Changing ‘just one DNA letter’ in female mice triggers growth of male genitalia
Changing a single “letter” in the DNA of female mouse embryos triggers the development of male genitals and testes, scientists have discovered.
“This is a remarkable discovery because such a small change – just one DNA letter out of approximately 2.8 billion – was enough to produce a dramatic developmental outcome,” said the study’s lead author. Nitzan Gonensenior researcher at Bar-Ilan University in Israel who studies how sex is determined during embryonic development, said in a statement. statement.
In 2018, Gonen and colleagues identified another part of the DNA it’s important for this chain reaction. This DNA extract, called activator 13 (Enh13), contains no instructions for any proteins. Instead, it acts as an “on-off” switch for SOX9. The SRY protein latches onto this switch, flips it, and sends 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, mice without Enh13 developed as females. The absence of Enh13 causes SOX9 activity to drop by about 80%, preventing testes from developing and paving the way for ovaries to develop, the researchers reported. Adjusting only certain bits of Enh13 has the same effect, the team discovered in a later study.
Scientists suspect that mutations in this on-off switch could contribute to some differences in sexual development (DSD) in men, which can result in a mismatch of a person’s sex chromosomes and sexual characteristics. In particular, it was clear that Enh13 might play a role in cases where XY individuals develop female characteristics, as they had explored in mouse studies.
But some studies have also hinted at a potential role under conditions that cause XX individuals to develop masculine characteristics. And the new research, published Thursday April 9 in the journal Natural communicationssupports this last idea.
The researchers modified Enh13 in female mouse embryos by removing three letters or inserting a letter into the part of the on-off switch that SRY latches onto. Both of these changes caused the female mice to develop small testicles and external male genitalia, although they also developed ovarian tissue.
For male sexual organs to develop, the mutation had to affect both copies of Enh13; cells carry two copies of chromosome 17, on which Enh13 is located. If only one copy was mutated, XX mice developed normal ovaries and no male organs.
Typically, the SOX9 gene must be turned off for ovaries to develop properly, and XX embryos use various mechanisms to achieve this. The new study suggests that mutations in Enh13 can release the brakes on SOX9, allowing the gene to activate to a small extent even in the absence of SRY protein.
Once activated, SOX9 can maintain and amplify its own activity, so “this minimal activation would be sufficient to trigger the self-amplification loop,” the study authors write.
In the long term, these findings could help scientists better understand how DSD arises in humans, the researchers say. For now, however, the work raises a number of hypotheses about the role of Enh13 in sexual development in both men and women, and additional research is needed to fully understand its effects.
“Our results show that it is not enough to focus only on genes,” Elisheva Abberbocka doctoral student from Bar-Ilan University who led the research, said in the statement. “Important disease-causing mutations can also reside in the non-coding genome, in regions of DNA that control gene activity rather than coding for proteins.”
This article is for informational purposes only and is not intended to offer medical advice.
