Critical find to understand sex disorder

Australian researchers have discovered a genetic regulator that plays a key role in determining a baby’s sex and, crucially, whether it will become one of the one in every 4500 people with a disorder of sex development.

Led by Andrew Sinclair at the Murdoch Children’s Research Institute (MCRI) in Melbourne, the team isolated a group of so-called “enhancers” that act on a gene that controls the growth of testes in the foetus.

At a basic level, if you’re born with two X chromosomes you become a girl, and if you have an X and a Y chromosome you’re a boy. But whether that genetic blueprint leads to typically male or female gonads, the testes and ovaries, and genitalia, the penis and scrotum, or vulva, vagina and clitoris, depends on a host of other factors.

One of those is the SRY gene, which sits on the Y chromosome and activates another gene called SOX9. It is SOX9 that tells the embryonic gonads, which can go either way, to head down the testes path.{%recommended 5981%}

How SRY influences SOX9 has been an enduring mystery, but at least part of the enigma is now in daylight.

The researchers found that three enhancers – sections of DNA that regulate gene expression – are drivers of SOX9, with profound implications when it all goes wrong.

In an analysis of 44 patients with disorders of sex development, the team found four people with mutations causing either duplications or deletions of the enhancers. Those changes resulted in something called complete sex reversal.

Duplications caused XX patients to develop testes, while deletions in XY patients caused a failure of testicular development and, instead, the growth of ovaries.

It is a finding that could, Sinclair explains, open up new lines of diagnosis for a group of disorders in which a genetic cause is found in only two out of five people.

“These enhancers lie on the DNA but outside genes, in regions previously referred to as junk DNA or dark matter,” says Sinclair. 

“The key to diagnosing many disorders may be found in these enhancers which hide in the poorly understood dark matter of our DNA.”

The researchers write that this “gene desert” is often excluded in genetic screens for disorders of sex development and should now be considered in unexplained cases.

It is a point reinforced by first author and MCRI PhD student, Brittany Croft: “This study is significant because in the past researchers have only looked at genes to diagnose these patients, but we have shown you need to look outside the genes to the enhancers.”

The research is published in the journal Nature Communications.

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