异常拼接对人类基因表达水平的全球影响
Benjamin Fair1, Carlos Buen Abad Najar1, Junxing Zhao2
1Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
bioRxiv : the preprint server for biology
|September 25, 2023
概括
替代拼接 (AS) 通过触发无意中介衰变 (NMD) 影响基因表达. 这项研究揭示了AS-NMD在大多数人类基因中显著影响蛋白质水平,而不仅仅是蛋白质多样性.
科学领域:
- 分子生物学分子生物学
- 基因组学就是基因组学.
- 基因调节 基因调节
背景情况:
- 替代拼接 (AS) 在人类基因中很常见,但其功能影响往往不清楚.
- 据认为AS主要是使蛋白质组多样化,但也可以通过无意中介衰变 (NMD) 影响基因表达.
- 由于NMD转录的快速降解,很难量化AS-NMD对基因表达的影响.
研究的目的:
- 通过使用人口规模的基因组数据,研究AS对基因表达水平的影响.
- 确定AS与NMD (AS-NMD) 结合的AS的流行率和功能后果.
- 评估AS是否主要使蛋白质组多样化或影响蛋白质表达水平.
主要方法:
- 在8个分子测试中分析了来自淋巴细胞细胞系的种群规模基因组数据.
- 新生的mRNA转录的测序以捕捉AS事件和NMD目标.
- 利用基因变异 (GWAS) 和一个拼接切换药物 (risdiplam) 来扰乱和评估AS-NMD.
主要成果:
- 测序新生的mRNA揭示了频繁的异常拼接,导致高水平的NMD向转录.
- 约15%的蛋白质编码转录被NMD降解,对于具有多个内子的低表达基因,降解率上升至近50%.
- 与AS相关的GWAS位点与NMD诱导的表达变化和蛋白质异型差异有关;药物诱导的AS扰动通常会触发NMD.
结论:
- AS-NMD对大多数人类基因的基因表达水平产生重大影响.
- AS的主要分子影响可能是通过改变蛋白质表达水平,而不是仅仅是使蛋白质组多样化.
- 了解AS-NMD对于解释基因调节和疾病关联至关重要.
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