Transcriptomic analysis of the hippocampus from six inbred strains of mice suggests a basis for sex‐specific susceptibility and severity of neurological disorders

Abstract

Identifying sex differences in gene expression within the brain is critical for determining why multiple neurological and behavioral disorders differentially affect males and females. Several disorders are more common or severe in males (e.g., autism and schizophrenia) or in females (e.g., Alzheimer's disease and depression). We analyzed transcriptomic data from the mouse hippocampus of six inbred strains (129S1/SvImJ, A/J, C57BL/6J, DBA/1J, DBA/2J, and PWD/Ph) to provide a perspective on differences between male and female gene expression. Our data show that 1) gene expression differences in males vs. females varies substantially across the strains, 2) only a few genes are differentially expressed across all of the strains (termed core genes), and 3) >2,600 genes differ in the individual strain comparisons (termed noncore genes). We found that DBA/2J uniquely has a substantial majority (89%) of differentially expressed genes (DEGs) that are more highly expressed in females than in males (female-biased); 129/SvImJ has a majority (69%) of DEGs that are more highly expressed in males. To gain insight into the function of the DEGs, we examined gene ontology and pathway and phenotype enrichment and found significant enrichment in phenotypes related to abnormal nervous system morphology and physiology, among others. In addition, several pathways are enriched significantly, including Alzheimer's disease (AD), with 32 genes implicated in AD, eight of which are male-biased. Three of the male-biased genes have been implicated in a neuroprotective role in AD. Our transcriptomic data provide new insight into the possible genetic bases for sex-specific susceptibility and severity of brain disorders. J. Comp. Neurol. 524:2696-2710, 2016. © 2016 Wiley Periodicals, Inc.

Sex differences in the molecular signature of the developing mouse hippocampus

“…Female and male mice of 1, 2, and 4 months of age ( n  = 5 for RNA-seq, n  = 3 for LC-MS/MS) were decapitated and the hippocampus rapidly dissected as described in [14]. The brain was bisected and the diencephalon and brain stem removed so that the medial aspect of the telencephalon was accessible.…”

“…The RNA-seq data analysis workflow has been described previously [14]. Briefly, quality control analysis of each sequenced library was performed using the fastQC software.…”

“…These sex-specific gene expression signatures persist into adulthood in brains of both mice and humans [12, 13]. Our detailed investigation of sex differences in transcript expression in inbred mouse strains showed that molecular sex differences are influenced by genetic background, revealing tens to hundreds of differentially expressed (DE) transcripts depending on the strain [14], which might suggest that sex differences in humans are population-specific. Neural sex differences in mammals also manifest on the macroscopic scale.…”

“…We have previously investigated sex differences in the hippocampal transcriptome in a variety of inbred strains [14] at a single age (60 days of age). Here, we expand on these findings by conducting a multi-omic analysis of the mouse hippocampus in postnatal development.…”

Prospects for finding the mechanisms of sex differences in addiction with human and model organism genetic analysis

“…Through correlational analysis, we have been able to move beyond sex‐specific QTL and identify sex‐specific gene expression networks . Such mechanisms of sex by genotype regulation of the molecular phenotypic variation have been observed in mental health issues in human and are expected to emerge in addiction relevant regions of the brain . High‐diversity mouse populations, such as the CC and DO populations (for review,) with known and reproducible genetic variation provide a valuable platform for studying the mechanisms that drive sex dimorphic addiction‐related traits.…”