Four Core Genotypes and XY* mouse models: Update on impact on SABV research

Abstract

The impact of two mouse models is reviewed, the Four Core Genotypes and XY* models. The models are useful for determining if the causes of sex differences in phenotypes are either hormonal or sex chromosomal, or both. Used together, the models also can distinguish between the effects of X or Y chromosome genes that contribute to sex differences in phenotypes. To date, the models have been used to uncover sex chromosome contributions to sex differences in a wide variety of phenotypes, including brain and behavior, autoimmunity and immunity, cardiovascular disease, metabolism, and Alzheimer's Disease. In some cases, use of the models has been a strategy leading to discovery of specific X or Y genes that protect from or exacerbate disease. Sex chromosome and hormonal factors interact, in some cases to reduce the effects of each other. Future progress will come from more extensive application of these models, and development of similar models in other species.

Keywords: Eif2s3x; SABV; Sex chromosomes; Sex differences; X chromosome; Y chromosome.

Figure 1.

Schematic drawing showing the breeding scheme and genotypes in the Four Core Genotypes (FCG) and XY* mouse models. Above, the FCG model produces four genotypes that are XX or XY, each genotype with either testes or ovaries. Comparison of the XX and XY mice with the same type of gonad leads to discovery of phenotypes in which the complement of sex chromosomes causes sex differences. Comparison of mice with testes vs. ovaries, with the same sex chromosomes, leads to discovery of phenotypes in which the presence or absence of Sry causes sex differences, including the effects of testicular vs. ovarian secretions. Below, the XY* model is especially good for detecting effects of X chromosome number, in comparisons of XO and XX gonadal females, or XY vs. XXY gonadal males. Comparisons of mice with a Y chromosome or not (XO vs. XY, XX vs. XXY) leads to detection of phenotypes in which the Y chromosome, or gonadal hormones, causes a sex difference. Figure modeled after (Arnold and Chen, 2009).