Master gene makes maleness mandatory.

Master gene makes maleness mandatory

In the Broadway production of "My Fair Lady," an exasperated Rex Harrison became famous for lamenting: "Why can't a woman--be more like a man?" Now, it seems, British molecular biologists have found the answer.

What women lack, these researchers say, is a single gene called SRY -- or the Sex-determining Region of the Y chromosome. The finding culminates two decades of work in which scientists have sought to identify the specific Y-chromosomal region responsible for masculinity--not only to understand the genetics of gender but also as a model for studing basic principles of embryo development.

The gene's discoverers say that this newly identified string of nucleic acids, present within every male mammalian cell so far examined, embodies the very essence of maleness. In humans, for example, the gene seems responsible for initiating the creation of testes after about seven weeks of fetal development. The testes, in turn, produce a cocktail of masculinizing hormones that influnce gender-related developmental path-ways throughout a man's life.

Researchers have known since 1959 that male mammalian cells, except sperm, have both an X chromosome and a Y chromosome, while female mammalian cells, except eggs, contain two Xs. They've also known that only a small portion of the Y chromosome confers masculinity. Indeed, mutant XY mammals whose Y chromosomes lack this male-determining portion develop as females. And XX individuals who, through a genetic quirk, have his critical bit of Y appended to their X chromosomes, develop as males.

Previously reported discoveries of candidate genes for maleness--including the widely publicized, 1987 isolation of a testis-determining factor gene (SN: 1/2/88, p.4) -- have all proven wrong. In the July 19 NATURE, Andrew H. Sinclair of the Imperial Cancer Research Fund in London and his colleagues say thei newly discovered SRY is the best candidate yet. Others agree, but all concur that final confirmation depends upon an upcoming series of experiments in which scientists will try to create make mice by inserting the SRY gene into female mouse embryos. Sinclair says he and his co-workers hope to complete those tests by the end of the year.

Meanwhile, the evidence that SRY is indeed the master gene for maleness appears compelling. For example, a true male-determining gene would probably be highly conserved through evolution, an so could be expected in a wide variety of animals within a given class, such as mammals. Using a molecular test dubbed a "Noah's Ark blot," the London researchers found the gene in blood cells of human XX males, and in male chimpanzees, rabbits, pigs, horses, cattle and tigers. The gene was absent in all females tested.

Furthermore, in the same issue of NATURE, a team of researchers led by John Gubbay of the MRC National Institute for Medical Research in London describe experiments showing that XY female mice lack the mouse version of SRY. And they found that in embryonic male mice, the gene becomes active at about the time testes development begins. Those findings bolster the evidence for its role in make development.

Unexpectedly, mouse and human studies indicate SRY remains active in adult make testes, suggesting the gene has some ongoing function even after completion of male development. The nature of that function remains a mystery.

Scientists remain uncertain about how SRY may regulate other genes that play a role in gender development. Perhaps significantly, Sinclair says, SRY's nucleic-acid sequence resembles those of known DNA-binding proteins. Such proteins have the ability to turn other genes on or off. He speculates that the SRY protein might suppress genes required for female development, or activate genes whose products add up to maleness.