X-chromosome regulation and sex differences in brain anatomy

Abstract

Humans show reproducible sex-differences in cognition and psychopathology that may be contributed to by influences of gonadal sex-steroids and/or sex-chromosomes on regional brain development. Gonadal sex-steroids are well known to play a major role in sexual differentiation of the vertebrate brain, but far less is known regarding the role of sex-chromosomes. Our review focuses on this latter issue by bridging together two literatures that have to date been largely disconnected. We first consider "bottom-up" genetic and molecular studies focused on sex-chromosome gene content and regulation. This literature nominates specific sex-chromosome genes that could drive developmental sex-differences by virtue of their sex-biased expression and their functions within the brain. We then consider the complementary "top down" view, from magnetic resonance imaging studies that map sex- and sex chromosome effects on regional brain anatomy, and link these maps to regional gene-expression within the brain. By connecting these top-down and bottom-up approaches, we emphasize the potential role of X-linked genes in driving sex-biased brain development and outline key goals for future work in this field.

Trial registration: ClinicalTrials.gov NCT00001246.

Keywords: Anatomy; Brain; Dosage compensation; Gametologs; MRI; Sex chromosomes; Sex differences.

Published by Elsevier Ltd.

Figures

Figure 1.. The gene content of the sex chromosomes is specialized.

A. The mammalian X and Y chromosomes are each present in a single copy in males, which has resulted in their enrichment in reproduction-related genes expressed in testis. The X chromosome is also enriched in genes expressed in the brain. The autosomes (A) are symbolized by one pair of homologous chromosomes (green). B. Human X-linked genes are more highly expressed in certain brain regions. For example, X-linked genes are more highly expressed in the hypothalamus compared to the cerebellum. Each dot represents expression of an X-linked gene. Dots labeled red are genes with at least 1.5 fold higher expression in hypothalamus, while thase labeled in purple have 1.5 fold higher expression in cerebellum. C. The sex chromosomes have retained a few shared genes, including PAR genes located in the pseudoautosomal region(s), and a small set of non-PAR homologous X/Y gene pairs. The X homologs of these X/Y gene pairs often escape X inactivation. In addition, some X-linked genes escape X inactivation even though they have lost their Y homolog. PAR genes are in green, X/Y genes and escape genes in purple.

Figure 2.. Sex differences due to random X inactivation and mosaicism in females.

We consider a brain-expressed X-linked gene with two different alleles (A, green, B, red) with slightly different functions. In males with a single X chromosome or in homozygous females with two identical alleles, there will be uniform expression of one or the other form (A or B allele) of the gene in each individual. In females heterozygous for the two alleles of the gene, one X chromosome will be silenced at random during development, resulting in patches of cells with expression of either allele A or allele B. The size of the patches is highly variable within the brain and between individual females (Wu et al., 2014). Thus, heterozygous females may exhibit much more variation in terms of expression of X-linked genes, as compared to males and homozygous females.

Figure 3.. Methods available for study of the nervous system [modified from (Sejnowski et al., 2014)].

Methods are shown as boxed domains within a 2-dimensional surface defined by varying temporal (x-axis) and spatial (y-axis) scales. The box with a dashed gray border indicates the spatio-temporal domain covered by in vivo structural neuroimaging (sMRI) - the method for brain measurement that will be the main focus of our article. Aabbreviations: EEG (electroencephalography), fMRI (functional magnetic resonance imaging), MEG (magnetoencephalography), PET (positron emission tomography), sMRI (structural magnetic resonance imaging), TMS (transcranial magnetic stimulation), 2-DG (2-deoxy-D-glucose), VSD (voltage sensitive dye).

Figure 4.. Developmental Trajectories for Total Brain Tissue Volume, Gray Matter Volume and White Matter Volume in Males and Females [adapted from (Giedd et al., 2015)].

Sex-specific group level trajectories (blue=males, red-females) for each volume (bold lines with shaded 95% confidence intervals) are shown with underlying raw data (points = scans, lines link scans from the same person). The age range covered is 5–25 years of age. For all plots, there are statistically significant sex-differences in both trajectory shape (i.e. sex-differences in the tempo of volume change, p

Figure 5.. Volumetric and Surface Projection Brain Maps Showing Regions of Statistically-Significant Sex-Biases in Regional GMV [from (Liu et al., 2020)].

Volume and surface based maps showing regions of statistically-significant sex-differences in GMV after correction for variation in total GMV.

Figure 6.. Regions of significant regional GMV variation across XO, XX, XY and XXY mice.

All colored regions show a statistically significant omnibus effect of karyotype group on regional GMV. Different colors define sets of clusters with distinct profiles of volume variation across mouse groups as shown in the boxplot. The orange and turquoise clusters capture regions where GMV differs most between XX and XY mice - i.e. regions of normative sex-differences in regional murine brain anatomy. Orange regions are volumetrically larger in XY vs. XY mice and include the bed nucleus of the stria terminalis - principle nucleus (BNSTp), medial preoptic nucleus (MPO) and medial amygdala (AMm). Turquoise regions are volumetrically larger in XX vs. XY mice, and include the sensorimotor cerebral cortex (CTXs), ventral thalamic nuclei (THv), and the substantia inominata (SA). In contrast, yellow, blue and red regions predominantly show volume differences between XO and XX mice and include the caudoputamen (CP -red), and reuniens nucleus of the thalamus (THr).

Figure 7.. Sex Chromosome Dosage Complement and Total Brain Volume Variation in Humans.

Participant groups with different sex-chromosome dosages vary greatly in their average total brain volume (Omnibus F-test for group: F=20.4, p