April 13, 2024

Genetic signature of Down syndrome found in ancient bones

Scientists diagnosed Down syndrome from DNA from the ancient bones of seven children, one of them 5,500 years old. 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 diseases.

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

Scientists have struggled to uncover the history of the disease. Today, older mothers are more likely to have a child with the disease. In the past, however, women would have been more likely to die young, which could have made Down syndrome rarer, and children born with it would have been less likely to survive without the heart surgery and other treatments that now prolong their lives. .

Archaeologists can identify some rare conditions, such as dwarfism, just from bones. But Down syndrome – also known as trisomy 21 – is an extremely variable condition.

People with it can present different combinations of symptoms and can present severe or milder forms. Those with characteristic almond-shaped eyes caused by Down syndrome may have relatively ordinary skeletons, for example.

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

On the other hand, it is not difficult to identify Down syndrome genetically, at least in living people. In recent years, geneticists have been testing their methods on DNA preserved in ancient bones.

It has been a challenge, however, because scientists cannot simply count complete chromosomes, which break down into fragments after death.

In 2020, Lara Cassidy, then a geneticist at Trinity College Dublin, and her colleagues used ancient DNA for the first time to diagnose a baby with Down syndrome. They were examining genes from skeletons buried in a 5,500-year-old tomb in western Ireland. The bones of a 6-month-old boy contained abnormally high amounts of chromosome 21 DNA.

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

The idea came to Dr. Rohrlach when he spoke with a scientist at the institute about his procedures for searching for ancient DNA. Because high-quality DNA sequencing is very expensive, the researchers were examining the bones with an inexpensive test called shotgun sequencing before choosing a few for further investigation.

If the bone still preserved DNA, the test revealed many small genetic fragments. They often come from microbes that grow in bones after death. But some bones also contained DNA recognizably human, and those with a high percentage were flagged for further testing.

Rohrlach discovered that the institute had examined nearly 10,000 human bones in this way, and the results of all the shotgun sequencing were stored in a database. It occurred to Dr. Rohrlach and his colleagues that they could scan the database for extra chromosomes.

“We thought, ‘No one has ever checked this kind of thing,’” Rohrlach said.

He and his colleagues wrote a program that sorted fragments of recovered DNA by chromosome. The program compared the DNA from each bone to the entire set of samples. He then identified specific bones that had an unusual number of sequences coming from a specific chromosome.

Two days after the initial conversation, the computer returned the results. “It turns out our hunch was right,” said Dr. Rohrlach, who is now an associate professor at the University of Adelaide in Australia.

They discovered that the institute’s collection included six bones with extra DNA from chromosome 21 – the signature of Down syndrome. Three belonged to babies up to one year old and the other three to fetuses that died before birth.

Rohrlach also followed up on Dr. Rohrlach’s 2020 study. He used his program to analyze the sequencing of the Irish skeleton and discovered that it also contained an extra chromosome 21, confirming his initial diagnosis.

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

The new research does not allow Rohrlach and his colleagues to determine how common Down syndrome was in the past. Many children with this disease likely died before adulthood, and children’s fragile bones are less likely to be preserved.

“There is a lot of uncertainty in sampling and what we could and could not find,” Dr. Rohrlach said. “I think it would be a very brave statistician to try to make much of these numbers.”

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

Normally, people from that culture were cremated after death, but these children were buried inside buildings, sometimes with jewelry. “These were special babies who were being buried in these homes, for reasons we still don’t understand,” Dr. Rohrlach speculated.

Dr. Gresky did not believe that the evidence made it possible to rule out chance for the set of cases.

“Maybe the bones were so well preserved,” she said. “Maybe the archaeologists were so good and well trained that they eliminated them all. Maybe they were buried in a way that made finding them much easier.”

Still, Dr. Gresky called the new study an important advance. On the one hand, it could allow archaeologists to compare remains genetically identified with Down syndrome and discover some hidden set of features common to all their skeletons.

And Dr. Gresky hopes other researchers will use ancient DNA to illuminate the hidden histories of other rare diseases: “Just look for them and talk about them. Otherwise, they will remain invisible.”

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