Human-specific protein-coding and lncRNA genes cast sex-biased genes in the brain and their relationships with brain diseases.

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Biology of Sex Differences Pub Date : 2024-10-29 DOI:10.1186/s13293-024-00659-3
Sha He, Xuecong Zhang, Hao Zhu
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Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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人类特异性蛋白编码基因和 lncRNA 基因在大脑中的性别偏向基因及其与脑部疾病的关系。
背景:与其他器官一样,大脑中的基因表达也显示出性别偏见。由于雌性和雄性人类在情绪、逻辑思维、运动、空间定向,甚至神经系统疾病的发病率等方面表现出明显的差异,因此大脑中的性别偏向尤其引人关注,但它们是如何决定的,是保守的还是特定的,以及偏向的后果是什么,这些问题仍然没有得到很好的探索和理解:方法:基于人类和猕猴16个和14个脑区发育期的RNA-seq数据集以及脑部疾病患者的RNA-seq数据集,我们使用线性混合模型(LMMs)区分了由相关因素和混杂因素引起的基因表达变化,并确定了四种性别偏倚基因。根据局部假符号率(LFSR)来衡量每种效应的效应大小和置信度。我们利用 biomaRt R 软件包从 BioMart Ensembl 网站获取了人类和猕猴的同源基因。我们使用CellOracle、GENIE3和Longtarget程序分析了性激素和lncRNA对性别偏倚基因的转录调控。使用多种方法进行基因组富集分析,揭示了性别偏倚基因的功能:结果:特异性系的性别偏向基因在很大程度上决定了人类和猕猴大脑中不同的性别偏向。在人类中,编码蛋白质的基因直接参与免疫相关功能,而编码lncRNA的基因则密切调控其他性别偏向基因的表达,尤其是具有免疫相关功能的基因。在疾病和正常样本基因表达中发现的性别差异表达基因(ssDEGs)也表明,编码蛋白质的ssDEGs在人类和猕猴中是保守的,但lncRNA ssDEGs并不保守。这些结果回答了上述问题,揭示了大脑性别偏差与脑部疾病性别易感性之间的内在关系,有助于研究人员研究人类和性别特异性ncRNA在脑部疾病中的靶点:人类特异性基因在很大程度上决定了大脑中的性别偏倚基因及其与脑部疾病的关系,其中蛋白编码基因对免疫反应相关功能做出了贡献,而lncRNA基因则对性别偏倚基因起着关键性的调控作用。哺乳动物基因组中特异性系的lncRNA比例很高,这表明性别偏见可能不仅在大脑中,而且在其他器官中也在迅速进化。
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
期刊最新文献
Sex differences in contextual fear conditioning and extinction after acute and chronic nicotine treatment. Sex dimorphism and tissue specificity of gene expression changes in aging mice. The Four Core Genotypes mouse model: evaluating the impact of a recently discovered translocation. Quantitative proteomic profiling reveals sexual dimorphism in the retina and RPE of C57BL6 mice. Human-specific protein-coding and lncRNA genes cast sex-biased genes in the brain and their relationships with brain diseases.
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