Identification and analysis of RNA structural disruptions induced by single nucleotide variants using Riprap and RiboSNitchDB.
Identification and analysis of RNA structural disruptions induced by single nucleotide variants using Riprap and RiboSNitchDB.
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DOI：
10.1093/nargab/lqaa057
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发表时间：
2020-09
影响因子：
4.6
通讯作者：
Ouyang Z
中科院分区：
文献类型：
--
作者：
Lin J;Chen Y;Zhang Y;Ouyang Z
RNA构象改变对细胞过程和表型变异具有重要影响。一类新的单核苷酸变异体（SNV）是RNA构象改变的遗传因子，被称为核糖核酸（riboSNitch）。核糖核酸酶已被证明与许多遗传疾病有关。然而，识别核糖核酸是非常困难的，因为RNA结构破坏的信号通常是微妙的。在这里，我们介绍了一种新的计算框架-基于配对概率的鲁棒分析（Riprap）的RIboSNitch预测器。Riprap基于对野生型和突变体RNA序列之间的局部结构构型的稳健分析，识别任何给定SNV周围的结构破坏区域。与以前的方法相比，Riprap在评估通过各种实验RNA结构探测方法捕获的数百个已知核糖核酸片段时显示出更高的准确性，这些方法包括RNA结构的平行分析（PARS）和通过引物延伸分析的选择性2′-羟基酰化（SHAPE）。此外，Riprap检测实验验证的核糖核酸酶，该核糖核酸酶调节人儿茶酚-O-甲基转移酶单倍型，并以碱基分辨率精确输出结构破坏区域。Riprap提供了一种解释疾病相关遗传变异的新方法。此外，我们构建了一个数据库（RiboSNitchDB），其中包括本研究中所有呈现的核糖核酸位点的注释和可视化，以及来自人类表达数量性状基因座的24 629个预测核糖核酸位点。
RNA conformational alteration has significant impacts on cellular processes and phenotypic variations. An emerging genetic factor of RNA conformational alteration is a new class of single nucleotide variant (SNV) named riboSNitch. RiboSNitches have been demonstrated to be involved in many genetic diseases. However, identifying riboSNitches is notably difficult as the signals of RNA structural disruption are often subtle. Here, we introduce a novel computational framework–RIboSNitch Predictor based on Robust Analysis of Pairing probabilities (Riprap). Riprap identifies structurally disrupted regions around any given SNVs based on robust analysis of local structural configurations between wild-type and mutant RNA sequences. Compared to previous approaches, Riprap shows higher accuracy when assessed on hundreds of known riboSNitches captured by various experimental RNA structure probing methods including the parallel analysis of RNA structure (PARS) and the selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE). Further, Riprap detects the experimentally validated riboSNitch that regulates human catechol-O-methyltransferase haplotypes and outputs structurally disrupted regions precisely at base resolution. Riprap provides a new approach to interpreting disease-related genetic variants. In addition, we construct a database (RiboSNitchDB) that includes the annotation and visualization of all presented riboSNitches in this study as well as 24 629 predicted riboSNitches from human expression quantitative trait loci.