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‘Colossal’ study of ancient human DNA reveals startling reason why northern Europe has highest rate of multiple sclerosis





An astonishing study of the DNA from almost 5,000 humans that lived up to 34,000 years ago has shed light on why there are higher rates of multiple sclerosis (MS) in Europe.

A team of 175 researchers from around the world - co-led by the University of Cambridge’s Prof Eske Willerslev - sequenced ancient DNA from bones and teeth and compared it to modern-day samples to map the spread of genes and diseases over time as populations migrated.

The Porsmose man from the Neolithic period, found in 1947 in Porsmose, Denmark. Picture: The Danish National Museum
The Porsmose man from the Neolithic period, found in 1947 in Porsmose, Denmark. Picture: The Danish National Museum

Four research papers, published in Nature, report the findings from the creation of the world’s largest ancient human gene bank, including

- the origins of neurodegenerative diseases including MS;
- why northern Europeans today are taller than those from southern Europe; and
- how genes known to increase the risk of diseases such as Alzheimer’s and type 2 diabetes can be traced back to hunter gatherers.

Further analysis of the findings could reveal more about the genetic markers of autism, ADHD, schizophrenia, bipolar disorder and depression.

Perhaps the most startling discovery was how genes that increase an individual’s risk of developing MS were introduced into north-western Europe around 5,000 years ago by sheep and cattle herders migrating from the east.

It is believed the genes provided a survival advantage to the herders - the Yamnaya people - by protecting them from catching infections from their sheep and cattle. But it also increased their risk of developing MS - and today northern Europe has the highest rate of MS in the world.

“It must have been a distinct advantage for the Yamnaya people to carry the MS risk genes, even after arriving in Europe, despite the fact that these genes undeniably increased their risk of developing MS,” said project director Prof Willerslev, a fellow of St John’s College, Cambridge, who is also based at the University of Copenhagen. “These results change our view of the causes of multiple sclerosis and have implications for the way it is treated.”

Prof Eske Willerslev. Picture: University of Copenhagen
Prof Eske Willerslev. Picture: University of Copenhagen

The scientists made the discovery by analysing the DNA from bones and teeth at documented locations across Eurasia to trace the geographical spread of MS from its origins on the Pontic Steppe - a region spanning parts of what are now Ukraine, south-west Russia and the west Kazakhstan region - where the livestock herders originated.

The age of the specimens studied ranges from the Mesolithic and Neolithic periods through to the Bronze Age, Iron Age and Viking period into the Middle Ages, with the oldest genome dating back to an individual who lived about 34,000 years ago.

The Yamnaya people are believed to be the ancestors of present-day inhabitants of much of north-western Europe and had a much weaker genetic influence on today’s population of southern Europe.

It solves a long-standing mystery of the ‘north-south gradient’, which describes how there are about twice as many modern-day cases of MS in northern Europe than southern Europe.

A Yamnaya bronze relief. Evolution to cope with pathogen pressures in the Bronze Age impacts genetic risk for multiple sclerosis today. Picture: SayoStudio
A Yamnaya bronze relief. Evolution to cope with pathogen pressures in the Bronze Age impacts genetic risk for multiple sclerosis today. Picture: SayoStudio

Earlier studies have identified 233 genetic variants - also affected by environmental and lifestyle factors - that increase an individual’s risk of developing MS by around 30 per cent.

The new research found the modern-day genetic risk profile for MS was present in bones and teeth that are thousands of years old.

“These results astounded us all,” said Dr William Barrie, a postdoc in the University of Cambridge’s Department of Zoology and co-author of the paper. “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.”

MS, a neurodegenerative disease, involves the body’s immune system attacking the ‘insulation’ that surrounds nerve fibres in the brain and spinal cord, causing relapses of symptoms and longer-term degeneration, known as progression.

Prof Lars Fugger, a co-author of the MS study professor and consultant physician at John Radcliffe Hospital, University of Oxford, said: “This means we can now understand and seek to treat MS for what it actually is: the result of a genetic adaptation to certain environmental conditions that occurred back in our prehistory.”

