MS: Ancient DNA holds clues about origins and genetic risk

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• Multiple sclerosis (MS) has no cure and affects almost 3 million people worldwide.
• Although experts do not know the precise cause of MS, it has a genetic component.
• A new study uses ancient DNA to track MS risk genes across thousands of years.
• The researchers uncover fascinating links between ancient shifts in lifestyle and MS-related genes.

Multiple sclerosis (MS) is a progressive neurodegenerative condition driven by the immune system. Specifically, the immune system mistakenly attacks and destroys the lining of nerves, called the myelin sheath.

Over time, as more and more myelin is removed, nerves can no longer transmit their signals, leading to mental and physical symptoms.

These symptoms include vision problems, a loss of sensation, and muscle weakness. As the disease progresses, disability becomes steadily more pronounced.

Worryingly, although MS is most common in Northern Europe, its prevalence is increasing globally. Today, it affects an estimated 2.8 million people.

Scientists still do not know why people develop MS, and currently, there is no cure.

However, a fascinating recent study sheds some light on the evolution of the genetic underpinnings of the condition and may, in the future, help move toward better treatments.

Multiple sclerosis and genetic risk

Although scientists are still working on understanding the precise reasons why MS affects some people, genetic risk factors play a role.

Researchers have already identified more than 200 gene regions linked to MS risk, most of which are associated with genes the code for proteins associated with the immune system. As MS is an autoimmune condition, this is perhaps not surprising.

The picture is complex, though. Not everyone with a gene variant associated with MS develops the condition. For instance, the gene variant with the strongest link to MS — called HLA-DRB1*15:01 — increases the risk threefold, but so far our understanding of genetic risk factors only explains around 30% of an individual’s risk of MS.

So, it seems that environmental factors, including infection, might trigger events within the body that eventually lead to MS in people with a genetic susceptibility. However, as it stands, there are many gaps in our understanding.

A fascinating new study in the journal Nature investigates the evolution of some of these MS-related genetic variants. Importantly, it helps answer a long-standing question: Why is MS much more prevalent in people with North European ancestry?

Why do Northern Europeans have a greater MS risk?

To investigate, the researchers compared around 410,000 genetic samples from UK Biobank participants who identified as “white British” with almost 5,000 ancient specimens.

These ancient DNA samples came from the bones and teeth of people living in Asia and Western Europe up to 34,000 years ago.

With these data, they could map the genesis and journey of MS risk variants through human populations. They first spotted the most significant MS risk gene variants — HLA-DRB1*15:01 — in an Italian Neolithic individual who lived around 5,800 Before the Common Era (BCE).

Starting around 5,300 BCE, it increased in prevalence within the Yamanya people. The Yamanya lived in steppe regions in modern-day Ukraine, southwest Russia, and Western Kazakhstan.

Experts consider the Yamanya to be the genetic ancestors of modern inhabitants of North-Western Europe.

These early livestock herders moved steadily west into Europe, bringing HLA-DRB1*15:01 in tow. This helps explain why, even today, people in Northern Europe have a greater risk of developing MS than other populations.

Why did the MS risk gene persist?

Evolution selects for genetic variants that confer specific traits that are favorable for the survival of an organism and its ability to reproduce.

One might imagine that a gene that trebles your risk of developing a debilitating and potentially fatal illness like MS would not be selected for. So, why did the prevalence of this genetic variant increase in the Northern European population, and then persist for millennia?

The authors of the study suggest that when HLA-DRB1*15:01 arrived on the scene, it may have imparted some benefits to these ancient people.

They explain that during the late Neolithic and Bronze Age, infectious disease risk increased. This was partly due to increasing population density.

At the same time, the Yamanya’s close contact with livestock opened them up to a suite of novel pathogens that humans would rarely have encountered before humans domesticated animals.

As the researchers explain, this increased contact with new and old pathogens would have meant that some variants in genes responsible for controlling the immune system could have conferred an evolutionary advantage they previously had not. There may also have been multiple potential effects of these genetic variants over an individual’s lifetime.

For instance, the researchers showed that HLA-DRB1*15:01 helps protect against tuberculosis, which was likely a growing risk at the time as it can be carried by animals. But it also makes carriers more susceptible to a form of leprosy.

Beyond HLA-DRB1*15:01, the scientists investigated a range of other MS-associated gene locations, finding that many were also linked to “protection against a wide range of infectious challenges.”

This includes infections such as those with the Epstein-Barr virus, mumps, chickenpox, influenza, and pneumonia.

‘Astounding’ findings improve understanding of MS

In conclusion, a significant change in these people’s lifestyle resulted in an increased exposure to pathogens, leading to an increased prevalence of MS risk variants in Northern European populations, as it confered protection to infection by these pathogens.

Study co-author Dr. William Barrie, from the University of Cambridge in the United Kingdom, explained in a press release:

“These results astounded us all. They provide a huge leap forward in our understanding of the evolution of MS and other autoimmune diseases. Showing how the lifestyles of our ancestors impacted modern disease risk just highlights how much we are the recipients of ancient immune systems in a modern world.”

Medical News Today discussed the study findings with Dr. Michael Sy, an associate professor of clinical neurology at the University of California, Irvine, who was not involved in this research.

Dr. Sy told MNT he was most excited about the complex implications about the genes highlighted in the study. “As these risk genes appear to affect the immune system, this study adds to the hypothesis that genes which confer an advantage in fighting infections also increase the risk of autoimmune disease,“ he noted.

“For example, another Nature article published in 2022 showed that those who carried a risk gene for Crohn’s disease — another autoimmune disease — were more likely to survive the Black Death,“ he pointed out.

MNT also spoke with Dr. Barbara S. Giesser, neurologist and MS specialist at the Pacific Neuroscience Institute at Providence Saint John’s Health Center in California, not involved in the study, about why its results are important.

Dr. Giesser has worked with people with MS since the 1980s. She explained that: “[n]erve damage in MS is caused by an attack on the immune system on the central nervous system.“

“Much of the immune system is under genetic control, and so any new insights into the genetic blueprint for MS will enable further understanding of how this process is triggered and may lead to more precise and effective therapies,” she added.

“Understanding the origins of MS may one day help identify MS earlier and more effectively prevent any damage to the central nervous system,“ Dr. Sy also noted.

The scientists behind the study now plan on opening their research up further to investigate the ancient origins of other neurodegenerative conditions, such as Alzheimer’s and Parkinson’s disease.

The authors hope these genetic insights will help shape future medical interventions for these difficult-to-treat conditions.