By Pesach Benson • April 9, 2026
Jerusalem, 9 April, 2026 (TPS-IL) — A single change in DNA — just one letter among billions — can completely reverse sexual development, according to a new study by Israeli and French scientists that sheds light on the powerful role of previously overlooked regions of the genome.
Scientists at Bar-Ilan University, working in collaboration with counterparts from the Weizmann Institute of Science in Israel and the University of Montpellier in France, found that inserting a single DNA base in a non-coding region caused genetically female (XX) mice to develop as fully male, with both testes and male genitalia.
The research, published in the peer-reviewed Nature Communications, highlights how tiny changes outside of genes themselves can have dramatic biological consequences.
“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,” said Dr. Nitzan Gonen, a researcher at Bar-Ilan’s Faculty of Life Sciences. “It shows that non-coding DNA can have a profound effect on development and disease.”
The mutation did not occur within a gene, but in a regulatory DNA segment known as Enh13, which controls the activity of Sox9, a gene that plays a critical role in the development of testes. In typical female development, Sox9 remains inactive, allowing ovaries to form. In males, however, Sox9 is switched on, triggering the formation of testes.
Researchers describe Enh13 as a kind of molecular switch or battleground. In male embryos, factors that promote testis development bind to this region and activate Sox9. In females, different factors bind to the same site to suppress the gene.
By introducing the mutation using CRISPR genome editing, the researchers disrupted this balance. The normal repression of Sox9 in XX embryos failed, allowing the gene to become active. As a result, the mice developed male reproductive anatomy despite having two X chromosomes.
The team created multiple mouse models with subtle alterations in the same regulatory region, including a single-letter insertion and a three-letter deletion. Both types of mutations led to the same outcome: complete sex reversal in XX mice. Further laboratory experiments showed how these small changes interfered with the normal regulatory mechanisms controlling Sox9.
The findings build on earlier work by the same research group, published in 2024, which demonstrated the reverse phenomenon. In that study, different small mutations in Enh13 caused genetically male (XY) mice to develop as females. Together, the results suggest that this regulatory element plays a dual role, both activating male development and ensuring female pathways remain intact when required.
Beyond its implications for basic science, the discovery could have clinical relevance. Differences of Sex Development, or DSD, affect approximately one in 4,000 births worldwide. These conditions involve atypical development of chromosomal, gonadal, or anatomical sex, and in more than half of cases, the underlying genetic cause remains unknown. The findings raise the possibility of more accurate diagnoses of DSD.
The findings could change how genetic testing is done more broadly. Many unexplained developmental disorders, not just DSD, may be caused by mutations in regulatory DNA. Incorporating these regions into genome analysis could help identify the causes of previously “mystery” conditions, improving patient care and genetic counseling.
Further down the road, a better understanding of how genes like Sox9 are switched on and off could eventually help clinicians diagnose certain forms of infertility or gonadal dysfunction and possibly guide interventions.
“Our findings show that it is not enough to look only at genes,” said Elisheva Abberbock, the PhD student who led the study. “Important disease-causing mutations may also lie in the non-coding genome, in DNA regions that control gene activity rather than encode proteins.”
The researchers believe that Enh13 may be only one example of many such regulatory elements hidden within the vast non-coding portion of DNA, which makes up about 98 percent of the human genome. They are now working to systematically identify similar regions and understand their role in development and disease.