Multiple sclerosis, an autoimmune disease that affects 2.9 million people, presents a biological puzzle.
Many researchers suspect that the disease is triggered by a virus, known as Epstein-Barr, which causes the immune system to attack the nerves and can leave patients struggling to walk or talk. But the virus can’t be the whole story, since nearly everyone is infected with it at some point in life.
A new study found a possible solution to this paradox in the skeletal remains of a lost tribe of nomads who herded cattle across the steppes of western Asia 5,000 years ago. It turns out that the nomads carried genetic mutations that most likely protected them from pathogens carried by their animals but that also made their immune systems more sensitive. These genes, the study suggests, made the nomads’ descendants prone to a runaway immune response.
The finding is part of a larger, unprecedented effort to understand how the evolutionary past has shaped the health of living people. Researchers are analyzing thousands of genomes of people who lived between Portugal and Siberia and between Norway and Iran roughly 3,000 to 11,000 years ago. They hope to trace the genetic roots of not only multiple sclerosis but also diabetes, schizophrenia and many other modern illnesses.
“We are taking ancient human genomics to a whole new level,” said Eske Willerslev, a geneticist at the University of Copenhagen who led the effort.
The researchers published the multiple sclerosis study as well as three other papers on the genetics and health of ancient peoples Wednesday in the journal Nature.
For more than a decade, Willerslev and other researchers have been pulling DNA from ancient human bones. By comparing the surviving genetic material with that of living people, the scientists have been able to track some of the most significant migrations of people across the world.
For example, they have chronicled the movement of farmers from what is now Turkey across Europe starting about 8,000 years ago. These early farmers encountered European hunter-gatherers who had lived on the continent for more than 30,000 years. In some places, hunter-gatherer DNA vanished from skeletons after the arrival of the farmers, suggesting violent conflicts. In other places, the two populations mingled enough to produce later generations with a mixed ancestry.
Thousands of years passed before the next big migrational shift.
About 5,000 years ago, European DNA began to show the genetic signatures of a group of pastoralists who lived on the steppes that stretch from Ukraine to Kazakhstan, called the Yamnaya.
The Yamnaya traveled on horses and in wagons across hundreds of miles of grassland, herding cows, goats and sheep along the way. Even without farms or cities, they prospered for centuries, burying their dead with gold and jewelry.
In the Bronze Age, the Yamnaya expanded their territory, sweeping through much of Asia as well as Europe. Willerslev and his colleagues have found that once in Europe, the group often wiped out the farmers it encountered, although they also had peaceful relations in some places.
Today, people in northern Europe can trace most of their ancestry to the Yamnaya. Farther south, Yamnaya ancestry is less common. People there instead have more ancestry from Near East farmers and Europe’s earlier hunter-gatherers.
Willerslev and his colleagues wondered what kind of genetic variations each ancient group carried by each ancient group and how they affected their health. To find out, the researchers studied some of their living descendants.
They took advantage of UK Biobank, a huge database of DNA and medical information. Most of the 433,395 volunteers whom the scientists studied were born in Britain, but 24,511 were born in other countries.
The researchers were able to tie thousands of genetic variants in the database to increased risks for a wide range of diseases. They then compared the volunteers’ DNA with the genetic fragments from ancient skeletons.
One analysis found that hunter-gatherers from Western Europe, for example, carried many of the variants that raise the risk for high cholesterol, high blood pressure and diabetes. Another showed that ancient Near East farmers carried a high burden of variants linked to anxiety and other mood disorders.
These findings don’t necessarily mean that these ancient people suffered from these conditions. Genetic variants lay the trap, but it’s often the environment that springs it.
Diabetes, for example, has become increasingly common in the modern world, in part because of the cheap, sugar-loaded food that makes up an increasing part of our diet. In earlier centuries, high-risk genes for diabetes may not have had the opportunity to give rise to the disease.
In some cases, Willerslev and his colleagues found, these genetic variants provided ancient peoples with a survival advantage.
The variants that raise the risk of multiple sclerosis, for example, became steadily more common among the Yamnaya. The nomads who carried them appear to have had more offspring than those who didn’t.
“These variants that are causing the high risk of multiple sclerosis today must in the past have had a benefit,” Willerslev said.
The new studies give some strong hints about what that benefit is. Some of the skeletons contained DNA not just from humans, but also from disease-causing viruses and bacteria. Many of these pathogens did not appear among hunter-gatherers or even among the earliest farmers in Europe. But the Yamnaya remains contained the genetic signatures of a number of pathogens, including the one that caused plague.
