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人类大脑中的毒素外子拼接:理解和准神经系统疾病的新前沿

Paolo Pigini, Huilin Xu, Yan Ji

bioRxiv : the preprint server for biology

|July 16, 2025

概括

毒素外子 (PE) 通过触发转录衰变来调节基因表达. 这项研究确定了人类大脑中的数千个PE,揭示了它们在神经健康和疾病中的关键作用.

科学领域:

基因组学和分子生物学
神经科学是一个神经科学.
生物信息学是一种生物信息学.

背景情况:

毒素外子 (PE) 是保存的序列,当包含在mRNA中时,会触发无意义介导衰变 (NMD),降低蛋白质水平.
PE对于转录后调节至关重要,但由于缺乏系统的,全转录组研究,它们的注释很差.
人类表现出NMD向转录的高度丰富,这表明PE在人类基因调节中起着重要作用.

研究的目的:

为了全面调查PEs在人类大脑中的功能和景观.
评估致病变体对PE拼接的影响及其与神经系统疾病的关联.
建立治疗策略的基础,以针对脑疾病中的PE错误拼接为目标.

主要方法:

对957个真核转录组进行比较分析,以根据特定标准 (PhyloP得分,长度,PTC引入,位置) 确定保存的PE.
对GTEx和BrainSpan RNA-seq数据集的分析,以计算组织和发育阶段PEs的百分比拼接值 (PSI).
整合ClinVar和SpliceAI数据库以识别影响PE拼接的致病变体;使用CRISPR初始编辑进行功能验证.

主要成果:

在人类基因组中确定了12014个PE,其中117个是大脑特有的,1214个显示大脑特异性的差异拼接.
在大脑发育过程中检测到1,610个带有拼接变化的PE,并确定了1,877个影响891个大脑PE的致病变体.
发现了影响PE的变体与神经发育/神经退行性疾病 (,智力障碍,前性痴呆症) 之间的关联.

结论:

皮质细胞是人类大脑中基因表达的关键调节者,在整个组织和发育过程中具有不同的模式.
影响PE拼接的致病变体与重大神经疾病有关,突出显示了它们的临床相关性.
这项研究为了解PE功能提供了全面的资源,并为开发神经疾病的新疗法提供了基础.

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