In a major study, researchers examined ancient DNA in the search for the origins of genetic risk variants for developing multiple sclerosis (MS). The genetic variants originated from pastoralist nomads who migrated to and populated Europe between 5,000 and 6,000 years ago. They were found to protect the ancient populations from several infectious diseases and thereby gave them a survival advantage.
Approximately 230 genetic variants are associated with developing MS, and these are quite common in much of the European population, especially among people of northern European origin.
This suggests that these variants underwent positive selection in the past by giving the prehistoric ancestors in Europe a survival advantage; otherwise, they would have been deselected through evolution.
A new major research study reveals the origin of the elevated genetic risk for developing MS and why having the genetic risk variants was probably an advantage for these prehistoric European people.
The research suggests novel opportunities for helping people with MS today by incorporating knowledge about the effects of risk variants in the past.
“This understanding might bring us closer to developing methods to rebalance the immune response so that the immune system does not attack the body itself in a way that ultimately leads to MS. The possibility of developing more targeted therapy might result in drugs with potentially fewer side-effects than the drugs currently used to treat people with MS,” explains a researcher behind the study, Astrid Iversen, Professor, Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, United Kingdom.
The research has been published in Nature.
Multiple traits associated with genetic MS risk variants
About 20% of the people originating in northern Europe have the genetic variant most strongly associated with the development of MS versus many fewer people in southern Europe.
Many of the genetic risk variants are quite common, and having many of them, plus being exposed to environmental risk factors, can lead the immune system to attack the body itself.
A well-known environmental MS risk factor is infection with Epstein-Barr virus, especially after the age of 18 years.
The researchers primarily aimed to discover the origin of the genetic predisposition to developing MS and therefore analysed the genetic data from a large data set of 1,300 ancient genomes from all of Europe from 12,000 years ago until a few centuries ago.
Europe’s population turned over several times
One group of hunter-gatherers originally populated prehistoric eastern Europe and another group western Europe.
Between 9,000 and 6,000 years ago, however, these hunter-gatherer populations were replaced by Neolithic farmers from the Anatolian highlands of present-day Turkey. The farmers slowly moved northward and westward through Europe, where they either replaced or assimilated with the existing populations.
About 5,000 to 6,000 years ago, the entire population of Europe came under pressure from the Yamnaya, nomadic pastoralist migrants originating from the Pontic Steppe (now Ukraine, southwestern Russia and western Kazakhstan) who travelled west and north.
The Yamnaya had large herds of livestock and also horses and carts, which enabled them to be very mobile. Their skin colour was fairer than the prevalent populations, and they were significantly taller and more robust than the agricultural populations.
The Yamnaya migrated to Europe from the east and relatively rapidly and often violently replaced or assimilated with the existing European populations. In northern Europe, they almost completely replaced the Neolithic farmers who lived there, whereas there was more assimilation in southern Europe.
The arrival of farming and pastoralist populations in Europe meant that the European people today have varying amounts of DNA from the original hunter-gatherers and agriculturalists. Modern northern Europeans, for example, have considerable amounts of Yamnaya DNA in their genome, and this proportion is smaller in southern Europe, where farmer ancestry predominates.
The Yamnaya brought diseases with them
The Yamnaya migration might also have changed the pathogenic landscape in Europe.
In the past, when Europeans lived in small hunter-gatherer groups, the conditions were not favourable for transmission of many infectious diseases.
Diseases such as rubella, measles and influenza (also called crowd diseases) spread poorly among the small hunter-gatherer groups and in isolated farming communities with very few individuals.
Agriculture resulted in population increases and the establishment of large communities which, together with limited livestock keeping and the use of human and animal excrement as fertilisers, increased the infection pressure from bacteria, viruses and parasites.
The communities that arose in Europe following the Yamnaya migration were even larger. The Yamnaya kept much larger herds of cattle, horses, sheep and goats than the Neolithic farmers and lived in close proximity to them; their diet was almost entirely restricted to meat and dairy products. This increased the risk of zoonotic transmission of viruses, bacteria and parasites from animals to humans, and both old and new diseases began to spread.
“Being exposed to all these diseases put a lot of pressure on people’s immune system. Many probably died, but those who survived must have carried genetic variants that enabled them to effectively fight the infections,” says Astrid Iversen.
