Scientists come with increasing evidence that human sex is not determined by sex chromosomes but by genes placed on those chromosomes.

This may explain the numerous cases of ambiguous genitalia in humans and why an individual's genitals might not match the reproductive organs inside. "What really matters is what people feel they are in terms of gender, not what their family or doctors think they should be," said Eric Vilain, a geneticist at the University of California, Los Angeles.

Genital ambiguity is estimated to occur at a pace of one in 4,500 births, and undescended testes count to one in 100 newborn boys.

The traditional idea was that the male development is "active," determined by the presence of the Y chromosome, while the female development is passive, due to the lack of the Y chromosome. Experiments made with castrated animal embryos showed that those embryos developed into females.

But in 1990, Cambridge's Peter Goodfellow found SRY, a gene located on the Y chromosome responsible for triggering the male development. Any mutation on it was found to induce female development. When researchers inserted SRY into a XX female fetus mouse, the offspring was born male. But Vilain says that SRY does not trigger male development directly, but by blocking an "antitestis" gene. In fact, males with SRY but XX chromosomes range in traits from normal males to an ambiguous mix.

Test-tube investigations showed that SRY can stop gene transcription, working through interference.

In 1994, Vilain's team achieved a male while the gene was missing. Vilain believes sex develops due to a fragile equilibrium between many promale, antimale, and possibly profemale genes, whose research was more neglected due to the traditional view of the female development as a default pathway.

Now, researchers are detecting evidence for profemale genes. DAX1, on the X chromosome, triggers the female development while inhibiting testis development, if not stopped by SRY. Over-expression of DAX1 develops an XY individual into a female.

Vilain's team has discovered also another gene, WNT4, acting in a similar way during female development. The two genes can work together against SRY and other promale genes. "Ovary formation may be just as coordinated as testis determination, consistent with the existence of an ovarian switch", report geneticist David Schlessinger and his collaborators in a 2006 review.

Vilain believes that - unlike the classical theory - sex hormones do not induce differentiated neural (brain) development and behavioral differences between the two sexes on their own. "SRY is expressed in the brain, thus genes influence brain sexual differentiation directly", said Vilain.

Of the newly discovered 50 genes involved in sex expression in mice, seven operate in the brain even before the gonads are formed. Vilain's team is collaborating with an Australian clinic to investigate expression patterns of the sex-specific genes in transsexual people.