Scientists find genetic signature of Down syndrome in old bones

Scientists have diagnosed Down syndrome based on DNA in the ancient bones of seven babies, one of which was as old as 5,500 years. Their method, published in the journal Nature Communications, could help researchers learn more about how prehistoric societies treated people with Down syndrome and other rare conditions.

Down syndrome, which now affects 1 in 700 babies, is caused by an extra copy of chromosome 21. The extra chromosome produces extra proteins, which can cause a wide range of changes, including heart defects and learning disabilities.

Scientists have struggled to piece together the history of the condition. Nowadays, older mothers are most likely to have a child with the condition. In the past, however, women were more likely to die young, which could have made Down syndrome rarer, and the children born with it would have been less likely to survive without the heart surgery and other treatments that extend their lives today.

Archaeologists can identify some rare conditions, such as dwarfism, from bones alone. But Down syndrome – also known as trisomy 21 – is a remarkably variable disease.

People who suffer from it can have different combinations of symptoms, and they can have severe or milder forms. For example, those with the characteristic almond-shaped eyes caused by Down syndrome may have relatively normal skeletons.

As a result, it is difficult for archaeologists to confidently diagnose ancient skeletons with Down syndrome. “You can't say, 'Oh, this change is there, so it's trisomy 21,'” says Dr. Julia Gresky, an anthropologist at the German Archaeological Institute in Berlin, who was not involved in the new research.

In contrast, Down syndrome is not difficult to identify genetically, at least in living people. In recent years, geneticists have tested their methods on DNA preserved in ancient bones.

It was a challenge, however, because the scientists cannot simply count entire chromosomes, which break up into fragments after death.

In 2020, Lara Cassidy, a geneticist then working at Trinity College Dublin, and her colleagues used ancient DNA for the first time to diagnose a baby with Down syndrome. They examined genes from skeletons buried in a 5,500-year-old tomb in western Ireland. The bones of a six-month-old boy contain unusually large amounts of DNA from chromosome 21.

Since then, Adam Rohrlach, a statistician at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and his colleagues have developed a new method to find the genetic signature, one they can use to quickly look at thousands of bones.

The idea came to Dr. Rohrlach when he spoke to a scientist at the institute about the procedures for searching for ancient DNA. Because high-quality DNA sequencing is very expensive, it turned out, the researchers were screening bones with a cheap test called shotgun sequencing before choosing a few for further study.

If the bone still retained DNA, the test revealed many small genetic fragments. Very often they came from microbes that grow in the bones after death. But some bones also contained DNA that was recognizably human, and were flagged at a high rate for additional study.

Dr. Rohrlach found that the institute had screened nearly 10,000 human bones in this way and that the results of all the shotgun sequencing had been stored in a database. It struck Dr. Rohrlach and his colleagues noted that they could scan the database for extra chromosomes.

“We thought, 'No one has ever checked for this kind of thing,'” Dr. Rohrlach said.

He and his colleagues wrote a program that sorted fragments of the recovered DNA by chromosome. The program compared the DNA from each bone to the full set of samples. Subsequently, certain bones were identified with an unusual number of sequences coming from a particular chromosome.

Two days after their first conversation, the computer had the results. “It turned out that our suspicions were correct,” says Dr. Rohrlach, who is now an associate professor at the University of Adelaide in Australia.

They discovered that the institute's collection contained six bones with extra DNA from chromosome 21 – the hallmark of Down syndrome. Three were from babies as old as a year old, and the other three were from fetuses that died before birth.

Dr. Rohrlach also followed the research of Dr. Cassidy from 2020 op. He used his program to analyze the shotgun sequencing for the Irish skeleton and discovered that it also carried an extra chromosome 21, confirming her initial diagnosis.

Furthermore, Dr. Rohrlach another skeleton with an extra copy of chromosome 18. That mutation causes a condition called Edwards syndrome, which usually leads to death before birth. The bones came from an unborn fetus that had died at 40 weeks and was severely deformed.

The new research shows Dr. Rohrlach and his colleagues did not determine how common Down syndrome occurred in the past. Many children with the condition likely died before adulthood, and children's fragile bones are less likely to be preserved.

“There's so much uncertainty in the sampling and in what we could and couldn't find,” said Dr. Rohrlach. “I think it would be a very brave statistician to try to make too much sense of these numbers.”

But Dr. Rohrlach found it significant that three children with Down syndrome and those with Edward syndrome were all buried between 2,800 and 2,400 years ago in two neighboring towns in northern Spain.

Normally in that culture people were cremated after death, but these children were buried in buildings, sometimes with jewelry. “They were special babies who were buried in these houses, for reasons we don't yet understand,” Dr. speculated. Rohrlach.

Dr. Gresky didn't think the evidence allowed ruling out chance for the cluster of cases.

“Maybe the bones would have been so well preserved there,” she said. “Maybe the archaeologists were so good and well trained that they took them all out. Perhaps they were buried in such a way that it became much easier to find them.”

Still, Dr. Gresky sees the new study as an important step forward. First, it may allow archaeologists to compare remains genetically identified with Down syndrome and discover some hidden features common to all their skeletons.

And dr. Gresky hoped other researchers would use ancient DNA to illuminate the hidden history of other rare diseases: “You just have to look for it, and you have to talk about it. Otherwise they remain invisible.”