常见变异对大脑基因表达的影响从RNA到蛋白质到精神分裂症风险
Qiuman Liang1, Yi Jiang1,2, Annie W Shieh3
1MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
遗传变异会影响基因表达,但下游效应尚不清楚. 影响RNA水平的大多数变异不会改变蛋白质水平,这表明调节发生在转录后.
科学领域:
- 遗传学 遗传学 是一个
- 神经科学是一个神经科学.
- 分子生物学分子生物学
背景情况:
- 影响基因表达的遗传变异在转录水平上得到了充分研究.
- 这些变异对蛋白质水平和生物过程的下游影响仍然在很大程度上未知.
- 了解这些下游影响对于将遗传风险与疾病机制联系起来至关重要.
研究的目的:
- 研究遗传变异如何影响从转录到蛋白质水平的基因表达.
- 确定受遗传变异影响的调节机制,特别是转录后调节.
- 探索奥米特异性定量特征位点 (QTLs) 与大脑疾病全基因组关联研究 (GWAS) 信号的关联.
主要方法:
- 在人类前额叶皮层样本中量化了核糖体占用率.
- 集成的核糖体占用数据与转录和蛋白质的个人资料.
- 进行了 cis-定量性质位点 (cis-QTL) 映射,以识别与转录 (eQTLs),核糖体占用 (rQTLs) 和蛋白质 (pQTLs) 水平相关的变异.
- 利用基于基因和基于变异的方法来识别omics特定的QTLs.
- 采用全转录组关联研究 (TWAS) 方法来识别精神分裂症 (SCZ) 风险基因.
主要成果:
- 确定了eQTL,rQTL和pQTL,揭示了不同分子层的遗传影响.
- 观察到,只有34%的eQTL传播其作用到蛋白质水平,这表明显著的转录后衰减.
- 发现与大脑疾病相关的欧米特异性QTLs GWAS信号主要是由转录调节驱动的.
- 识别了74个SCZ风险基因跨转录组,核糖体占用率和蛋白质组数据,其中很大一部分对蛋白质表达的影响有限.
结论:
- 与大脑疾病相关的遗传变异通常通过调节机制起作用,而这些调节机制不会显著改变蛋白质丰度.
- 转录后过程在调节遗传变异对基因表达的影响方面发挥着关键作用,导致转录水平效应的广泛减弱.
- 整合多学科数据提供了对遗传变异效应及其与复杂疾病相关性的全面了解.
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