Scientists uncover multiple sclerosis gene origins

farmed cows

The genetic origins of a devastating immune disorder, multiple sclerosis, may lie in crop and animal domestication. Photo credit: Annie Spratt via Unsplash

Researchers have uncovered the origins of the genes responsible for multiple sclerosis (MS), a life-changing condition affecting the brain and spinal cord. Four revolutionary papers released in the scientific journal Nature in January of this year detail how the migration of ancient populations may have driven the spread of specific genes, including those underpinning MS, and offer insight into why these genes would have been important at the time.

Almost 3 million people are estimated to have MS worldwide. As an autoimmune condition, MS is caused by the body’s own immune cells mistakenly attacking the nervous system, causing symptoms such as visual disturbances, problems with balance and coordination, and extreme fatigue. There are different types of MS, where symptoms either come and go in episodes known as relapses, or steadily worsen over time without periods of remission. Importantly, there is currently no cure for any type, although treatments such as steroids can be used to help with recovery from symptoms. MS, like most autoimmune conditions, is much more common in women than men, and is found at much higher rates in white Northern Europeans. It is the origins of this higher genetic risk that one of the four studies sought to uncover. 

An expansive international collaboration between researchers, including those at the University of Oxford, was successful in genetically analysing the bones and teeth of approximately 5,000 human specimens held in collections across Europe and Western Asia. This has provided the first gene bank of its kind, where DNA can be compared from modern to ancient times with the aim of elucidating how the lives of our ancestors might have impacted the diseases we suffer from today. Combining this prehistoric gene bank with the UK Biobank, a large biomedical database containing genetic and lifestyle information from UK participants, the researchers compared the ancient genomic profiles they had gathered to 410,000 modern individuals.

The aim was to identify whether specific regions of modern European genomes had any significant correlation with the ancient ancestry. Comparison between the ancient and modern genomics profiles found strong similarity in an area named human leukocyte antigen (HLA). Located on chromosome 6, HLA has an important function in regulating and inducing the immune response by recognising whether cells are disease-causing pathogens or the body’s own cells. These genes are hugely variable, explaining why people might respond so differently to the same infection. To date, 233 common genetic variants have been previously associated with MS, with 32 of these located in the HLA region. The researchers found that an increase in ancient ancestry in the HLA region of modern genomes correlated with an increased risk of developing MS, and that the proportion of this ancient ancestry was higher in northern compared to southern Europeans.  

The study links MS-linked genetic variations to the shift of European populations from hunter-gatherers to farmers growing crops and domesticating animals. This shift would have led to major changes in the character of their genomes, due to natural selection pressures and the mixing of different populations. About 5,000 years ago, the mass migration of a population of cattle herders  (“pastoralists”) named the Yamnaya entered north-western Europe from what is now known as Russia, Ukraine, and Kazakhstan. A nomadic people, the Yamnaya had developed certain genes which would have been protective to them, increasing the activity of the immune system to boost the ability to overcome plagues or common pathogens derived from the animals they herded. The researchers suggested that this increased reactivity originating with the Yamnaya may be linked to disadvantageous traits for individuals today, when we no longer face threat from these pathogens, such as in the autoimmune reaction of MS.

The study links MS-linked genetic variations to the shift of European populations from hunter-gatherers to farmers growing crops and domesticating animals.

Professor Lars Fugger, of the University of Oxford and John Radcliffe Hospital, and a co-author of the study, commented that ‘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’. Genetic factors are collectively estimated to account for a third of the total disease risk, although it is also worth noting that lifestyle and environmental factors play a major role in developing MS. For example, the strongest associated gene carries a threefold risk in developing MS, whilst delayed infection with the common Ebstein-Barr virus (EBV) in early adulthood is associated with an increased risk of 32-fold. Lifestyle factors such as vitamin D deficiency in adolescence or smoking have also been associated with MS development. However, just as many people will have an EBV infection or lifestyle factor for MS but never go on to develop the disease, the same is true for genetics. It is the combination of all of these factors, and how they collectively influence the occurrence of MS which will be important to identify.

While the origins of disease is certainly crucial information, it is the translation to clinical care which will directly benefit patients most.

The conclusions made by these papers are not infallible. Speculations about why a certain gene would have been historically advantageous may be drawn from the evidence available, but even the best reasons are far from definite. A major limitation of these studies is that they are restricted by the populations they include; this may provide evidence for the higher incidence of MS in northern Europeans, but what about in populations where MS is less common? A lower incidence does not make the research less worthwhile. Samira Asgari, in commentary for Nature News and Views, argues that ‘although human biology is shared, each population has a unique history and focusing on a single population limits opportunities for discoveries that can bring insights that advance medicine’. While the origins of disease is certainly crucial information, it is the translation to clinical care which will directly benefit patients most.