“These variants seem to give some kind of protection from infectious diseases,” Willerslev said.
A number of studies on multiple sclerosis suggest that the variants that raise the risk of the disease also make the immune system’s attack against viruses and bacteria more aggressive.
Willerslev and his colleagues argued that the Yamnaya were more vulnerable to animal diseases than previous humans were. The Yamnaya depended on animals for meat and milk and were in constant contact with their herds as they moved across the steppes.
Those conditions provided a new opportunity for diseases to jump to humans. In response, the Yamnaya evolved immune-related genes that helped them fend off the new enemies.
“They’ve made a really, really compelling case,” Yassine Souilmi, a genomicist at the University of Adelaide in Australia, said of Willerslev and his colleagues. “I’ll be shocked if further experimental testing doesn’t match their conclusions.”
Dr. Lars Fugger, a multiple sclerosis expert at the University of Oxford who collaborated with Willerslev on the new studies, said that the disease may not have become common until recent decades. In today’s environment, with less infectious disease than past centuries, he said, a strong immune system becomes more likely to misfire, attacking its own body.
“Many of us are living in an environment that is squeaky clean,” Fugger said. “The balance is no longer there.”
Understanding the evolutionary roots of multiple sclerosis could guide researchers to better treatments for the disease. Currently, the only effective treatments for the condition are drugs that suppress the immune system. To Fugger, those drugs seem like blunt instruments against a delicately balanced part of our biology.
“Rather than just knocking it out, we should just try to find out in greater detail how it’s unbalanced, and then try to recalibrate it,” he said.
The researchers are starting similar analyses of other diseases, such as schizophrenia and psoriasis. “This is just the beginning,” Fugger said.
For now, they are continuing to rely on the UK Biobank, which means their results will be largely limited to genes that have influenced the health of northern Europeans. “It would be phenomenal to have similar studies in other parts of the world,” said Lluis Quintana-Murci, an evolutionary geneticist at Institut Pasteur who was not involved in the research.
But there are few opportunities to carry out such studies. Many countries lack detailed electronic health records, for one thing. And unethical behavior of Western scientists has left many Indigenous populations uninterested in donating DNA to such efforts.
Souilmi, who is helping to build a database for Indigenous Australians, said that the different evolutionary path of each population could reveal important insights about human biology in general. “By studying other parts of the world, we’re actually broadening our understanding of all human conditions today,” he said.
Many researchers suspect that the disease is triggered by a virus, known as Epstein-Barr, which causes the immune system to attack the nerves and can leave patients struggling to walk or talk. But the virus can’t be the whole story, since nearly everyone is infected with it at some point in life.
A new study found a possible solution to this paradox in the skeletal remains of a lost tribe of nomads who herded cattle across the steppes of western Asia 5,000 years ago. It turns out that the nomads carried genetic mutations that most likely protected them from pathogens carried by their animals but that also made their immune systems more sensitive. These genes, the study suggests, made the nomads’ descendants prone to a runaway immune response.
The finding is part of a larger, unprecedented effort to understand how the evolutionary past has shaped the health of living people. Researchers are analyzing thousands of genomes of people who lived between Portugal and Siberia and between Norway and Iran roughly 3,000 to 11,000 years ago. They hope to trace the genetic roots of not only multiple sclerosis but also diabetes, schizophrenia and many other modern illnesses.
“We are taking ancient human genomics to a whole new level,” said Eske Willerslev, a geneticist at the University of Copenhagen who led the effort.
The researchers published the multiple sclerosis study as well as three other papers on the genetics and health of ancient peoples Wednesday in the journal Nature.
For more than a decade, Willerslev and other researchers have been pulling DNA from ancient human bones. By comparing the surviving genetic material with that of living people, the scientists have been able to track some of the most significant migrations of people across the world.
For example, they have chronicled the movement of farmers from what is now Turkey across Europe starting about 8,000 years ago. These early farmers encountered European hunter-gatherers who had lived on the continent for more than 30,000 years. In some places, hunter-gatherer DNA vanished from skeletons after the arrival of the farmers, suggesting violent conflicts. In other places, the two populations mingled enough to produce later generations with a mixed ancestry.
Thousands of years passed before the next big migrational shift.
About 5,000 years ago, European DNA began to show the genetic signatures of a group of pastoralists who lived on the steppes that stretch from Ukraine to Kazakhstan, called the Yamnaya.
The Yamnaya traveled on horses and in wagons across hundreds of miles of grassland, herding cows, goats and sheep along the way. Even without farms or cities, they prospered for centuries, burying their dead with gold and jewelry.
