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. 2016 Oct 13:7:183.
doi: 10.3389/fgene.2016.00183. eCollection 2016.

Large Scale Gene Expression Meta-Analysis Reveals Tissue-Specific, Sex-Biased Gene Expression in Humans

Benjamin T Mayne  1 , Tina Bianco-Miotto  2 , Sam Buckberry  3 , James Breen  4 , Vicki Clifton  5 , Cheryl Shoubridge  1 , Claire T Roberts  1
Affiliations

Large Scale Gene Expression Meta-Analysis Reveals Tissue-Specific, Sex-Biased Gene Expression in Humans

Benjamin T Mayne et al. Front Genet. .

Abstract

The severity and prevalence of many diseases are known to differ between the sexes. Organ specific sex-biased gene expression may underpin these and other sexually dimorphic traits. To further our understanding of sex differences in transcriptional regulation, we performed meta-analyses of sex biased gene expression in multiple human tissues. We analyzed 22 publicly available human gene expression microarray data sets including over 2500 samples from 15 different tissues and 9 different organs. Briefly, by using an inverse-variance method we determined the effect size difference of gene expression between males and females. We found the greatest sex differences in gene expression in the brain, specifically in the anterior cingulate cortex, (1818 genes), followed by the heart (375 genes), kidney (224 genes), colon (218 genes), and thyroid (163 genes). More interestingly, we found different parts of the brain with varying numbers and identity of sex-biased genes, indicating that specific cortical regions may influence sexually dimorphic traits. The majority of sex-biased genes in other tissues such as the bladder, liver, lungs, and pancreas were on the sex chromosomes or involved in sex hormone production. On average in each tissue, 32% of autosomal genes that were expressed in a sex-biased fashion contained androgen or estrogen hormone response elements. Interestingly, across all tissues, we found approximately two-thirds of autosomal genes that were sex-biased were not under direct influence of sex hormones. To our knowledge this is the largest analysis of sex-biased gene expression in human tissues to date. We identified many sex-biased genes that were not under the direct influence of sex chromosome genes or sex hormones. These may provide targets for future development of sex-specific treatments for diseases.

Keywords: human; meta-analysis; microarray; organs; sex-biased gene expression.

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Figures

Figure 1
Figure 1
Total number of detectable sex-biased genes relative to the sample size in each tissue. A bubble plot of each tissue where the size of the bubble is proportional to the sample size of the tissue. Bubbles that are higher on the y-axis are tissues that demonstrate a higher number of detectable sex-biased genes. Nucleus accumbens (NC); amygdala (AMY); cerebellum (CB); anterior cingulate cortex (AnCg); dorsolateral frontal cortex (DLPFC); frontal cortex (FC); hippocampus (HC).
Figure 2
Figure 2
Sex differences in autosomal gene expression in the human brain. (A) A volcano plot representing the autosomal genes that were sex-biased in the AnCg. Pink colored dots represent genes that were significantly expressed more highly in females and blue colored dots represent genes that were expressed more highly in males. (B) A four-way venn diagram showing the overlap of sex-biased autosomal gene expression in different regions of the human brain. Most genes that were found to be sex-biased in one region were not sex-biased in another region. The top GO terms that were enriched for sex-biased genes in (C) Nucleus accumbens (NC), (D) anterior cingulate cortex (AnCg) and (E) hippocampus (HC).
Figure 3
Figure 3
Sex-biased gene expression differences on chromosome 1 in the heart and kidney. Each dot represents a gene, blue dots are genes that were expressed more highly in males and pink dots are those expressed more highly in females. The ideogram of chromosome 1 was obtained from the (National Centre for Biotechnology Information, 2016) (NCBI).
Figure 4
Figure 4
X-linked sex-biased gene expression. The total number of genes located on the X chromosome that were expressed more highly in females (pink) and males (blue) compared to the opposite sex, respectively.
Figure 5
Figure 5
Forest plots of the standardized mean difference of KDM6A expression showing higher expression in females in the liver (A), lung (B), CB (C), and DLPFC (D). Each blue box is representative of the study size in each data set and horizontal lines are standard error. The yellow diamond represents the overall gene summary for KDM6A in each tissue.
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