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The Times Online, December 11, 2009

Scientists find single ‘on-off’ gene that can change gender traits

Scientists have identified the gene that keeps females female. An international team found that the action of a single gene is all that stops females from developing male physical traits, including testes and facial hair.

When this gene was artificially “switched off” in adult female mice their ovaries began to turn into testes and they started to produce a level of testosterone found in healthy male mice.

The discovery could eventually revolutionise gender reassignment therapy and improve treatments for babies who are born with a mixed gender.

The research, published today in the journal Cell, challenges a common perception that gender is determined purely by the X-chromosomes and Y-chromosomes. The gene that was switched off, known as FOXL2, lies on a non-sex chromosome that is shared by males and females. Related Links

“We take it for granted that we maintain the sex we are born with, including whether we have testes or ovaries. But this work shows that the activity of a single gene, FOXL2, is all that prevents adult ovary cells turning into cells found in testes,” said Robin Lovell-Badge, from the National Institute for Medical Research, a co-author of the paper.

The gene appears to have a “see-saw” relationship with another gene, SOX9, which is normally active only in males. When one is on, the other is automatically off. In the first few days of male development SOX9 is turned on, and this stops FOXL2 from becoming active for the rest of the man’s life. The reverse occurs in females, with FOXL2 being switched on first.

The discovery that gender depends, at least in part, on the competing action of genes that are shared by both sexes suggests that gender can be more easily manipulated than previously thought.

FOXL2 was already known to be important for the growth of ovaries during development and for their maintenance during a woman’s life. However, scientists did not anticipate that egg-producing cells in the ovary could be co-opted by a competing male gene to carry out the male reproductive functions.

“We expected the mice to stop producing eggs, but what happened was much more dramatic,” said Mathias Treier, of the European Molecular Biology Laboratory, who led the study.

Using genetic engineering techniques, the FOXL2 gene was switched off in adult female mice. Any developed eggs in the ovary died. Follicles, which eventually grow into eggs, slowly transformed into cells that looked like Sertoli cells, which produce sperm in the testes.

After the genetic therapy, the female mice also developed testosterone-producing cells, and their levels of testosterone surged.

The physical effects of this were harder to assess as male and female mice have fewer distinctive traits — there is no difference in hairiness, for instance, and little difference in size. However, the scientists anticipate that in humans the effect would be similar to when testosterone is given in tablet form. In gender reassignment therapy this causes females to lose developed breasts and grow beards. Their voices deepen too.

Apart from the changes to their reproductive organs, the mice showed no signs of adverse effects and had a normal lifespan.

The researchers anticipate that temporarily suppressing SOX9 in males would have the opposite effect. Turning it off would automatically trigger the ovary development gene to come on, leading to cells in the testes turning into follicles and ceasing the production of testosterone.

Applying the therapy in humans is a long way off, but the researchers say that it could dramatically improve clinicians’ ability to change a person’s gender. Rather than be placed on medication for the rest of their life, only a short course of gene therapy would be required.



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