Thousands of genes are expressed differently in the brains of men and women, researchers have discovered.
The findings could help explain differences in neurodevelopmental, psychiatric, and neurodegenerative disorders between the sexes.
While men are more likely to experience schizophrenia, attention deficit hyperactivity disorder, and Parkinson’s disease, women are more prone to mood disorders and Alzheimer’s disease.
The U.S. study, in Science, is the first systemic single-cell survey of sex differences in gene expression across multiple regions of the human brain.
“Together, these findings provide a comprehensive map of molecular sex differences in the human brain and offer initial insight into their underlying mechanisms and potential functional consequences,” Alex DeCasien, PhD, from the National Institute of Mental Health in Bethesda, Maryland, told Inside Precision Medicine.
DeCasien and co-workers conducted a high-resolution analysis of gene expression in tissue samples from the brains of 15 men and 15 women using single-nucleus RNA sequencing.
They then used data from earlier large neuroimaging studies to select six cortical regions to sample, four of which showed sex-related differences in grey matter volume and two in which no such differences were found.
The team found subtle but widespread differences in gene activity between men and women. Biological sex explained very little of the variance in gene expression across the brain, at less than 1%, but differences were widespread—with more than 3000 genes showing different expression according to sex in at least one cortical region.
The greatest sex-related differences in gene expression were on the sex chromosomes. However, most of the genes showing sex-related variations in expression were autosomal—carried on one of the 22 numbered non-sex chromosomes.
The predominant driver for sex-biased expression of genes on these autosomal chromosomes were sex steroid hormones such as estrogen and testosterone.
Surprisingly, more than half the X chromosome genes in women were expressed in both alleles for at least one cell type. This indicated that many had escaped X chromosome inactivation—a female phenomenon in which one of the two X chromosomes is switched off early in development to stop women producing double the number of X-linked gene products to men.
“That finding has implications for understanding sex-biased disease susceptibility because several genes implicated in neurodevelopmental disorders reside on the X chromosome,” commented Jessica Tollkuhn, PhD, from Cold Spring Harbor Laboratory, and S Marc Breedlove, from Michigan State University, in an accompanying Perspective article.
They noted that autosomal genes showing sex-biased expression were substantially enriched for extracellular matrix components, hormone signaling pathways, and metabolic processes. “Genes with greater expression in women were enriched for mitochondrial and synaptic functions, whereas male-biased genes were associated with metabolic and structural pathways,” the editorialists added.
“By pinpointing these sexually differentiated processes, the data provide a treasure trove for the discovery of biomarkers of and/or therapeutic targets for differential disease risk in men and women.”
DeCasien and team added: “These findings raise the possibility that sex differences in gene expression modulate the magnitude of genetic effects at risk loci, contributing to differences in disease vulnerability and to reduced portability of polygenic risk prediction across sexes.”
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