A tiny DNA change in a non-coding regulatory region can flip biological sex in mammals. Researchers showed that a single-letter mutation in a stretch of DNA called Enh13 causes genetically female (XX) mice to develop male reproductive organs by unleashing the testis-determining gene Sox9. The study was led by scientists at Bar-Ilan University and published in Nature Communications.
“Just one DNA letter out of approximately 2.8 billion” was sufficient to drive this dramatic outcome, said Dr. Nitzan Gonen. The team demonstrated that modifying both copies of Enh13 in female mice triggered male gonad formation, according to a press release published on EurekAlert.
A pivotal switch
Sex determination in mammals depends on the interplay of sex chromosomes and gene activity. Sox9 serves as a pivotal switch for testis formation. In XY embryos it is activated to guide male development. In XX embryos it is normally kept silent to permit ovaries to form.
Experiments mapping Enh13’s function show the element is essential for triggering Sox9 in the developing testis, according to Scinexx. In XX mice carrying these targeted mutations, the normal repression of Sox9 failed. The gene became active in the gonad, leading to testis development, male genital formation, and full male sexual development even in the presence of two X chromosomes.
The work also indicates that the Enh13 mechanism operates across mammals, including humans, where the same regulatory logic determines whether SOX9 is activated or silenced during gonad formation.