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. 2018 Jul 10;115(28):7398-7403.
doi: 10.1073/pnas.1802889115. Epub 2018 Jun 26.

Sex-chromosome dosage effects on gene expression in humans

Armin Raznahan  1 , Neelroop N Parikshak  2   3 , Vijay Chandran  4 , Jonathan D Blumenthal  5 , Liv S Clasen  5 , Aaron F Alexander-Bloch  5 , Andrew R Zinn  6   7 , Danny Wangsa  8 , Jasen Wise  9 , Declan G M Murphy  10 , Patrick F Bolton  10 , Thomas Ried  8 , Judith Ross  11 , Jay N Giedd  12 , Daniel H Geschwind  2   3
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Sex-chromosome dosage effects on gene expression in humans

Armin Raznahan (VSports最新版本) et al. Proc Natl Acad Sci U S A. .

Abstract

A fundamental question in the biology of sex differences has eluded direct study in humans: How does sex-chromosome dosage (SCD) shape genome function. To address this, we developed a systematic map of SCD effects on gene function by analyzing genome-wide expression data in humans with diverse sex-chromosome aneuploidies (XO, XXX, XXY, XYY, and XXYY) VSports手机版. For sex chromosomes, we demonstrate a pattern of obligate dosage sensitivity among evolutionarily preserved X-Y homologs and update prevailing theoretical models for SCD compensation by detecting X-linked genes that increase expression with decreasing X- and/or Y-chromosome dosage. We further show that SCD-sensitive sex-chromosome genes regulate specific coexpression networks of SCD-sensitive autosomal genes with critical cellular functions and a demonstrable potential to mediate previously documented SCD effects on disease. These gene coexpression results converge with analysis of transcription factor binding site enrichment and measures of gene expression in murine knockout models to spotlight the dosage-sensitive X-linked transcription factor ZFX as a key mediator of SCD effects on wider genome expression. Our findings characterize the effects of SCD broadly across the genome, with potential implications for human phenotypic variation. .

Keywords: Klinefelter syndrome; Turner syndrome; X-inactivation; sex chromosomes; sex differences V体育安卓版. .

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Consistent gene-expression changes with altered sex-chromosome dosage. (A) Cross-table showing all pairwise SCD group contrasts within the microarray dataset shaded by X- and/or Y-chromosome disparity. (B) Expression heatmap for the 10 genes that show DE across all contrasts involving disparity in X- or Y-chromosome count. The column color bar encodes SCD group membership for each sample. (C) Density plots showing the observed mean proportion of expression variance explained by SCD for 14 gametolog genes (red line) vs. null distribution (black line) of this variable for 10,000 randomly sampled sets of nongametolog sex-linked genes of equal size. Results are provided separately for X and Y chromosomes.
Fig. 2.
Fig. 2.
Data-driven partitioning of sex-chromosome genes by dosage sensitivity. (A) 2D multidimensional scaling (MDS) plot of sex-chromosome genes by their mean expression profiles across all seven SCD groups. Genes are coded by both the four-class model (shape) and k-means cluster grouping (color). MDS2 arranges X-linked genes along the established gradient of X-linked dosage sensitivity that ranges from extreme XCIE (XIST) to full XCI. A cluster of low/nonexpressed genes that lack SCD sensitivity is colored gray (SI Appendix, Text S4 and Fig. S2). (B) Cross-table showing enrichment of k-means clusters for four-class model gene groups. (C) Dot and line plots showing observed (solid colored) and predicted (dashed gray) mean expression for each k-means gene cluster across karyotype groups. (D) Close-up of observed (solid colored) vs. predicted (dashed gray) mean expression profiles of XCIE and XCI gene clusters. Observed expression profiles still counter predictions when analysis is restricted to core genes in each cluster with XCIE/XCI statuses that have been confirmed across three independent reports (thick colored line). (E) Heatmap showing normalized (vs. XX mean) expression of dosage-sensitive genes in the XCIE and XCI clusters (rows) for each sample (columns; the color bar encodes the SCD group). (F) Pie-charts showing that XCIE and XCI gene clusters from k-means display mirrored over/underrepresentation for three genomic features that have been linked to XCIE in prior research: (i) persistence of a surviving Y-linked homolog; (ii) location within younger evolutionary strata of the X chromosome; and (iii) presence of euchromatic vs. heterochromatic epigenetic markers.
Fig. 3.
Fig. 3.
WGCNA of sex-chromosome dosage effects. (A) Dot and line plots detailing mean expression (± 95% CI) by SCD group for eight SCD-sensitive and functionally coherent gene-coexpression modules. (B) Top two GO term enrichments for each module exceeding the threshold for statistical significance (dashed red line). (C) Heatmap showing statistically significant DE of gene-coexpression modules between karyotype groups. (D) Cross-tabulation showing enrichment of Turquoise, Brown, Blue, and Green modules for the dosage-sensitive clusters of sex-chromosome genes detected by k-means. (E) Gene-coexpression network for the Blue module showing the top decile of coexpression relationships (edges) between the top decile of SCD-sensitive genes (nodes). Nodes are positioned in a circle for ease of visualization. Node shape distinguishes autosomal (circle) from sex-chromosome (square) genes. Sex-chromosome genes within the Blue module are colored according to their k-means cluster designation. Larger node and gene name sizes reflect greater SCD sensitivity. Edge width indexes the strength of coexpression between gene pairs.
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