Researchers uncover the evolutionary origins of multiple sclerosis

A team of researchers based at the Universities of Oxford, Cambridge, Copenhagen, Bristol and California (Berkeley) recently published a study investigating the evolutionary origins of multiple sclerosis (MS). 

MS is a chronic autoimmune disease characterised by the immune system attacking the brain and spinal cord. Though it cannot be cured, various treatments exist to alleviate some of its symptoms. The lifelong condition has several symptoms, some of which include fatigue, vision impairment, mobility issues, and cognitive difficulties. It affects more than 2.5 million people globally and is a leading cause of disability in young adults. 

Seeking to better understand the genetic origins of MS, the researchers came together to sequence ancient human genomes and uncover evidence that the genetic risk for the condition has been shaped by pathogen-driven evolution. The massive project had been in the works for many years, featuring the work of local and international collaborators. 

In an interview with senior co-author Dr. Lars Fugger (Department of Clinical Neurosciences), he discussed the study and its implications.

“MS has been, and still is, an enigmatic disease,” Dr. Fugger said. “We have been aware of risk genes for a number of years, but it’s unclear where the genes came from.” 

In the past, technical issues have limited research on autoimmune disease aetiology. Dr. Fugger added that the maturation of sequencing technology for ancient DNA samples was required before studies such as this one could advance.

With the availability of greater technological capacity, the team was able to extract ancient DNA from human petrous bones and teeth. The ages of the samples ranged from the eleventh to eighteenth centuries. 

Through analysing the DNA, it was uncovered that the migration of pastoralist herders from the Pontic-Caspian Steppe, a region spanning across Eastern Europe to Central Asia, introduced the genetic variants responsible for increasing the risk of MS into Western Europe. This group of herders, recognised as the Yamnaya people, migrated approximately 5,000 years ago. Before this migration took place, however, the population began domesticating animals, a practice which contributed to the ability to migrate.

“This population underwent a huge societal lifestyle change,” Dr. Fugger said. “They were domesticating animals, and they were living with these animals 24/7. Living with animals like they did means you will be exposed to all kinds of pathogens.” 

Consuming potentially undercooked meat and unpasteurised milk products greatly increased exposure to pathogens such as bacteria, viruses, worms, and parasites, he added. 

“That lifestyle change was also a story of survival of the fittest.”

Dr. Lars Fugger

“That lifestyle change was also a story of survival of the fittest,” Dr. Fugger continued. “Individuals who could handle the bombardment of all these pathogens, all these microorganisms, would of course have been the survivors.”

These genes were consequently selected for over time. The genetic variants provided an advantage to the Yamnaya people to protect against pathogens and other infectious diseases, likely those associated with domesticated animals and their products. As a result of the Yamnaya-related migration, the pastoral herders mixed with the populations of Europe which predominantly had a farmer-based genetic makeup. 

The late Neolithic and Bronze Ages thus marked a period of increased population mixing between divergent genetic and cultural groups. It was also characterised by a high rate of disease infections caused by increased population density and contact with domestic animals. The Steppe genetic variants have continued to survive in DNA because of the protection they have historically provided. 

Generally speaking, autoimmune diseases such as MS have increased in frequency over the last few decades. While medical experts recognise that environmental and lifestyle factors have contributed to the genetic risks of these conditions, they have traditionally held a limited understanding of the genetic ancestry and origin behind these risks. In the case of MS, its geographical concentration has also been a mystery. The prevalence of MS varies depending on ethnicity and geographical factors, but it is most commonly observed in Europe, particularly among Northern Europeans. 

This intermixing in Europe helps explain why MS is more prevalent in the northern hemisphere and commonly observed in individuals with Nordic or European ancestry. The issue, however, is that these genetic variants that have survived through human evolutionary history because of the protection they afforded now increase the likelihood of developing MS. 

“We don’t have the same load of pathogens today,” Dr. Fugger said. “These genes were selected in one context. They are now cast in a completely different context because the environment has changed.”

With the advent of modern advancements that enable better hygiene and disease prevention, as well as changes in lifestyle, environment, and diet, these genetic variants make individuals more susceptible to autoimmune diseases such as MS. Previously beneficial genetic variants interact differently in today’s context. This was demonstrated by comparing the ancient DNA to the UK Biobank, a biomedical database that holds genetic data from half a million volunteer UK participants.

“The genes the MS patients carry are normal genes.”

Dr. Lars Fugger

“The genes the MS patients carry are normal genes,” Dr. Fugger said. “They are not dangerous per se because they are not mutations. It shows you what a massive role the environment is playing.” 

The aim of the study was to demystify the disease, he added. It seeks to reduce misconceptions about the chronic condition and reveal a broader evolutionary story of adaptation behind its genetic risk. Similarly, it poses implications for autoimmune disease treatment.

“The therapy we’re using today to treat MS patients is based on suppressing the immune system,” Dr. Fugger said. “This study is showing that, going forward, another way of treating MS patients instead of suppressing the immune system is to recalibrate it. When you suppress the immune system, you will have infections as a side effect.”

The research team is now continuing its investigations of genetic evolutionary history with other conditions such as Parkinson’s and Alzheimer’s disease. Unravelling the genetic origins of diseases helps medical experts better understand and develop treatment for them, while simultaneously empowering patients to gain a deeper understanding of their own conditions.

Image credit: Freepik

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