Prof Astrid Iversen, a fellow co-author based at the University of Oxford, added: “We now lead very different lives to those of our ancestors in terms of hygiene, diet and medical treatment options and this combined with our evolutionary history means we may be more susceptible to certain diseases than our ancestors were, including autoimmune diseases such as MS.”

A mixing pot – ancient steppe (top), farmer (middle) and hunter-gatherer (bottom) populations mixed to form present-day Europeans. Picture SayoStudio
A mixing pot – ancient steppe (top), farmer (middle) and hunter-gatherer (bottom) populations mixed to form present-day Europeans. Picture SayoStudio

Analysis of the bones and teeth, held in museum collections, enabled researchers at the Lundbeck Foundation Geogenetics Centre at the University of Copenhagen to create the first gene bank of its kind over five years with €8million funding from the Lundbeck Foundation. The data was compared to modern DNA from 400,000 people living in Britain, held in the UK Biobank.

“Creating a gene bank of ancient DNA from Eurasia’s past human inhabitants was a colossal project, involving collaboration with museums across the region,” said Prof Willerslev. “We’ve demonstrated that our gene bank works as a precision tool that can give us new insights into human diseases, when combined with analyses of present-day human DNA data and inputs from several other research fields. That in itself is amazing, and there’s no doubt it has many applications beyond MS research.”

Other neurological conditions will now be investigated, including Parkinson’s and Alzheimer’s diseases, and psychiatric disorders including ADHD and schizophrenia.

Disease researchers across the world have also requested access to the ancient DNA profiles, and the ultimate aim is to make the gene bank open access.

Another of the Nature papers published reports that genetic differences between ancient populations in western Eurasia were substantially higher than previously estimated, and much higher than in present-day populations.

The Porsmose man from the Neolithic period, found in 1947 in Porsmose, Denmark. The Danish National Museum
The Porsmose man from the Neolithic period, found in 1947 in Porsmose, Denmark. The Danish National Museum

And a further paper overturns the commonly-held view that the ancestors of present-day Danes were Stone Age hunter-gatherers. It follows analysis of DNA from 100 skeletons of the prehistoric inhabitants of the region now known as Denmark - who lived between 10,000 years ago and 2,700 years ago. It shows that since the last Ice Age around 12,000 years ago, Denmark has experienced two near-total population turnover events.

Around 5,900 years ago, farmers with genetic roots in Anatolia - the Asian part of present-day Turkey – brought a new farming culture to Denmark which led to changes in diet, and they completely replaced the hunter-gatherers in the region. Then 5,000 years ago, the Anatolian farmers were eliminated by the arrival of the Yamnaya people, who are the closest ancestors of present-day ethnic Danes.

The international team was also led by Prof Thomas Werge at the University of Copenhagen and Prof Rasmus Nielsen at University of California, Berkeley.

Genetic traits from our ancestors

New insights into our genetic histories have been revealed by comparing DNA from 1,664 archaeological skeletons of the prehistoric inhabitants of the Eurasia to profiles of present-day Europeans,

The ancient DNA ranges in age from the Mesolithic (Middle Stone Age) to around 1,000 BC.

Dr. Evan Irving-Pease, at The Globe Institute, University of Copenhagen, first author of a second Nature paper on the new findings, said: “It’s striking that the lifestyles of the people in the Eurasian region over the last 10,000 years have resulted in a genetic legacy that impacts their present-day descendants, in terms of both their physical appearance and their risk of developing a number of diseases.”

They found:

- the genetic predisposition of north-western Europeans to be taller than southern Europeans is likely to have come from the Yamnaya people.

- our disease risk is influenced by how much DNA a person has from the ancient populations that migrated across Eurasia after the last Ice Age. Southern Europeans typically have a lot of ancient farmer DNA, meaning they are genetically predisposed to developing bipolar disorder, while north-western Europeans carry more genetic risk for multiple sclerosis, and Eastern Europeans have an increased genetic risk of developing Alzheimer’s and type 2 diabetes.

- lactose tolerance - the ability to digest the sugar in milk and other dairy products – emerged in Europe around 6,000 years ago.

- the ability to prosper on a vegetable-rich diet was coded into the genes of Europeans by the dawn of the Neolithic Age, around 5,900 years ago.



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