Genetics of sexual development: A new paradigm

Abstract

The classical paradigm of human and mammalian sexual development, largely based on work of Alfred Jost, depicts the genetic factor(s) that determine(s) sex as influencing only the fate of the gonad. A maleness factor produces testes (Primary Sex Determination). These organs secrete hormones which cause male Secondary Sexual Differentiation. In absence of the maleness factor, by default the gonad becomes an ovary, and the absence of testicular hormones leads to female secondary differentiation. In this article a new paradigm is proposed, to accommodate recent findings. Sexual dimorphism precedes gonadal development, in a Pregonadal Stage. Furthermore, female development is not by default-both male (Y) and female (X) sex-chromosomal primary sex-determining mechanisms probably exist. The human/mammalian male Y-chromosomal sex-determining gene is now known (SRY/Sry), and a candidate for a non-inactivated, X-linked, female determining factor, is under study. However, the proximate gonad-determining genes are probably on autosomes. Pathways between the primary factors and the proximate gonad-determining genes are indirect and complex. A hypothetical gene Z has been proposed, that inhibits the testis determiner and is itself the target of suppression by SRY/Sry. Candidates for proximate testis and ovary-determining factors and for Z also exist. The "default" concept has also been superseded with respect to secondary sexual differentiation. Absence of testicular hormones does not produce a normal female phenotype; ovarian genes and hormones are necessary. Finally, sex-chromosomal sex-determining genes influence the development not only of non-gonadal organs of secondary sexual development, but also of organs outside of the reproductive system.

Sexual dimorphism in environmental epigenetic programming

“…However, female development is not carried out by default since recent studies suggest that both Y and X sex-chromosomal primary mechanisms of sex determination probably exist [16]. In addition, sex-chromosomal sexdetermining genes can influence not only the development of non-gonadal secondary sexual organs but also of organs outside of the reproductive system, such as brain [16].…”

Nutritional developmental epigenomics: immediate and long-lasting effects

“…However, female development is not carried out by default, since recent studies suggest that both Y and X sex-chromosomal primary mechanisms of sex determination probably exist (75) . In addition, sex-chromosomal sex-determining genes can influence not only the development of nongonadal secondary sexual organs but also of organs outside the reproductive system, such as the brain (75) . In order to accommodate recent findings it has been proposed that sexual dimorphism precedes gonadal development.…”

Epigenetic mechanisms involved in developmental nutritional programming

“…Recently, it was found that the sexual dimorphism between male and female cells in their response to chemical exposure to either ethanol or camptothecin apparently occurred at fetal stages that preceded the production of sex hormones and, accordingly, could be directly attributed to a sex chromosome effect [93,94] . Sex-determining genes on sex-chromosomes can influence not only the development of non-gonadal secondary sexual organs but also of organs outside of the reproductive system, such as brain [95] . Indeed, at the level of the whole body, the sex-chromosomes are crucial for establishment of sex-dimorphism of cellular functions [42] .…”