A general theory of sexual differentiation

Abstract

A general theory of mammalian sexual differentiation is proposed. All biological sex differences are the result of the inequality in effects of the sex chromosomes, which are the only factors that differ in XX vs. XY zygotes. This inequality leads to male-specific effects of the Y chromosome, including expression of the testis-determining gene Sry that causes differentiation of testes. Thus, Sry sets up lifelong sex differences in effects of gonadal hormones. Y genes also act outside of the gonads to cause male-specific effects. Differences in the number of X chromosomes between XX and XY cells causes sex differences in expression (1) of Xist, (2) of X genes that escape inactivation, and (2) of parentally imprinted X genes. Sex differences in phenotype are ultimately the result of multiple, independent sex-biasing factors, hormonal and sex chromosomal. These factors act in parallel and in combination to induce sex differences. They can also can offset each other to reduce sex differences. Other mechanisms, operating at the level of populations, cause groups of males to differ on average from groups of females. The theory has advantages for directing attention to inherent sex-biasing factors that operate in many tissues to cause sex differences, to cause sex-biased protection from disease, and to frame questions for further study.

Sex differences in obesity: X chromosome dosage as a risk factor for increased food intake, adiposity and co-morbidities

“…It is possible that some effects of hormones and sex chromosome genes are in opposite directions, such that in composite, they reduce the differences between sexes. This hypothesis has been raised in the literature previously [10] and will be important to test experimentally.…”

“…This sets the path for the development of male or female differences, determined by a combination of genetic effects (presence of genes on the Y chromosome that influence testis development, and the presence on the X chromosome of dosage-responsive genes) and distinct gonadal secretions from testes and ovaries [10]. Thus, sex differences in metabolism and fat storage in humans and animals are likely influenced by genetic as well as hormonal differences between males and females.…”

A Guide for the Design of Pre-clinical Studies on Sex Differences in Metabolism

“…One of the most important differences is that the mammalian testis-determining Sry gene on the Y chromosome causes the development of testes in males (Arnold, 2017). In the absence of Sry in XX females, autosomal or X-linked genes induce differentiation of ovaries.…”

When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

“…Sex differences are common, and generally attributed to the hormonal changes induced by gonadal differentiation; however, there is considerable evidence supporting a role for the sex chromosomes in sexual dimorphism, distinct from sex determination (reviewed in [25]). Mouse breeding schemes that generate XX males and XY females to compare with normal XY males and XX females (known as the 'FourCore Genotypes' model) have revealed a role for the sex chromosomes in sexually dimorphic traits including adiposity, metabolic disease, cardiovascular injury and behaviour [25].…”

“…Mouse breeding schemes that generate XX males and XY females to compare with normal XY males and XX females (known as the 'FourCore Genotypes' model) have revealed a role for the sex chromosomes in sexually dimorphic traits including adiposity, metabolic disease, cardiovascular injury and behaviour [25]. The role is likely to be even more pronounced in humans due to the larger number of escape genes (see §2), but separation of effects from hormonal influences is challenging in the absence of such controlled breeding.…”