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Modern Genetic Analysis Chapter 16. The Genetic Basis of Development Sex Determination in Mammals: Coordinated Control by the Endocrine System
Genetics In Process 16-2: The mutational analysis of mammalian sex determination

The Y chromosome testis-determining gene was identified through mapping and characterization by Robin Lovell-Badge and Peter Goodfellow of a genetic syndrome common to mice and humans that almost certainly affects this factor (see the adjoining molecular map). This syndrome is called sex reversal. Sex-reversed XX individuals are phenotypic males and have been shown to carry a fragment of the Y chromosome in their genomes. In general, these Y chromosome duplications arise by an illegitimate recombination between the X and Y chromosomes that fuses a piece of the Y chromosome to a tip of one of the X chromosomes. The part of the Y chromosome that includes these duplications was cloned; by subsequent molecular analysis, Lovell-Badge and Goodfellow identified from this region a transcript that is expressed in the appropriate location of the developing kidney capsule.

The gene encoding this transcript was named the sex reversal on Y gene (SRY in humans, Sry in mice), because it was identified on the basis of the sex-reversal syndrome, but it is certainly the same gene as TDY~Tdy. Lovell-Badge and Goodfellow used a transgene to provide spectacular evidence in support of this identity (see photograph). A cloned 14-kb genomic fragment of the mouse Y chromosome, including the Sry gene, was inserted into the mouse genome by germ-line transformation. An XX offspring containing this inserted Sry DNA (the transgene) was completely male in external and internal phenotype and, as predicted, possessed the somatic tissues of the testisincluding the Leydig cells that make testosterone. (It should be noted, however, that this mouse was sterile. The sterility is probably a consequence of having two X chromosomes in a male germ cell, because XXY male mice are similarly sterile.) Thus, a single genetic unit was directly shown to greatly alter the mammalian sexual phenotype, completely consistent with the role of SRY~Sry as the gene that determines testis development.

The role of the androgen receptor in receiving the testosterone signal and establishing the male secondary sexual characteristics was elucidated through the study of rare Tfm mice lacking this receptor. Chromosomally XY mice hemizygous for the X-linked Tfm (Testicular feminization) mutation develop as phenotypic females (see Figure 4-26), except that they are infertile and are typically diagnosed at puberty because of their failure to menstruate. Tfm XY mice have testes, but the target cells that must decide between alternative pathways regarding sexually dimorphic characteristics lack androgen receptors and so are completely insensitive to the presence of testosterone. Thus, these mice develop along the default developmental pathway, which leads to phenotypic feminization.

© 1999 by W. H. Freeman and Company. All rights reserved.