Multiple sclerosis is an autoimmune disease that pushes the body’s immune defenses to attack the central nervous system, damaging the sheath that insulates the nerve fibers. It is a multifactorial disorder, in which multiple causes interact with each other to give rise to the disease. Among these, some genetic variants that increase the risk of suffering from multiple sclerosis by up to three times for those who carry them, particularly common in the European population, especially in the Nordic countries. New research published in recent weeks in Nature has mapped the evolutionary origin of these genetic variants, revealing that they are most likely the legacy of the ancient shepherds who lived in the Pontic steppes five thousand years ago, a region between Asia and Eastern Europe (which today includes Ukraine, southern Russia and Kazakhstan), and that these now harmful mutations have spread, reaching us, because they originally had positive effects for their carriers.
A multifactorial disease
As we said, multiple sclerosis is a disease that does not have a single cause. It is not a hereditary disease, for example, and therefore there is no single gene, or set of genes, that makes those who suffer from it ill. But at the same time, there is still a certain genetic family relationship so that in some families multiple sclerosis has a much higher incidence than in common. Currently, science has discovered 233 genetic variants that increase the risk of developing the disease, and all together it is believed that they explain approximately 30% of the absolute risk of suffering from multiple sclerosis. The rest is done by the environment, as in the case of an infection with the Epstein–Barr virus (relatively common, but capable of increasing the chances of developing multiple sclerosis by 32 times), and by lifestyles, for example the smoking and obesity during adolescence.
In Europe there is also a certain North-South gradient in the incidence of the disease, which makes it relatively more common in Nordic countries compared to Mediterranean ones, also linked to a greater presence of genetic risk factors in Northern European populations. A gene variant identified by the acronym HLA-DRB1*15:01, for example, is present in the genome of a fifth of Northern Europeans, and increases the chances of developing multiple sclerosis threefold. In their new study, researchers led by William Barrie, from the University of Cambridge, decided to investigate where these genetic variants come from, and why they are still present so often in the DNA of Europeans, despite the fact that they are clearly harmful.
To do so, the scientists combined 86 newly sequenced genomes from medieval and post-medieval Denmark, combining the data with that of more than 1,500 ancient genomes collected at archaeological sites across Europe, to obtain a reference genetic database that captures variants genetics that appeared on our continent over a period of over 10 thousand years. At this point, they drew on the UK Biobank (a repository that contains thousands of genomes of English citizens accompanied by information on their health), analyzing 410 thousand modern DNAs to see how similar they were to those of ancient Europeans, and how much these similarities were associated with the risk of developing multiple sclerosis.
The results, according to Barrie, were surprising. The analyzes have in fact revealed that the modern Finnish, Swedish and Icelandic populations present the greatest genetic similarities with those of the so-called Yamnaya culture, which inhabited the Pontic steppes over five thousand years ago. And the greater the similarities with these ancient European ancestors, the higher the genetic risks of developing multiple sclerosis. Having identified the origin of the variants that predispose to the risk of developing the disease, all that remained was to find out if and what role they originally played.
The immune hypothesis
The researchers’ analyzes showed that some of the genetic variants that confer a risk for multiple sclerosis have become more frequent in European populations over the last 5,000 years. It is therefore probable that they have been subjected to what is called positive selection, that is, that in the course of evolution they have been favored by natural selection for some adaptive advantage that they provide to their carriers.
At this point we enter the field of hypotheses, but Barrie believes that the genes in question could probably have had a protective effect against infections in a critical period of the cultural evolution of our species, in which the birth of agriculture and pastoralism have enormously increased the size of human settlements, and therefore the likelihood of epidemics. Multiple sclerosis is an autoimmune disease, in which excessive activation of the immune system leads it to attack cells and molecules in our body. In this context, a genetic variant that enhances the immune system can therefore be harmful, increasing the likelihood that we will mistake our own cells for an intruder. But faced with the risk of infections, paradoxically, the same variant could instead have a positive effect, making the body more capable of fighting invading microorganisms.
It is therefore possible that in the first, ancient, European cities, some genetic mutations provided our ancestors with a greater ability to resist epidemics caused by an increase in population density. And today the same genetic variants instead expose European populations, particularly in northern countries where they are more widespread, to a greater risk of developing multiple sclerosis. An undoubtedly fascinating hypothesis, which however will require further research in the future to be demonstrated.