Genetic MS risk originated primarily from the Yamnaya
The analysis of ancient genomes revealed that many of the genetic variants associated with an increased risk of developing MS originated from the Yamnaya.
This also helps to explain why more northern Europeans than southern Europeans develop MS, since the former carry much more Yamnaya DNA.
HLA-DRB1*15:01 is a prominent HLA variant associated with MS. It was strongly selected in the Yamnaya, giving them a survival advantage, even though it is now associated with a considerably increased risk of developing MS.
Astrid Iversen explains that although HLA-DRB1*15:01 is associated with an increased risk of developing MS, it is also associated with some protection from various types of infectious diseases, such as tuberculosis, gastrointestinal infections and sexually transmitted infections.
“Until 200 years ago, 25% of children died before reaching one year old. A further 25% died before they turned 15 years. Infectious diseases caused many of these deaths. European ancestors, therefore, had a huge advantage if they had genetic variants that protected them better against various infectious diseases, since it improved children’s survival – even though the same genetic variants also increased the risk of developing MS later in life. Whether MS was even a problem in the past is unknown, since approximately 70% of the risk of developing MS stems from environmental factors and only 30% of the risk is genetic,” explains Astrid Iversen.
Immune system imbalanced
There may also be a good explanation for MS remaining as one of the genetic legacies of the Yamnaya.
The immune system has two responses to external threats: TH1 and TH2.
TH1 responses are proinflammatory responses to bacteria and viruses, whereas TH2 responses are anti-inflammatory responses, such as those triggered by a parasitic infection (until two centuries ago, parasitic infections were widespread and could last for decades).
The two types of responses counteract each other, so that an anti-inflammatory TH2 response reduces the effectiveness of a proinflammatory TH1 response. These can be visualised as weights on a seesaw. Responding effectively to a viral or bacterial infection with an adequate proinflammatory response requires the immune system to make an extraordinary proinflammatory response to counteract the hampering effect of the anti-inflammatory response.
This mechanism works effectively when the immune system is in balance, and Astrid Iversen says that this is relevant for MS.
“Our immune system is adapted to be in balance and works optimally in an environment with many viral, bacterial and parasitic infections. Today, however, the conditions are very different, because hygiene is better and we have few, if any, parasite infections. This means that the extraordinary response of the immune system to viral or bacterial infections can become so strong that it increases the risk of attacking the body itself, which can result in autoimmune disease, such as MS among people with a genetic predisposition.”
She elaborates that even though people in the past had a genetic risk of developing MS, many probably did not develop it because their immune system was very busy fighting viruses, bacteria and parasites, perfectly balanced to perform this task.
“But living conditions have changed, and this study is demystifying MS, because we now understand that the disease risk did not just suddenly appear but has arisen based on genetic variants being better adapted to another environment than the one most people live in today,” adds Astrid Iversen.
May lead to new types of treatment
Astrid Iversen explains that this realisation may pave the way for new ways of treating people with MS. Today, people with MS are treated with drugs that effectively disable large parts of the immune system and have potentially severe side-effects.
However, the new study indicates that the immune system of people with MS may benefit from restoring the balance in the immune system.
In fact, some researchers and doctors have investigated the possibility of infecting people with MS with parasites from pigs, because this can provide the immune system with a balance between viral and bacterial infections versus parasitic infections, under which the immune system probably works best. However, the new study also cautions about this.
“Experiments with parasites from pigs have been small scale and the results have been inconclusive. However, we have found that the genetic risk of developing MS comes from the Yamnaya, and we know that they kept horses, sheep, goats and cows, but not pigs. This suggests that infecting people with MS with parasites derived from, for example, cows and horses may make more sense,” explains Astrid Iversen.
She elaborates that if such studies were to yield good results, then the long-term aim would be to identify the relevant antigens in parasites from horses and cows, so that instead of infecting people with MS with parasites, they could receive a drug that could restore the balance of the immune system.
“People with genetic variants associated with MS would probably have survived very well in the past, but today they are genetically predisposed to develop a terrible disease. Understanding ancient European ancestry may enable us to find solutions for the future. Moreover, our study demonstrates how the genetics and habits of our ancestors continue to shape our health today.”, concludes Astrid Iversen.