In the Bronze Age, the Yamnaya expanded their territory, sweeping through much of Asia as well as Europe. Willerslev and his colleagues have found that once in Europe, the group often wiped out the farmers it encountered, although they also had peaceful relations in some places.
Today, people in northern Europe can trace most of their ancestry to the Yamnaya. Farther south, Yamnaya ancestry is less common. People there instead have more ancestry from Near East farmers and Europe’s earlier hunter-gatherers.
Willerslev and his colleagues wondered what kind of genetic variations each ancient group carried by each ancient group and how they affected their health. To find out, the researchers studied some of their living descendants.
They took advantage of UK Biobank, a huge database of DNA and medical information. Most of the 433,395 volunteers whom the scientists studied were born in Britain, but 24,511 were born in other countries.
The researchers were able to tie thousands of genetic variants in the database to increased risks for a wide range of diseases. They then compared the volunteers’ DNA with the genetic fragments from ancient skeletons.
One analysis found that hunter-gatherers from Western Europe, for example, carried many of the variants that raise the risk for high cholesterol, high blood pressure and diabetes. Another showed that ancient Near East farmers carried a high burden of variants linked to anxiety and other mood disorders.
These findings don’t necessarily mean that these ancient people suffered from these conditions. Genetic variants lay the trap, but it’s often the environment that springs it.
Diabetes, for example, has become increasingly common in the modern world, in part because of the cheap, sugar-loaded food that makes up an increasing part of our diet. In earlier centuries, high-risk genes for diabetes may not have had the opportunity to give rise to the disease.
In some cases, Willerslev and his colleagues found, these genetic variants provided ancient peoples with a survival advantage.
The variants that raise the risk of multiple sclerosis, for example, became steadily more common among the Yamnaya. The nomads who carried them appear to have had more offspring than those who didn’t.
“These variants that are causing the high risk of multiple sclerosis today must in the past have had a benefit,” Willerslev said.
The new studies give some strong hints about what that benefit is. Some of the skeletons contained DNA not just from humans, but also from disease-causing viruses and bacteria. Many of these pathogens did not appear among hunter-gatherers or even among the earliest farmers in Europe. But the Yamnaya remains contained the genetic signatures of a number of pathogens, including the one that caused plague.
“These variants seem to give some kind of protection from infectious diseases,” Willerslev said.
A number of studies on multiple sclerosis suggest that the variants that raise the risk of the disease also make the immune system’s attack against viruses and bacteria more aggressive.
Willerslev and his colleagues argued that the Yamnaya were more vulnerable to animal diseases than previous humans were. The Yamnaya depended on animals for meat and milk and were in constant contact with their herds as they moved across the steppes.
Those conditions provided a new opportunity for diseases to jump to humans. In response, the Yamnaya evolved immune-related genes that helped them fend off the new enemies.
“They’ve made a really, really compelling case,” Yassine Souilmi, a genomicist at the University of Adelaide in Australia, said of Willerslev and his colleagues. “I’ll be shocked if further experimental testing doesn’t match their conclusions.”
Dr. Lars Fugger, a multiple sclerosis expert at the University of Oxford who collaborated with Willerslev on the new studies, said that the disease may not have become common until recent decades. In today’s environment, with less infectious disease than past centuries, he said, a strong immune system becomes more likely to misfire, attacking its own body.
“Many of us are living in an environment that is squeaky clean,” Fugger said. “The balance is no longer there.”
Understanding the evolutionary roots of multiple sclerosis could guide researchers to better treatments for the disease. Currently, the only effective treatments for the condition are drugs that suppress the immune system. To Fugger, those drugs seem like blunt instruments against a delicately balanced part of our biology.
“Rather than just knocking it out, we should just try to find out in greater detail how it’s unbalanced, and then try to recalibrate it,” he said.
The researchers are starting similar analyses of other diseases, such as schizophrenia and psoriasis. “This is just the beginning,” Fugger said.
For now, they are continuing to rely on the UK Biobank, which means their results will be largely limited to genes that have influenced the health of northern Europeans. “It would be phenomenal to have similar studies in other parts of the world,” said Lluis Quintana-Murci, an evolutionary geneticist at Institut Pasteur who was not involved in the research.
But there are few opportunities to carry out such studies. Many countries lack detailed electronic health records, for one thing. And unethical behavior of Western scientists has left many Indigenous populations uninterested in donating DNA to such efforts.
Souilmi, who is helping to build a database for Indigenous Australians, said that the different evolutionary path of each population could reveal important insights about human biology in general. “By studying other parts of the world, we’re actually broadening our understanding of all human conditions today,” he said.
