Changing just one "letter" in the DNA of female mouse embryos triggers the development of male genitalia and testes, scientists have found.

"This is a remarkable finding because such a tiny change — just one DNA letter out of ~2.8 billion — was enough to produce a dramatic developmental outcome," senior study author Nitzan Gonen, a senior investigator at Bar-Ilan University in Israel who studies how sex is determined during embryonic development, said in a statement.

Back in 2018, Gonen and colleagues pinpointed another stretch of DNA that is important for this chain reaction. This snippet of DNA, called enhancer 13 (Enh13), doesn't carry instructions for any proteins. Instead, it acts as an "on-off" switch for SOX9. The SRY protein latches onto this switch, flipping it and sending SOX9 into overdrive.

In previous work, the researchers also found that, by eliminating this on-off switch, they could reverse the sex of male mouse embryos. Even though they carried XY sex chromosomes, the mice without Enh13 developed as females. Enh13's absence causes SOX9 activity to fall by about 80%, which prevents the development of testes and instead ushers the development of ovaries, the researchers reported. Tweaking only select bits of Enh13 has the same effect, the team found in a later study.

The scientists suspect that mutations in this on-off switch may contribute to certain differences of sexual development (DSD) in humans, which can cause a person's sex chromosomes and sexual characteristics to be mismatched. In particular, it was clear Enh13 might play a role in cases where XY individuals develop female characteristics, as they'd explored in mouse studies.

But some studies also hinted at a potential role in conditions that cause XX individuals to develop male features. And the new research, published Thursday (April 9) in the journal Nature Communications, backs up this latter idea.

The researchers tweaked Enh13 in female mouse embryos by either deleting three letters or inserting one letter into the portion of the on-off switch that SRY latches onto. Both of these modifications caused small testes and male external genitalia to develop in the female mice, although they also grew some ovarian tissue.

For male sex organs to develop, the mutation had to affect both copies of Enh13; cells carry two copies of chromosome 17, which Enh13 is found on. If only one copy was mutated, the XX mice developed normal ovaries and no male organs.

Typically, the SOX9 gene must be switched off for ovaries to develop properly, and XX embryos use various mechanisms to achieve that. The new study suggests that mutations in Enh13 can lift the brakes on SOX9, allowing the gene to activate to a small degree even without any SRY protein present.

Once activated, SOX9 can sustain and amplify its own activity, so "this minimal activation would be enough to trigger the self-amplification loop," the study authors wrote.

In the long run, these results could help scientists better understand how DSDs emerge in humans, the researchers say. For now, though, the work raises a number of hypotheses about Enh13's role in sex development in both males and females, and more research is needed to fully unpack its effects.

"Our findings show that it is not enough to look only at genes," Elisheva Abberbock, a doctoral student at Bar-Ilan University who led the research, said in the statement. "Important disease-causing mutations may also lie in the non-coding genome, in DNA regions that control gene activity rather than encode proteins."

Nicoletta Lanese is the health channel editor at Live Science and was previously a news editor and staff writer at the site. She is a recipient of the 2026 AHCJ International Health Study Fellowship, with a project focused on antibiotic stewardship practices in Japan and the U.S. They hold a graduate certificate in science communication from UC Santa Cruz and degrees in neuroscience and dance from the University of Florida. Beyond Live Science, Lanese's work has appeared in The Scientist, Science News, the Mercury News, Mongabay and Stanford Medicine Magazine, among other outlets. Based in NYC, she also remains involved in dance and performs in local choreographers' work.