Sex in mammals is genetically determined; females normally have two X chromosomes, and males normally have one X and one Y chromosome. But sometimes an individual with two X chromosomes is born with male genitalia, in a case of XX male sex reversal. The incidence of XX male sex reversal in humans is roughly 1 in 20,000–25,000 male births. Results from recent studies suggest that changes in expression of the gene Sox3 can cause complete XX male sex reversal in mice and may underlie some cases of unexplained XX male sex reversal in humans.

Male development is normally dependent on early embryonic expression of the gene Sry, located on the Y chromosome, which induces testis formation and activates the male development pathway. But Paul Thomas (University of Adelaide, Australia) and his colleagues found that ectopic expression of Sox3, a gene located on the X chromosome, in developing gonads resulted in XX mice that were male in appearance, reproductive structures and behavior but were sterile owing to a lack of sperm production (J. Clin. Invest. doi:10.1172/JCI42580; published online 22 December 2010).

Sox3 is important in the development of the brain and central nervous system but was not previously known to be able to trigger male development. The new results from Thomas' studies indicate that Sox3 can act as a surrogate for Sry and shed light on the evolutionary relationship between these two genes. “We have suspected for a long time that SOX3 is the evolutionary precursor gene for SRY. By showing that SOX3 can activate the male pathway in the same way as SRY, we now believe this to be true,” said Thomas in a press release.

Credit: Gary Caviness

Given that Sox3 ectopic expression was able to induce sex reversal in mice, it seemed possible that changes to SOX3 could be associated with XX male sex reversal in humans. Therefore, in collaboration with researchers at other institutions in Australia and internationally in London (UK), Lisbon (Portugal) and Los Angeles and Berkeley (CA), Thomas' group analyzed the genomes of 16 humans with XX male sex reversal and found that 3 of these individuals had genomic rearrangements near the SOX3 locus. Such rearrangements may be the underlying cause of sex reversal in some affected individuals. In a press release, Thomas stated, “This discovery provides new insight into the genetic causes of disorders of sexual development... [and will] ultimately help us to develop therapies or technologies to improve clinical outcomes.”