One Letter Change in DNA Can Reverse Sex
Does inheriting a Y chromosome normally produce male offspring? Not necessarily.
Posted April 15, 2026 | Reviewed by Lybi Ma
Most people know that a baby’s sex is determined by whether it inherits an X or a Y chromosome from its father. Inheriting a Y chromosome normally produces male offspring. Not necessarily, according to a new study.
This recent study, published in the journal Nature Communications and led by Nitzan Gonen of Bar-Ilan University, reports that changing only one letter of the 2.8 billion letters in DNA reverses the sex of mice. Gonen says the same DNA region exists in humans.
What is most interesting about this new finding is that the mutation is not in a DNA region that codes for a gene. Consequently, mutations in this region of DNA would not be identified in people with differences of sex development because genetic analysis of such patients typically means the search for only mutations in their genes .
Remarkably, 98 percent of our DNA does not code for genes. Once considered “junk DNA,” it is now well appreciated that these non-coding regions act like software to regulate whether a gene is activated to produce a protein, or not.
In an email, Gonen explains that their finding shows “How really small changes in parts that were once considered ‘junk DNA’ can have detrimental effects on development and disease.”
The single-letter mutation was introduced in XX mice (normally female) into a DNA regulatory element, which is a non-coding sequence of DNA known as Enh13.
A regulatory element is a short sequence of DNA that acts as a docking station for a cellular signaling protein to bind to. There are many signaling proteins in cells, called transcription factors. Each one fits like a lock-and-key into its matching DNA regulatory element. When the transcription factor binds to that short DNA sequence, it unlocks the command-and-control process that turns particular genes on or off.
In retrospect, it makes sense that so much of our DNA does not make genes but instead manages the intricate process of turning genes on or off to make specific proteins. This is vital because the DNA in every cell in our body has a complete blueprint to make every protein that can be made. Only a very specific subset of genes must be turned on in each cell; for example, to make it a neuron instead of a bone cell.
In this case, the Enh13 regulatory element activates genes that make the specific proteins that will produce either male or female reproductive organs. This new research shows that if the lock-and-key fit of the transcription factor is gummed up by changing only one DNA letter in the Enh13 regulatory element of XX mice, the animal’s sex will be reversed. Those mice develop testicles and male genitals.
The study advances the authors’ earlier work, published in 2024, which shows that other small mutations in the same regulatory element could have the opposite effect in XY mice. These mice would normally develop into males, but small mutations in Enh13 of XY mice cause them to develop as females.
Together, the findings suggest that Enh13 has a dual role in acting to assign the proper sex. “Enh13 serves as a double-edged sword,” Gonen says. It promotes the formation of male sex organs in male mice, but that action must be repressed in female development.
Gonen says that one in 4000 newborn babies has differences in sex development. “We in the lab believe that Enh13 is just the ‘tip of the iceberg,’ and that many other critical regulatory elements lie in the non-coding genome,” needed for proper sex development. “We are working towards systematically identifying all of them.”
It is stunning to think that whether or not you develop the appropriate sex at birth can hinge on only one “typo” in 2.8 million letters of our DNA. Food for thought in the current backdrop of so much vitriol and controversy in government over transgender people.
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R. Douglas Fields, Ph.D. , teaches at the University of Maryland, College Park and is the author of the book Electric Brain .
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This article is part of the Bringwise Psychology Journal — daily insights on human behavior, mental health, and personal growth.