It's generally understood that the biological sex of an embryo is determined by the chromosomes at conception – two X chromosomes will develop as female, while an XY combo will become male. But this simple rule may be too simple. A new genetics study out of Australia has identified extra pieces of the puzzle that could explain some disorders of sex development (DSD).
The Y chromosome dictates male development through certain genes: it carries a gene called SRY, which in turn ramps up activity on another gene known as SOX9. High levels of SOX9 triggers development of testes in an embryo, creating a biological boy.
In the new study, a team from the University of Melbourne and the Murdoch Children's Research Institute investigated this mechanism in more detail. The researchers set out to check how the SOX9 gene was regulated by segments of DNA known as enhancers, and how disruptions to these enhancers could lead to DSD conditions.
"We discovered three enhancers that, together ensure the SOX9 gene is turned on to a high level in an XY embryo, leading to normal testis and male development," says Andrew Sinclair, lead author of the study. "Importantly, we identified XX patients who would normally have ovaries and be female but carried extra copies of these enhancers (high levels of SOX9), and instead developed testes. In addition, we found XY patients who had lost these SOX9 enhancers, (low levels of SOX9) and developed ovaries instead of testes."
These enhancers were found among what has in the past been referred to as "junk DNA." Although this makes up about 90 percent of human DNA, it has historically been overlooked because it doesn't contain genes. But that doesn't mean it's useless, as studies like this highlight. With about a million enhancers regulating the activity of about 22,000 genes, clues to new treatments could be hiding in this so-called junk DNA.
"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 research was published in the journal Nature Communications.
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