What a difference an X or Y makes: sex chromosomes, gene dose, and epigenetics in sexual differentiation

Abstract

A modern general theory of sex determination and sexual differentiation identifies the factors that cause sexual bias in gene networks, leading to sex differences in physiology and disease. The primary sex-biasing factors are those encoded on the sex chromosomes that are inherently different in the male and female zygotes. These factors, and downstream factors such as gonadal hormones, act directly on tissues to produce sex differences and antagonize each other to reduce sex differences. Recent studies of mouse models such as the four core genotypes have begun to distinguish between the direct effects of sex chromosome complement (XX vs. XY) and hormonal effects. Several lines of evidence implicate epigenetic processes in the control of sex differences, although a great deal of information is needed about sex differences in the epigenome.

Figure 1

Four classes of primary sex-determining factors that are encoded by the sex chromosomes. Class I are Y genes found only in males. Class II are X genes that escape inactivation and are inherently expressed higher in females than males. Class III are X genes that are imprinted and have a sex-biasing effect because of expression of the paternal imprint only in XX cells. Class IV are putatitve heterochromatic regions on the sex chromosomes (the X chromosome is illustrated here), which act as sinks to sequester heterochromatizing factors from other chromosomes and alter the epigenetic status of autosomes. Reprinted from Arnold, 2011, Trends in Genetics.

Figure 2

Sex differences in the mammalian transcriptome. Data from microarray profiling are illustrated. Histograms show the distribution of M?F ratios of expression of all genes measured, including autosomal genes (black, dotted line) and X chromosome genes (red). In each tissue, about the same number of genes are expressed higher in males than females, and most sex differences are well below two-fold. X inactivation is effective in preventing higher expression of most X genes in females. Although the amount of sexual dimorphism (width of the histograms) differs across tissues, the degree of sexual bias in X genes is matched, tissue for tissue, to the sexual bias of autosomal genes, presumably because they interact with each other in gene networks. Reprinted from Itoh et al., (2007).

Figure 3

The Four Core Genotypes Model. When XY gonadal males (XYM) are mated to XX gonadal females, the offspring comprise four genotypes: XX gonadal females and males (XXF, XXM both without Sry), and XY gonadal males and females (XYF, XYM, both with Sry). The four genotypes represent a 2 X 2 comparison of the effects of gonadal sex (comparing mice with testes vs. mice with ovaries) and the effects of sex chromosome complement (XX vs. XY). A, When a sex difference is caused by gonadal hormones, the two groups of mice with testes differ from the two groups with ovaries, irrespective of their sex chromosome complement. B, When the sex difference is caused by sex chromosome complement, then the two groups of XX mice differ from the two XY groups, irrespective of their type of gonad. Not diagramed are cases in which the two factors interact.

Figure 4

Representative differences among FCG mice. FCG mice were gonadectomized as adults, and then implanted with equal amounts of testosterone (left) or nothing (right). On the left is graphed the number of neurons in the spinal nucleus of the bulbocavernosus (SNB). Gonadal males have more neurons than gonadal females, irresective of their sex chromosome complement, indicating that this sex difference is dominantly controlled by gonadal hormones. To measure nociception (right), the mice were place on a hot plate and the latency to lick the paws was measured. XX mice responded more slowly than XY mice, irrespective of their previous gonadal status, indicating that the complement of sex chromosomes causes the difference. SNB data from De Vries et al., 2002, and nociception data from Gioiosa, Chen, et al., (2008a).

Figure 5

Summary of possible sex-specific epigenetic modifications that could influence chromatin status and gene expression in a gender-specific manner.