Possible role for H–Y antigen in the primary determination of sex

Abstract

IN mammals, the genetic basis of sex determination and differentiation seems to be simple^1,2. A gene or set of genes on the Y chromosome causes the indifferent embryonic gonad to develop as a testis³. Thus an ovary develops in the absence of the Y and a testis in its presence. The testis then secretes testosterone which induces male development of the accessory glands and ducts^4,5. The masculinising action of testosterone on its target cells is mediated by the product of a gene on the X chromosome. This product activates all the genes required for manifestation of the male phenotype in response to circulating testosterone¹. Evidence for this crucial involvement of the X chromosome in male sexual differentiation comes from a mutation of the relevant gene in the mouse (Tfm), resulting in failure to respond to testosterone. A chromosomally XY animal with this mutant gene develops testes, because the Y chromosome is present, but shows no further male differentiation, thus exhibiting the syndrome known as ‘testicular feminisation’⁶. This insensitivity to androgen is caused by a mutational deficiency of the nuclear–cytosol androgen-receptor protein not only in mice^7–9 but also in man¹⁰. Thus the part that the X chromosome plays in male sexual differentiation has been clarified at the level of an individual gene situated on this chromosome.