A strategic research alliance: Turner syndrome and sex differences

Abstract

Sex chromosome constitution varies in the human population, both between the sexes (46,XX females and 46,XY males), and within the sexes (e.g., 45,X and 46,XX females, and 47,XXY and 46,XY males). Coincident with this genetic variation are numerous phenotypic differences between males and females, and individuals with sex chromosome aneuploidy. However, the molecular mechanisms by which sex chromosome constitution impacts phenotypes at the cellular, tissue, and organismal levels remain largely unexplored. Thus, emerges a fundamental question connecting the study of sex differences and sex chromosome aneuploidy syndromes: How does sex chromosome constitution influence phenotype? Here, we focus on Turner syndrome (TS), associated with the 45,X karyotype, and its synergies with the study of sex differences. We review findings from evolutionary studies of the sex chromosomes, which identified genes that are most likely to contribute to phenotypes as a result of variation in sex chromosome constitution. We then explore strategies for investigating the direct effects of the sex chromosomes, and the evidence for specific sex chromosome genes impacting phenotypes. In sum, we argue that integrating the study of TS with sex differences offers a mutually beneficial alliance to identify contributions of the sex chromosomes to human development, health, and disease.

Keywords: Turner syndrome; sex chromosome aneuploidy; sex chromosome evolution; sex differences.

Figure 1.. Evolution of the human sex chromosomes resulted in four gene classes on the X chromosome.

(A) Sex chromosome evolution began with ordinary autosomes. SRY emergence began Y chromosome differentiation, followed by a series of inversions that resulted in loss of crossing-over between the male-specific region of the Y (MSY) and the non-pseudoautosomal region of the X (NPX). The pseudoautosomal region (PAR) on the short arm retained X-Y crossing over. (B) Four classes of genes on the X chromosome underwent different evolutionary trajectories as a result of Y chromosome decay. The black wavy lines indicate the level of mRNA expressed from each gene. PAR1 genes (1) retained X-Y crossing-over and remain expressed from both the X and Y chromosomes. X-Y pair genes (2) reside in the NPX and MSY and do not cross-over, but due to high dosage sensitivity the Y gene was preserved and expression retained on both X chromosomes in 46,XX females. X-inactivated genes (3) had intermediate dosage sensitivity, which allowed for Y chromosome decay. This was followed by upregulation on the X chromosome to retain ancestral dosage in males, and subsequent inactivation of one allele in females. Escape genes (4) followed the same initial path as the X-inactivated genes, but did not become inactivated. Some escape genes may have avoided the step of X-upregulation, indicated by the gray dashed arrow bypassing this step. These genes are predicted to have lower levels of mRNA expression (gray wavy lines) compared to genes that underwent X-upregulation. (C) Functions of select human X-Y pair genes, adapted from (Bellott et al., 2014).

Figure 2.. Mechanisms of sex chromosome contributions to TS and sex differences.

(A) PAR genes are typically more highly expressed in 46,XY males compared with 46,XX females, due to spreading of XCI, and expressed at the lowest levels 45,X individuals. (B) Left, X-Y pair genes may have differential mRNA expression levels from the X and Y homologs such that 46,XY or 46,XX individuals have unequal total expression. These genes escape XCI in 46,XX females so expression is lower in 45,X females. Right, X-Y pair genes may encode functionally divergent proteins that lead to molecular sex differences between 46,XX and 46,XY individuals. A combination of both mechanisms may also exist. (C) Genes that escape XCI without a Y homolog may contribute to sex differences due to differences in mRNA expression. Generally, expression of genes that escape XCI is higher in females.

Figure 3.. X and Y genes that may contribute to Turner syndrome and sex differences.

This schematic includes two categories of genes that contribute to TS and sex differences phenotypes: X-Y pair genes and PAR1 genes (not shown are X escape genes without a Y homolog; these may also contribute to sex differences). PAR1 genes are listed in order from distal to proximal. Genes discussed in case studies are marked with an asterisk.