| Testis-Determining Factor |
The presence of a Y chromosome is usually necessary and sufficient for male development: a 45XO human is female, while a 47XXY is male. It also typically leads to formation of a testis in the mammalian embryo - the primary sex-determining event. The testis then produces and secretes the male hormones, androgens, resulting in the formation of male genitalia. In the absence of Y, the pathway leads to development of a female (Fig. 4). Therefore, the Y must contain a testis-determining factor.
The region of the Y chromosome that carries the testis-determining factor contains a gene called SRY (sex region Y). Its product binds to DNA, acting as a transcription factor that is critical for testis production. Scientists studying sex reversal, a difference between the chromosomal sex and the phenotypic sex, confirmed the importance of SRY. They determined that infertile males who were XX had all acquired a particular snippet of the Y chromosome, which was translocated to X. That small fragment of the Y carries SRY. Conversely, many XY females have a deletion of the part of the Y that includes SRY. Introduction of the mouse SRY gene into an XX mouse causes the formation of testis and the animal develops as a male anatomically; however, it does not produce sperm. Thus, SRY is the testis-determining factor, and is the only gene on the Y chromosome that is essential for development of male genitalia. Some genes required for male fertility are on the Y chromosome, while others are on the X or on autosomal chromosomes. The DAZ genes on the Y are essential for sperm formation; deletion of DAZ results in male infertility.
In the first few weeks of development a human embryo develops a sexually indifferent gonad, which can become either a testis or an ovary. Without SRY to stimulate testis development, the gonad becomes an ovary and the embryo develops into a female; the development pathways of both male and female are complex, however, and are regulated by several gene products (Fig. 4). For example, the product of the DAX1 gene (present on the X chromosome) appears to interact with SRY: an excess of SRY leads to testis formation, while an excess of DAX1 leads to ovary formation. A mutation in DAX1 leads to sterile males but has no effect on females. An extra copy of DAX1 in a male leads to a sex-reversed XY female. An SOX9 mutation (on chromosome 17) in a male leads to sex-reversed XY females, while an extra copy of SOX9 in a female can result in a sex-reversed XX male. Conversely, an extra copy of WNT4, which is implicated in ovary formation, in a male results in a sex-reversed XY female.