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基于转录组分析智力发育过程中性别差异的关键基因

张家玮, 郑小丽, 周海倩, 朱朕, 韩威, 殷东敏^*

脑功能基因组学教育部和上海市重点实验室，华东师范大学生命科学学院，上海 200062

摘要

智力包括了逻辑推理能力、理解能力、自我意识能力、学习能力、计划能力、创造能力和解决问题等能力。智力发育存在性别差异，女性智力的成熟时间往往早于男性。然而，关于智力发育性别差异的关键基因及其分子网络机制尚不清楚。迄今为止，全基因组关联分析(Genome-Wide Association Studies, GWAS)发现了507 个与智力显著相关的基因。本论文首先分析了BrainSpan 人脑RNA-seq 数据集中大脑在各个发育阶段的转录测序数据，发现在胚胎晚期，507 个智力基因在大脑中的平均表达水平男性高于女性，而在青春期则相反。接着进一步构建了大脑中表达水平具有性别差异的智力基因的互作网络，包括胚胎晚期中男性高表达的智力基因互作网络HELP-M (intelligence genes with higher expression levels in prenatalmales)、青春期女性高表达的智力基因互作网络 HELP-F (intelligence genes with higher expression levels in pubertal females)。结果表明，这两个网络的关键基因均是Ep300 和Ctnnb1。其中Ep300 在HELP-M 和HELP-F 中调控了53 个基因的转录，Ctnnb1 在HELP-M和HELP-F 中调控了45 个基因转录，Ctnnb1 在HELP-M以及Ep300 在HELP-F 中分别发挥更重要的作用。对不同发育时间的大鼠进行测序验证，发现在青春期雌性大鼠前额叶皮层中HELP-F的智力基因和关键基因Ep300、Ctnnb1表达水平显著高于雄性大鼠，并且参与了神经发育等相关生物过程。以上结果揭示了在神经发育过程中表达水平具有性别差异的智力基因网络及其关键基因。

关键词： 智力发育; 关键基因; 性别差异

Transcriptomic analysis of key genes involved in sex differences in intellectual development

ZHANG Jia-Wei, ZHENG Xiao-Li, ZHOU Hai-Qian, ZHU Zhen, HAN Wei, YIN Dong-Min^*

Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, School of Life Sciences, East China Normal University, Shanghai 200062, China

Abstract

Intelligence encompasses various abilities, including logical reasoning, comprehension, self-awareness, learning, planning, creativity, and problem-solving. Extensive research and practical experience suggest that there are sex differences in intellectual development, with females typically maturing earlier than males. However, the key genes and molecular network mechanisms underlying these sex differences in intellectual development remain unclear. To date, Genome-Wide Association Studies (GWAS) have identified 507 genes that are significantly associated with intelligence. This study first analyzed RNA sequencing data from different stages of brain development (from BrainSpan), revealing that during the late embryonic stage, the average expression levels of intelligencerelated genes are higher in males than in females, while the opposite is observed during puberty. This study further constructed interaction networks of intelligence-related genes with sex-differential expression in the brain, including the prenatal male network (HELP-M: intelligence genes with higher expression levels in prenatal males) and the pubertal female network (HELP-F: intelligence genes with higher expression levels in pubertal females). The findings indicate that the key genes in both networks are Ep300 and Ctnnb1. Specifically, Ep300 regulates the transcription of 53 genes in both HELP-M and HELP-F, while Ctnnb1 regulates the transcription of 45 genes. Ctnnb1 plays a more prominent role in HELP-M, while Ep300 is more crucial in HELP-F. Finally, this study conducted sequencing validation on rats at different developmental stages, and the results indicated that in the prefrontal cortex of female rats during adolescence, the expression levels of the intelligence genes in HELP-F, as well as key genes Ep300 and Ctnnb1, were higher than those in male rats. These genes were also involved in neurodevelopment-related biological processes. The findings reveal a sex-differentiated intelligence gene network and its key genes, which exhibit varying expression levels during the neurodevelopmental process.

Key words: intellectual development; key genes; sex difference

收稿日期：　　录用日期：

通讯作者：殷东敏　　E-mail:

DOI: 10.13294/j.aps.2024.0079

引用本文：

张家玮, 郑小丽, 周海倩, 朱朕, 韩威, 殷东敏. 基于转录组分析智力发育过程中性别差异的关键基因[J]. 生理学报 2025; 77 (2): 211-221.

ZHANG Jia-Wei, ZHENG Xiao-Li, ZHOU Hai-Qian, ZHU Zhen, HAN Wei, YIN Dong-Min. Transcriptomic analysis of key genes involved in sex differences in intellectual development. Acta Physiol Sin 2025; 77 (2): 211-221 (in Chinese with English abstract).