Conceptual frameworks and mouse models for studying sex differences in physiology and disease: why compensation changes the game.

A sophisticated mechanistic understanding of physiology and disease requires knowledge of how sex-biasing factors cause sex differences in phenotype. In therian mammals, all sex differences are downstream of the unequal effects of XX vs. XY sex chromosomes. Three major categories of sex-biasing factors are activational and organizational effects of gonadal hormones, and sex chromosome effects operating outside of the gonads. These three types of effects can be discriminated from each other with established experimental designs and animal models. Two important mouse models, which allow conclusions regarding the sex-biasing effects of sex chromosome complement, interacting with gonadal hormone effects, are the Four Core Genotypes model and the XY* model. Chromosome Y consomic strains give information about the role of the Y chromosome. An important recent change in sexual differentiation theory is the increasing realization that sex-biasing factors can counteract the effects of each other, reducing rather than producing sex differences in phenotype. This change in viewpoint rationalizes a change in experimental strategies for dissecting sex chromosome effects. The overall goal is to understand the sexome, defined as the sum of effects of sex-biasing factors on gene systems and networks.