A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development.

TLDR

The SRY gene on the Y chromosome drives testis formation, but mutations at a Z locus can render individuals insensitive to SRY, and such recessive sex‑reversal mutations are documented in various animals and may help identify the human Z gene. The authors propose that the wild‑type Z protein acts as a negative regulator of male sex determination, with its loss permitting male development. They review XX individuals with male traits, noting that in males SRY represses the Z gene to permit male development. Analysis of three families revealed that XX individuals with male traits lack SRY and likely carry recessive Z mutations, a hypothesis that also accounts for XY females with SRY.

Abstract

The mammalian Y chromosome carries the SRY gene, which determines testis formation. Here we review data on individuals who are XX but exhibit male characteristics: some have SRY; others do not. We have analyzed three families containing more than one such individual and show that these individuals lack SRY. Pedigree analysis leads to the hypothesis that they carry recessive mutations (in a gene termed Z) that allow expression of male characteristics. We propose that wild-type Z product is a negative regulator of male sex determination and is functional in wild-type females. In males, SRY product represses or otherwise negatively regulates Z and thereby allows male sex determination. This hypothesis can also explain other types of sex reversal in mammals, in particular, XY females containing SRY. Some of these individuals may have mutations at the Z locus rendering them insensitive to SRY. Recessive mutations (such as the polled mutation of goats) leading to sex reversal are known in a variety of animals and might be used to map and ultimately clone the human Z gene.