Molecular Genetics of Sex Determination
Molecular Genetics of Sex Determination
In humans, the choice between male or female development is genetically determined. Sex determination take place when the bipotential embryonic gonad becomes either testis or ovary. This process is directed by genes that have been discovered by genetic analysis of sex-reversed patients and confirmed by knockout experiments in mice. The testis-determining pathway is better known than the ovary pathway. SRY, a gene located on the Y chromosome, triggers a complex genetic cascade leading to testicular differentiation. In this cascade, two genes play a crucial role in male differentiation, SOX9 and FGF9, which contribute to testicular cord formation. However, only a minority of 46,XY sex-reversed patients can be explained by mutations in known genes such as SRY, SOX9, WTI, and SF1, suggesting that other genes influencing sex determination are yet to be discovered. In females, some rare genes that induce ovarian failure or female-to-male sex reversal have been found through gene-targeted inactivation in mice or positional cloning of mutations in humans and goats. In both sexes, genetic analysis of sex-reversed individuals (XX males, XX and XY hermaphrodites, and XY with complete or partial dysgenesis) remains an approach of choice to isolate new genes involved in sex determination.
Sex determination is defined as the commitment of the indifferent gonad to a testis or an ovary, a developmental process that is genetically programmed in a critically timed and gene dosage-dependent manner. Much about our understanding of this process has been obtained from observations of gene knockout experiments in mice and from genetic studies of human patients with sex-reversal syndrome. Most of them are 46,XY complete and partial females, and the genes responsible for these phenotypes, mostly isolated by positional cloning, are involved in the testis-determining pathway. Sex reversal also concerns XX individuals with male and hermaphrodite phenotypes. Ovarian differentiation is then stopped and the testis differentiation take place in the absence of Y sequences. However, very few genes are known to be involved in the genetic control of the ovarian differentiation. The focus of this review is on the genetic mechanisms whereby the mammalian indifferent gonad develops into a testis or an ovary and mutations affecting this process.
In humans, the choice between male or female development is genetically determined. Sex determination take place when the bipotential embryonic gonad becomes either testis or ovary. This process is directed by genes that have been discovered by genetic analysis of sex-reversed patients and confirmed by knockout experiments in mice. The testis-determining pathway is better known than the ovary pathway. SRY, a gene located on the Y chromosome, triggers a complex genetic cascade leading to testicular differentiation. In this cascade, two genes play a crucial role in male differentiation, SOX9 and FGF9, which contribute to testicular cord formation. However, only a minority of 46,XY sex-reversed patients can be explained by mutations in known genes such as SRY, SOX9, WTI, and SF1, suggesting that other genes influencing sex determination are yet to be discovered. In females, some rare genes that induce ovarian failure or female-to-male sex reversal have been found through gene-targeted inactivation in mice or positional cloning of mutations in humans and goats. In both sexes, genetic analysis of sex-reversed individuals (XX males, XX and XY hermaphrodites, and XY with complete or partial dysgenesis) remains an approach of choice to isolate new genes involved in sex determination.
Sex determination is defined as the commitment of the indifferent gonad to a testis or an ovary, a developmental process that is genetically programmed in a critically timed and gene dosage-dependent manner. Much about our understanding of this process has been obtained from observations of gene knockout experiments in mice and from genetic studies of human patients with sex-reversal syndrome. Most of them are 46,XY complete and partial females, and the genes responsible for these phenotypes, mostly isolated by positional cloning, are involved in the testis-determining pathway. Sex reversal also concerns XX individuals with male and hermaphrodite phenotypes. Ovarian differentiation is then stopped and the testis differentiation take place in the absence of Y sequences. However, very few genes are known to be involved in the genetic control of the ovarian differentiation. The focus of this review is on the genetic mechanisms whereby the mammalian indifferent gonad develops into a testis or an ovary and mutations affecting this process.
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