Transcription profiling by high throughput sequencing of hippocampus from adult males and females of six inbred strains of mice

Identifying sex differences in gene expression within the brain is critical for determining why multiple neurological and behavioural disorders differentially affect males and females. Several are more common or severe in males (e.g., autism and schizophrenia) or 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) significant gene expression differences in males versus females varies substantially across the strains, 2) 12 genes exist that are differentially expressed across the inbred strains (termed core genes), and 3) there are >2,600 significantly differentially expressed genes (DEGs) among the strains (termed non-core genes). We found that DBA/2J uniquely has a substantial majority (89%) of DEGs that are more highly expressed in females than males; 129/SvImJ is the most strongly male-biased with a majority (69%) of DEGs that are more highly expressed in males. To gain insight into the sex-biased DEGs, we examined gene ontology, 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, 8 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 understanding the possible genetic bases for sex-specific susceptibility and severity of brain disorders. Hippocampal mRNA from adult males and females of six inbred strains of mice were analyzed by RNA sequencing of 3 biological replicates using an Illumina HiSeq 2500鉴定大脑内基因表达的性别差异，对于解析多种神经及行为障碍为何在男女群体中呈现差异化的发病易感性与病情严重程度至关重要。部分疾病在男性群体中更为高发或病情更严重（如自闭症与精神分裂症），另有部分则在女性群体中更常见或病情更重（如阿尔茨海默病与抑郁症）。本研究针对6种近交品系（129S1/SvImJ、A/J、C57BL/6J、DBA/1J、DBA/2J及PWD/Ph）小鼠的海马体转录组数据展开分析，旨在系统解析雌雄个体间的基因表达差异。本研究数据显示：1) 雌雄个体间的显著基因表达差异在不同近交品系间存在显著异质性；2) 存在12个在所有近交品系中均呈差异表达的基因，此类基因被称为核心基因；3) 各品系间共存在超过2600个显著差异表达基因（differentially expressed genes, DEGs），此类基因被归为非核心基因。研究发现，DBA/2J品系具有独特的性别表达偏好：其体内89%的DEGs在雌性个体中表达量显著高于雄性；而129S1/SvImJ（原文简写为129/SvImJ）则表现出最强的雄性表达偏向性，其69%的DEGs在雄性个体中表达量更高。为深入解析具有性别偏向性的DEGs，本研究对基因本体（gene ontology, GO）、通路及表型富集情况进行了分析，结果发现此类基因显著富集于神经系统形态与生理异常相关的表型等多个类别中。此外，多个通路呈现显著富集特征，其中包括阿尔茨海默病（Alzheimer's disease, AD）通路：该通路共涉及32个基因，其中8个为雄性偏向表达基因；且其中3个雄性偏向基因已被证实可在阿尔茨海默病进程中发挥神经保护作用。本研究的转录组数据为解析脑部疾病的性别特异性易感性与病情严重程度的潜在遗传基础提供了全新的研究视角。本研究采用Illumina HiSeq 2500测序平台，对6种近交品系成年雌雄小鼠的海马体mRNA开展了3次生物学重复的RNA测序分析。