Europe today.
Today, with increasing prevalence of MS over the last five decades, we again observe a correlation with changes in our environment. The fine balance of cells within the immune system appears disrupted by these changes, perhaps partly by the developed world’s increased sanitation.
The Bronze Age was critical as a determinant of modern immune responses. The emergence of the pastoralist Steppe lifestyle may have had an impact on immune response as great as or greater than the emergence of farming, held to be the greatest lifestyle change in history.
There is loads more in the paper so please give it a read/share! I've spent the past year working on this with an amazing team - so thank you to Lars Fugger, @danjlawson, @EvanIrvingPease, @Donny69994464, @GabrieleScorran, Kate Attfield, Lise Torp Jensen, Astrid Iversen,
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Nicholas A. Christakis @NicholasAChristakis
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Sep 27, 2022
Wonderful work & thread showing that co-evolution between pathogens and humans ~2-5,000 years ago likely resulted in divergent ancestry-specific selection on immune genes, which incidentally drove increase in genetic risk for Multiple Sclerosis (upon infection with EBV, usually).