Ancient skeletons provide clues to modern medical mysteries
Multiple sclerosis, an autoimmune disease that affects 2.9 million peoplepresents a biological puzzle.
Many researchers suspect that the disease is caused by a virus known as Epstein-Barr, which causes the immune system to attack the nerves and can cause patients to have difficulty walking or talking. But the virus cannot be the whole story, as almost everyone gets 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 nomadic tribe that 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 transmitted by their animals, but also made their immune systems more sensitive. These genes, the study suggests, predisposed the nomads’ offspring to a runaway immune response.
The find is part of a larger unprecedented attempt to understand it how the evolutionary past has shaped the health of living humans. Researchers are analyzing thousands of genomes from people who lived between Portugal and Siberia and between Norway and Iran about 3,000 to 11,000 years ago. They hope to uncover the genetic roots of not only multiple sclerosis, but also diabetes, schizophrenia and many other modern diseases.
“We’re taking ancient human genomics to a whole new level,” says Eske Willerslev, a geneticist at the University of Copenhagen who led the study.
The researchers published the study on multiple sclerosis and three other papers on the genetics and health of ancient peoples on Wednesday in the journal Nature.
For more than ten years, Dr. Willerslev and other researchers DNA from ancient human bones. By comparing the surviving genetic material with that of living people, the scientists have managed to track some of the most important migrations of humans around the world.
For example, they have mapped the movements of farmers from modern-day Turkey across Europe, which began 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 disappeared from skeletons after the arrival of farmers, indicating violent conflict. In other places, the two populations mixed enough to produce later generations of mixed ancestry.
Thousands of years passed before the next major migration shift occurred. About 5,000 years ago, European DNA began showing the genetic signatures of a group of pastoralists who lived on the steppes stretching from Ukraine to Kazakhstan, called the Yamnaya.
The Yamnaya traveled on horseback and in chariots across hundreds of miles of grassland, herding cows, goats, and sheep along the way. Even without farms or towns, they prospered for centuries, burying their dead with gold and jewelry.
In the Bronze Age, the Yamnaya expanded their territory, spanning much of Asia and Europe. Dr. Willerslev and his colleagues have found that once in Europe, the group often wiped out the peasants it encountered, although in some places they also had peaceful relations.
Today, people in Northern Europe can trace most of their ancestry to the Yamnaya. Further south, Yamnaya ancestry is less common. The people there, on the other hand, have more ancestry from Near Eastern farmers and the former hunter-gatherers of Europe.
Dr. Willerslev and his colleagues wondered what kind of genetic variations each ancient group carried, and how these affected their health. To find out, the researchers studied some of their living descendants.
They used the UK Biobank, a huge database of DNA and medical information. Most of the 433,395 volunteers the scientists studied were born in Britain, but 24,511 were born in other countries.
The researchers were able to link 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 of ancient skeletons.
One analysis found that hunter-gatherers from Western Europe, for example, carried many of the variants that increase the risk of high cholesterol, high blood pressure and diabetes. Another study found that farmers in the ancient Near East bore a heavy burden of variants linked to anxiety and other mood disorders.
These findings do not necessarily mean that these ancient people suffered from these conditions. Genetic variants are the pitfall, but it is often the environment that causes it.
For example, diabetes is becoming increasingly common in the modern world, partly because of the cheap, sugary foods that make up an increasing part of our diets. In earlier centuries, risk genes for diabetes may not have had the chance to cause the disease.
In some cases, Dr. Willerslev and his colleagues, these genetic variants offered ancient peoples a survival advantage.
For example, the variants that increase the risk of multiple sclerosis were becoming increasingly common among the Yamnaya. It seems that the nomads who wore them had more descendants than those who did not.
“These variants that cause the high risk of multiple sclerosis today must have had some benefit in the past,” said Dr. Willerslev.
The new studies provide some strong clues about what that benefit is. Some skeletons contain DNA not only from humans, but also from disease-causing viruses and bacteria. Many of these pathogens did not occur among hunter-gatherers or even among the first farmers in Europe. But the Yamnaya remains contain the genetic signatures of a number of pathogens, including the one that caused the plague.
“These variants appear to provide some form of protection against infectious diseases,” said Dr. Willerslev.
A number of studies in multiple sclerosis suggest that the variants that increase the risk of the disease also make the immune system’s attack on viruses and bacteria more aggressive.
Dr. Willerslev and his colleagues argued that the Yamnaya were more vulnerable to animal diseases than earlier humans. The Yamnaya depended on animals for meat and milk and were in constant contact with their herds as they moved across the steppes.
These conditions offered a new opportunity for diseases to spread to humans. In response, the Yamnaya developed immune-related genes that helped them fend off the new enemies.
“They’ve made a very, very compelling argument,” Yassine Souilmi, a genomicist at the University of Adelaide in Australia, said of Dr. Willerslev and his colleagues. “I will be shocked if further experimental testing does not match their conclusions.”
Dr. Lars Fugger, an expert on multiple sclerosis at the University of Oxford who worked with Dr. Willerslev to the new studies, said the disease has only become common in recent decades. In today’s environment, with fewer infectious diseases than in centuries past, a strong immune system is more likely to make a mistake and attack its own body.
“Many of us live in environments that are spotless,” said Dr. Fugger. “The balance is no longer there.”
Understanding the evolutionary roots of multiple sclerosis could lead researchers to better treatments for the disease. Currently, the only effective treatments for the condition are medications that suppress the immune system. For Dr. Fugger, these drugs seem like blunt instruments against a delicately balanced part of our biology.
“Rather than simply turning it off, we should try to find out in more detail how it’s out of balance, and then try to recalibrate it,” he said.
The researchers are starting similar analyzes of other diseases, such as schizophrenia and psoriasis. “This is just the beginning,” said Dr. Fugger.
For now, they continue to rely on the UK Biobank, meaning their results will be largely limited to genes that have affected the health of Northern Europeans. “It would be phenomenal to see similar studies take place in other parts of the world,” says Lluis Quintana-Murci, an evolutionary geneticist at the Institut Pasteur who was not involved in the study.
But there are few opportunities to conduct such studies. For example, many countries lack detailed electronic health records. And due to the unethical behavior of Western scientists, many indigenous peoples are not interested in donating DNA to such efforts.
Dr. Souilmi, who helps with that build a database for Indigenous Australians, said each population’s different evolutionary path could reveal important insights about human biology in general. “By studying other parts of the world, we are actually broadening our understanding of all human conditions today,” he said.