Scientists have identified a key enhancer of Sox9 -- a gene critical for male sex development -- and demonstrated that deleting that non-coding DNA results in male-to-female sex reversal in mice.
 
The study, published in Science, deepens understanding of the normal process of sex determination in mammals. The findings could also have important implications for patients with differences in sex development (DSDs), in which reproductive organs don't develop as expected.

The Sox9 gene is crucial for male differentiation and the proper formation of testes; if Sox9 is mutated or incorrectly expressed, an individual who is chromosomally male (XY) can develop ovaries instead of testes.
 
Previously, it was known that some patients with DSDs have changes in their genome near the Sox9 gene that alter its expression and lead to sex reversal. But it was unclear exactly why.

In the current study, the scientists identified an enhancer (a short region of DNA that can increase gene transcription) that is necessary to regulate expression of the Sox9 gene. Enh13, a 557–base pair element located 565 kilobases 5′, is essential to initiate mouse testis development.  
 
When the scientists deleted the enhancer in mouse models, they discovered that Sox9 expression was decreased enough to cause complete sex reversal; mouse embryos that were chromosomally male (XY) developed as phenotypically normal females, with ovaries that were indistinguishable from those of XX females.
 
"We believe that many undiagnosed patients have mutations in regulatory regions -- such as the one that we identified near Sox9 -- and regulatory regions are usually not investigated by genetic testing," said the author. "Often genes important for sex determination are also crucial for other developmental processes, and a mutation in one gene or its regulatory region can impact a patient's health in many ways. As we begin to understand the genetic underpinnings of these disorders, we can improve our care of these patients."
 
Going forward, the team is investigating other enhancers involved in the regulation of Sox9 and other sex-determining genes, and hopes to also understand how Sox9 expression is repressed in females, leading to the development of ovaries.
 
http://news.feinberg.northwestern.edu/2018/06/understanding-the-epigenetics-of-sex-determination/
http://science.sciencemag.org/content/early/2018/06/13/science.aas9408