Scientists have discovered that changing just one “letter” in the DNA of a female mouse embryo causes the development of male reproductive organs and testes.
“This is a remarkable discovery because such a small change, just one letter out of about 2.8 billion DNA letters, was enough to produce a dramatic developmental outcome,” study lead author Nizan Gonen, a senior researcher at Israel’s Bar-Ilan University who studies how sex is determined during embryonic development, said in a statement.
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In 2018, Gonen and colleagues identified another region of DNA that is important for this chain reaction. This piece of DNA, called enhancer 13 (Enh13), has no instructions for proteins. Instead, it acts as an “on/off” switch for SOX9. The SRY protein seizes this switch and flips it, putting SOX9 into overdrive.
In a previous study, the researchers also discovered that by eliminating this on-off switch, they could reverse the sex of male mouse embryos. Mice lacking Enh13 grew up female, even though they had XY sex chromosomes. The researchers reported that lack of Enh13 reduces SOX9 activity by about 80%, which impedes testicular development and instead promotes ovarian development. The team’s subsequent work found that tweaking only selected bits of Enh13 had the same effect.
Researchers suspect that mutations in this on and off switch may contribute to certain differences in human sexual development (DSD), which can cause mismatches in a person’s sex chromosomes and sexual characteristics. In particular, it was clear that Enh13 may play a role in when XY individuals express female characteristics, as investigated in mouse studies.
However, some studies suggest a potential role for symptoms in causing male characteristics to develop in XX individuals. And a new study published Thursday (April 9) in the journal Nature Communications supports this latter idea.
The researchers tweaked Enh13 in female mouse embryos by either deleting three letters or inserting one letter into the part of the on-off switch that SRY latches onto. Both of these modifications caused the female mice to develop smaller testes and male external genitalia, but also grew some ovarian tissue.
For male reproductive organs to develop, the mutation had to affect both copies of Enh13. Cells have two copies of chromosome 17, where Enh13 is present. When only one copy was mutated, XX mice developed normal ovaries and no male organs.
Normally, the SOX9 gene needs to be switched off for the ovaries to develop properly, and XX embryos use different mechanisms to achieve that. New research suggests that mutations in Enh13 release the brakes on SOX9, allowing the gene to be activated to a small degree in the absence of the SRY protein.
Once activated, SOX9 can maintain and amplify its own activity, so “this minimal activation is sufficient to trigger a self-amplifying loop,” the study authors wrote.
In the long term, the researchers say, these results could help scientists better understand how disorders of sexual differentiation develop in humans. But for now, this study raises a number of hypotheses about the role of Enh13 in both male and female sexual development, and further research is needed to fully elucidate its effects.
“Our results show that looking at genes alone is not enough,” Elisheva Averbok, a doctoral student at Bar-Ilan University who led the study, said in a statement. “Important disease-causing mutations may also be present in DNA regions of the non-coding genome that do not code for proteins but rather control gene activity.”
This article is for informational purposes only and does not provide medical advice.
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