Tabby (Ta), a murine X-linked mutant gene, produces a syndrome of ectodermal dysplasia including anhidrosis (absence of sweat glands). Development of sweat glands is related to that of dermal ridges (dermatoglyphics) and abnormal ridges may be associated with absence of sweat glands in the human syndrome of hypohidrotic ectodermal dysplasia (HED). We have found that dermal ridges occur in normal mice but are lacking in Ta mutants. Previously we showed that epidermal growth factor (EGF) reverses delayed eyelid opening and incisor eruption in Ta mice. We now report that EGF induces development of dermal ridges and functional sweat glands in Ta/Y hemizygotes, indicating a role in mammalian morphogenesis. Ta seems to be genetically homologous to human X-linked HED, as Ta maps close to loci homologous to linkage markers of HED and the two syndromes share many traits, including absence of all or most sweat glands. Absence of these glands causes hyperpyrexia, a clinical emergency in infants with HED; reversal of the trait in the mouse homologue of the disease indicates that an important genetically determined congenital defect in humans may become treatable.

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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.

Introduction Recent studies on male homosexuals showed increased fecundity of maternal female relatives of homosexual probands, compared to those of heterosexual controls. We have suggested that these data could be explained by the transmission, in the maternal line, of an X-linked genetic factor that promotes androphilic behavior in females and homosexuality in males. Aim Our original studies were on relatives of male subjects who declared themselves to be exclusively homosexual. However, the relationship between homosexuality and bisexuality, including the possibility of shared genetic factors, is complex and largely unexplored. To cast light on this issue, in the present study we examined whether relatives of bisexuals show the same indirect fitness advantage as previously demonstrated for homosexuals. Main Outcome Measures Subjects completed a questionnaire on their sexual orientation, sexual behavior, and their own and their relatives’ fecundity. Methods We studied 239 male subjects, comprising 88 who were exclusively or almost exclusively heterosexual (pooled to comprise our “heterosexual” group), 86 who were bisexual, and 65 exclusively or almost exclusively homosexual individuals (pooled in our “homosexual” group). Bisexuals were here defined on the basis of self-identification, lifetime sexual behavior, marital status, and fecundity. Results We show that fecundity of female relatives of the maternal line does not differ between bisexuals and homosexuals. As in the previous study on homosexuals, mothers of bisexuals show significantly higher fecundity, as do females in the maternal line (cumulated fecundity of mothers, maternal grandparents, and maternal aunts), compared to the corresponding relatives of heterosexual controls.This study also shows that both bisexuals and homosexuals were more frequently second and third born. However, only homosexuals had an excess of older male siblings, compared to heterosexuals. Conclusions We present evidence of an X-chromosomal genetic factor that is associated with bisexuality in men and promotes fecundity in female carriers.

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