Rare genetic syndrome in 1,000-year-old skeleton is oldest case ever found: ScienceAlert

The earliest ever recorded case of the genetic condition Klinefelter Syndrome has just been discovered – in a 1,000-year-old skeleton excavated from an archaeological site in Portugal.

Klinefelter syndrome, occurring in about one in every thousand male births, is a condition where individuals are born with an extra copy of the X chromosome – resulting in an XXY combination.

While it often produces no obvious symptoms (many cases are never diagnosed), men with the condition are usually tall, with wide hips and sparse body hair. The condition has also been linked to infertility, a lower sex drive and a slightly increased risk of type 2 diabetes.

This latest discovery will now help experts determine the prevalence of Klinefelter Syndrome over the centuries.

A multidisciplinary approach covering genetic, statistical, archaeological and anthropological data was required to reach the diagnosis.

After the skeleton obtained was radiocarbon dated to the 11th century, the team undertook a DNA analysis. Part of that analysis involved computationally mapping fragments of the X and Y chromosomes to the reference human genome.

“We were immediately excited the first time we saw the results,” says evolutionary biologist João Teixeira of the Australian National University.

“However, ancient DNA is often degraded and of low quality and abundance, which means we were initially cautious.”

The skull used in the research. (Australian National University)

Using the Bayesian inference model and a bespoke approach, the researchers were able to be more confident about their diagnosis by comparing their results to a theoretical XXY karyotype (a complete set of chromosome information with an extra X).

In other words, probability modeling was used to fill in some of the gaps in the DNA data, confirming that there was a different ratio of genes between those belonging to the Y and X chromosomes.

The same approach can be improved and extended to analyze DNA in other cases where only fragments are available, the researchers say – from modern-day crime scenes to archaeological digs.

“Given the fragile state of DNA, we developed a new statistical method that could take into account the characteristics of ancient DNA and our observations to confirm the diagnosis,” says Teixeira.

An observational study of the skeleton also revealed features consistent with Klinefelter Syndrome – including taller than average height, wider than average hips and a misalignment of the jaw and teeth.

The skeleton itself was well preserved, the researchers report, taken from the Torre Velha site in northeastern Portugal. It likely belonged to an adult male more than 25 years old at the time of his death, who was approximately 180 centimeters tall.

While Klinefelter Syndrome was first identified in 1942, no ancient case has been documented before, making this easily the earliest case on record – and providing some clues to help experts better understand it.

The researchers are keen to point out how important it was to use different lines of evidence using different fields of scientific study to figure out that this skeleton really came from someone with Klinefelter syndrome.

Thanks to the genetic analysis techniques scientists now have access to, ancient DNA is being used to make all kinds of discoveries: covering animal evolution, human history, the spread of disease, and much more.

“In recent years, ancient DNA has helped rewrite the history of human populations around the world,” says paleogeneticist Bastien Llamas of the University of Adelaide in Australia.

“Our study shows that it is now a valuable resource for biomedical research and the growing field of evolutionary medicine.”

The research was published in Lancet.

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