Bioinformatics Section, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
Shenzhen Clinical Research Center for Tuberculosis, National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, Guangdong, China.
Biol Sex Differ. 2024 Oct 29;15(1):86. doi: 10.1186/s13293-024-00659-3.
Gene expression shows sex bias in the brain as it does in other organs. Since female and male humans exhibit noticeable differences in emotions, logical thinking, movement, spatial orientation, and even the incidence of neurological disorders, sex biases in the brain are especially interesting, but how they are determined, whether they are conserved or lineage specific, and what the consequences of the biases are, remain poorly explored and understood.
Based on RNA-seq datasets from 16 and 14 brain regions in humans and macaques across developmental periods and from patients with brain diseases, we used linear mixed models (LMMs) to differentiate variations in gene expression caused by factors of interest and confounding factors and identify four types of sex-biased genes. Effect size and confidence in each effect were measured upon the local false sign rate (LFSR). We utilized the biomaRt R package to acquire orthologous genes in humans and macaques from the BioMart Ensembl website. Transcriptional regulation of sex-biased genes by sex hormones and lncRNAs were analyzed using the CellOracle, GENIE3, and Longtarget programs. Sex-biased genes' functions were revealed by gene set enrichment analysis using multiple methods.
Lineage-specific sex-biased genes greatly determine the distinct sex biases in human and macaque brains. In humans, those encoding proteins contribute directly to immune-related functions, and those encoding lncRNAs intensively regulate the expression of other sex-biased genes, especially genes with immune-related functions. The identified sex-specific differentially expressed genes (ssDEGs) upon gene expression in disease and normal samples also indicate that protein-coding ssDEGs are conserved in humans and macaques but that lncRNA ssDEGs are not conserved. The results answer the above questions, reveal an intrinsic relationship between sex biases in the brain and sex-biased susceptibility to brain diseases, and will help researchers investigate human- and sex-specific ncRNA targets for brain diseases.
Human-specific genes greatly cast sex-biased genes in the brain and their relationships with brain diseases, with protein-coding genes contributing to immune response related functions and lncRNA genes critically regulating sex-biased genes. The high proportions of lineage-specific lncRNAs in mammalian genomes indicate that sex biases may have evolved rapidly in not only the brain but also other organs.
基因表达在大脑中表现出性别偏向，就像在其他器官中一样。由于女性和男性在情绪、逻辑思维、运动、空间定位甚至神经紊乱的发病率方面存在明显差异，因此大脑中的性别偏向尤其有趣，但它们是如何确定的，是保守的还是谱系特异性的，以及偏向的后果是什么，这些仍然知之甚少。
基于来自人类和猕猴 16 个和 14 个大脑区域在发育期间以及患有脑部疾病的患者的 RNA-seq 数据集，我们使用线性混合模型（LMM）来区分由感兴趣的因素和混杂因素引起的基因表达变化，并确定四种类型的性别偏向基因。每个效应的效应大小和置信度都是根据局部错误信号率（LFSR）来衡量的。我们利用 biomaRt R 包从 BioMart Ensembl 网站获取人类和猕猴的同源基因。使用 CellOracle、GENIE3 和 Longtarget 程序分析性别偏向基因的性别激素和 lncRNA 的转录调控。使用多种方法通过基因集富集分析揭示性别偏向基因的功能。
谱系特异性性别偏向基因极大地决定了人类和猕猴大脑中明显的性别偏向。在人类中，那些编码蛋白质的基因直接有助于免疫相关功能，而那些编码 lncRNA 的基因则强烈调节其他性别偏向基因的表达，特别是那些具有免疫相关功能的基因。在疾病和正常样本中基因表达时鉴定出的性别特异性差异表达基因（ssDEGs）也表明，蛋白质编码的 ssDEGs 在人类和猕猴中是保守的，但 lncRNA ssDEGs 不是保守的。结果回答了上述问题，揭示了大脑中性别偏向与大脑疾病性别偏向易感性之间的内在关系，并将帮助研究人员研究针对大脑疾病的人类和性别特异性 ncRNA 靶标。
人类特异性基因极大地塑造了大脑中的性别偏向基因及其与大脑疾病的关系，其中蛋白质编码基因有助于免疫反应相关功能，而 lncRNA 基因则关键调节性别偏向基因。哺乳动物基因组中谱系特异性 lncRNA 的高比例表明，性别偏向可能不仅在大脑中，而且在其他器官中也迅速进化。
