Maleness gene may be master gene switch.

The recently discovered gene for maleness appears to serve as a master control switch with the ability to turn on or off other genes involved in sexual development, according to research presented this week.

Peter Goodfellow, one of the British geneticists who first reported the discovery of this maleness gene (SN: 7/28/90, p.61), says his team now has evidence the gene makes a protein that binds to specific regions of DNA. If the maleness gene - named SRY for the sex-determining region of the Y chromosome - makes such a DNA-binding protein, it could control the expression of secondary genes involved in determinig gender.

"The SRY protein has a region that binds to DNA," Goodfellow told the Short Course in Medical and Experimental Mammalian Genetics, held at the Jackson Laboratory in Bar Harbor, Maine. "I think we've stumbled onto a family of [gene-reading] factors that are used quite. widely during development."

Goodfellow, who works at the Imperial Cancer Research Fund in London, collaborated with a group at the British Medical Research Council (MRC) National Institute for Medical Research to track down the smallest bit of DNA responsible for making a male. In the May 9 NATURE they reported identifying a comparatively short stretch of DNA on the Y chromosome that could turn a female mouse embryo into a male mouse capable of copulating with females. That stretch of mouse DNA, which they dubbed Sry, resembles the human SRY gene.

Mouse and human embryos start out female. Even trained experts cannot tell the difference between male and female mouse embryos until the twelfth day of development, when squiggly sperm ducts become detectable in the tissue destined to become testes. Once testes arise, they churn out hormones that govern the development of other male features.

Goodfellow and his colleagues theorized that the maleness genes must be active at the time of the testes' differentiation in order for it to direct male sexual development. To prove it, they searched for the protein produced by the gene in mouse embryonic gonads. Interestingly, the gene only directed protein production for the two days preceding testis development, then shut down until the male mouse reached sexual maturity.

To see if the maleness gene was sufficient to make a male, the team then spliced the mouse version of the gene into 158 fertilized mouse eggs. Eleven of the resulting mice were genetically female - bearing two X chromosomes - but also contained the spliced-in maleness gene. Three of these genetically female mice developed as males, the other eight as females.

"We have shown that [the maleness gene] . . . is sufficient for sex-reversal," Goodfellow says. He surmises that the maleness gene spliced into an inappropriate site in the chromosomes of the eight mice who failed to become males.

In an editorial accompanying Goodfellow's paper in NATURE, Anne McLaren with MRC's Mammalian Development Unit agrees that the gene "must be part of that cascade" that makes a male.

The converted females were sterile, however, a fact that Goodfellow says demonstrates that additional genes are needed to produce a fully functional male. His group is now searching for those genes using as their detector the newly discovered DNA-binding properties of the SRY protein.