背景:从等位基因特异性角度揭示功能性遗传变异对于促进我们对基因调控和遗传疾病的理解至关重要。最近,各种等位基因特异性事件,如等位基因特异性基因表达,等位基因特异性甲基化,和等位基因特异性结合,由于高通量测序方法的发展,已经在全基因组范围内进行了探索。RNA二级结构,在RNA修饰等多个RNA相关过程中起着至关重要的作用,翻译和拼接,已成为相关研究的重要焦点。然而,鉴定与等位基因特异性RNA二级结构相关的遗传变异的工具仍然缺乏。
结果:这里,我们开发了一种称为“AStruct”的计算工具,使我们能够从基于RT-stop的结构探测数据中检测等位基因特异性RNA二级结构(ASRS)。AStruct在模拟数据集和公共icSHAPE数据集中均显示出强大的性能。我们发现,具有较高AStruct评分的单核苷酸多态性(SNP)在编码区富集并倾向于功能性。这些SNP是高度保守的,有可能破坏参与m6A修饰或蛋白质结合的位点,并且经常与疾病相关。
结论:AStruct是一种工具,专门用于在基于RT-stop的结构探测数据中的杂合SNP处调用等位基因特异性RNA二级结构事件。它利用等位基因变体,不同小区条件下的碱基配对和RT-stop信息,以检测动态和功能性ASRS。与基于序列的工具相比,AStruct考虑了动态细胞条件,并在检测功能变体方面表现出色。AStruct以JAVA实现,可在以下网址免费访问:https://github.com/canceromics/AStruct。
BACKGROUND: Uncovering functional genetic variants from an allele-specific perspective is of paramount importance in advancing our understanding of gene regulation and genetic diseases. Recently, various allele-specific events, such as allele-specific gene expression, allele-specific methylation, and allele-specific binding, have been explored on a genome-wide scale due to the development of high-throughput sequencing methods. RNA secondary structure, which plays a crucial role in multiple RNA-associated processes like RNA modification, translation and splicing, has emerged as an essential focus of relevant research. However, tools to identify genetic variants associated with allele-specific RNA secondary structures are still lacking.
RESULTS: Here, we develop a computational tool called \'AStruct\' that enables us to detect allele-specific RNA secondary structure (ASRS) from RT-stop based structuromic probing data. AStruct shows robust performance in both simulated datasets and public icSHAPE datasets. We reveal that single nucleotide polymorphisms (SNPs) with higher AStruct scores are enriched in coding regions and tend to be functional. These SNPs are highly conservative, have the potential to disrupt sites involved in m6A modification or protein binding, and are frequently associated with disease.
CONCLUSIONS: AStruct is a tool dedicated to invoke allele-specific RNA secondary structure events at heterozygous SNPs in RT-stop based structuromic probing data. It utilizes allelic variants, base pairing and RT-stop information under different cell conditions to detect dynamic and functional ASRS. Compared to sequence-based tools, AStruct considers dynamic cell conditions and outperforms in detecting functional variants. AStruct is implemented in JAVA and is freely accessible at: https://github.com/canceromics/AStruct .