监管特征支持对3'UTR变体的解释
Lindsay Romo1, Scott D Findlay2, Christopher B Burge2
1Harvard Medical Genetics Training Program, Boston Children's Hospital, Boston, MA 02115.
bioRxiv : the preprint server for biology
|August 14, 2023
概括
在3'未翻译区域 (UTRs) 中识别遗传变异的影响具有挑战性. 我们的研究表明,调节元件的变异更有可能影响基因表达和患者表型,有助于变异解释.
科学领域:
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
- 生物信息学是一种生物信息学.
背景情况:
- 确定3'未翻译区域 (UTR) 中变异的临床意义是遗传研究中的一个重大挑战.
- 3' UTR 在基因调节中起着至关重要的作用,但它们中的变异往往难以解释.
研究的目的:
- 分析3' UTR变异并确定它们与基因表达和表型的关联.
- 开发一种工具来预测3' UTR变异的功能影响.
主要方法:
- 对跨多个数据集的3' UTR变体的分析,重点关注调控元素,如RNA结合蛋白质基因,eCLIP峰值和microRNA位点.
- 研究了对异构变体的反应中异位基因特异性蛋白质结合和基因表达差异.
- 在替代性多基化单体和在PolyA位点附近的检查变体.
- 将调查结果集成到 RegVar 软件工具中,用于变体解释.
主要成果:
- 调节元件 (RNA结合蛋白质基因,eCLIP峰值,microRNA位点) 中的变异与基因表达和表型变化相关的可能性高达16倍.
- 调节动机中的异合体变异体显示出异位基因特异性蛋白质结合和基因表达.
- 靠近多基化位点的变异也显示出更高的影响基因表达和表型的可能性.
- 与良性变异相比,ClinVar致病性3' UTR变异在监管区域内存在的可能性是良性变异的20倍.
结论:
- 位于3' UTRs内的调节元件中的变异对基因表达和表型产生重大影响.
- RegVar工具有效地解释3' UTR变异,预测它们可能影响基因表达和临床结果.
- 该工具将有助于优先考虑实验验证的变体,并在临床环境中识别致病变体.
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