2024-03-26 16:11:19
On January 10, 2024, a very exciting paper was published in Nature that deals with a previously less researched aspect of the autoimmune disease multiple sclerosis. The study involved a large international team led by Professor Eske Willerslev from the Universities of Cambridge and Copenhagen, Professor Thomas Werge from the University of Copenhagen and Professor Rasmus Nielsen from the University of California, Berkeley. With contributions from 175 researchers from around the world.
In MS, the myelin sheaths of the nerve fibers in the CNS are broken down by the immune system, which can lead to sensory impairment. The symptoms appear in spurts and can often resolve at the beginning. However, permanent neuronal deficits can occur later. There is currently no clear explanation as to why the immune system attacks the body, nor is there a cure. However, the course can be slowed down and the symptoms alleviated.
Multiple sclerosis prevalence
Von Lokal_Profil, CC BY-SA 2.5,
MS affects approximately 2.5 million people worldwide, although the incidence varies from region to region. The greatest frequency is found in Europe. Northern Europeans seem to be the most vulnerable here. The aim of the paper was to answer why this is and how this disease was able to spread so widely on a single continent compared to other areas of the world.
Risk factors
In order to answer these questions effectively, the researchers first differentiated between possible risk factors. There are environmental influences such as pathogens and lifestyle influences such as smoking that influence the disease, but also genetic risk factors. Genome-wide association studies (GWAS) have uncovered around 233 common gene variants that promote MS. 32 of these genes are located in the HLA region, the human leukocyte antigen region. The “most dangerous” gene variant HLA-DRB1*15:01 triples the probability of developing multiple sclerosis. Unlike most environmental and lifestyle influences, genetic factors can be inherited and therefore explain spatial distribution well.
ancestors
Today, the ancestral diversity of European populations can be traced back to the following underlying peoples: western hunter-gatherers, eastern hunter-gatherers, Caucasian hunter-gatherers, farmers and steppe dwellers. The paper’s researchers used an enormously large database of genomes from the Mesolithic, Bronze Age and Medieval periods – essentially genomes from the last 10,000 years.
“Creating a gene bank of ancient DNA from early human inhabitants of Eurasia was a colossal project that required collaboration with museums across the region”
Eske Willerslev, professor at Cambridge and co-author of the study.
With the help of this database, they were able to determine which of the populations at that time carried the genetic risk factors and how they spread. They discovered the HLA-DRB1*15:01 gene for the first time in an Italian individual from the Neolithic period, determined by carbon dating to be 5836 BCE. They also found that these genes became increasingly common in the steppe population around 5,300 years ago, during the time of the Yamnaya culture. This steppe population makes up a large part of the ancestry of northern European countries, such as Sweden and Finland. So this is also consistent with these areas having the increased incidence of MS. Ergo, the risk genes appear to come primarily from this steppe population. Conversely, this means that having the steppe population in your own ancestry brings with it an increased likelihood of developing MS.
selection
So after the steppe population was identified as having an underlying ancestry with an increased risk of MS, the researchers asked themselves whether the spread of the risk was due to positive selection, i.e. natural selection. To do this, they used a number of methods, such as CLUES and PALM, and were able to determine that the increased risk of developing MS actually spread through selection in the steppe population. This is done through selection that favors haplotypes with mixed ancestors, i.e. haplotypes that have more than one ancestral population. This mechanism is actually quite well known because ancestral diversity provides some protection against harmful mutations.
Nevertheless, it is interesting that the risk genes for MS have spread through selection, because selection is typically found when it brings an evolutionary advantage, i.e. gives the selected individuals some sort of advantage in survival or reproduction. Intuitively, this is not the case with multiple sclerosis. So the question arises, what advantage should the risk of developing MS bring?
“It must have been a distinct advantage for the Yamnaya people to carry the MS risk genes, even after their arrival in Europe, although these genes undeniably increased their risk of developing MS.”
Eske Willerslev
And this is where the researchers’ answers become speculative, because the databases they used contain too little data. That’s why they were only able to come to their conclusion based on circumstantial evidence. It seems to be the case that the MS risk genes, such as the HLA-DRB1*15:01 gene, not only have the function of promoting MS, but also offer a certain level of protection against other diseases such as tuberculosis or parasites. And these are diseases that became more and more widespread around 5,000 years ago because the population density became greater and mutual infection became more and more likely. As a result, these genes conferred a certain advantage over their less effective variants and were thus spread through positive selection.
conclusion
Multiple sclerosis is much more common in northern areas of the world, such as Sweden, Finland and Norway. The cause of this exciting phenomenon was unclear for a long time until the paper was published on January 10, 2024. The scientists found that most of the risk genes appeared for the first time with an increased probability in the steppe population, which is the ancestor of the northern European populations. They have now identified the underlying ancestors, but the next question was why the steppe population develops these risk genes in greater numbers compared to the other populations that do not. Do these genes have an evolutionary advantage? Actually yes, they have. In addition to their risk function, they also provide a certain level of protection against diseases such as tuberculosis and parasites. And this protection became more and more important as some diseases became more and more dominant due to environmental influences and lifestyle. The MS risk genes have undergone positive selection and can still be found in the descendants of the steppe population today.
If interested
Multiple Sclerosis: Between Research and Clinic, Multiple Sclerosis: Inflammation and Neurodegeneration, Multiple Sclerosis: The Disease with a Thousand Faces, A Dose of Myelin, Please! – Vaccination against multiple sclerosis, Multiple sclerosis, Can kisses lead to multiple sclerosis?
Sources
Barrie , W. , Yang , Y. , Irving-Pease , EK , Attfield , KE , Scorrano , G. , Jensen , LT , Armen , AP , Dimopoulos , EA , Stern , AJ , Refoyo-Martinez , A. , Pearson , 2005 . A., Ramsøe, A., Gaunitz, C., Demeter, F., Jørkov, ML, Møller, SB, Springborg, B., Klassen, L., Hyldgård, IM, . . . . . . . . . Willerslev, E. (2024). Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations. Nature, 625(7994), 321–328.
News-Medical. (2024, January 15). Ancient genomes reveal origins of multiple sclerosis risk in Europe.
Wexler, M. (2024, January 12). Ancient DNA reveal how MS risk genes spread across Europe. Multiple Sclerosis News Today.
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