aenmd: annotating escape from nonsense-mediated decay for transcripts with protein-truncating variants.
aenmd: annotating escape from nonsense-mediated decay for transcripts with protein-truncating variants.
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DOI：
10.1093/bioinformatics/btad556
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发表时间：
2023-09-02
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导致过早终止密码子（PTC）的DNA变化代表了临床相关致病基因组变异的很大一部分。典型地，PTC通过无义介导的mRNA衰变（NMD）诱导转录物降解，并使这种变化成为功能丧失的等位基因。然而，某些含有PTC的转录物逃避NMD，并可以发挥显性负或功能获得（DN/GOF）效应。因此，系统鉴定人类PTC致病变异体及其对NMD的易感性有助于研究DN/GOF等位基因在人类疾病中的作用。在这里，我们提出了aenmd，一个软件，用于注释含PTC的转录变体对预测逃脱NMD。该系统方便用户使用，而且自成一体。它提供了目前其他方法所没有的功能，并基于已建立和实验验证的NMD逃逸规则;该软件旨在大规模工作，并与现有的分析工作流程无缝集成。我们将aenmd应用于gnomAD、Clinvar和GWAS目录数据库中的变体，并报告了这些数据库中导致人类PTC的变体的患病率，以及这些变体的子集，这些变体可以通过NMD逃逸产生DN/GOF效应。aenmd是用R编程语言实现的。代码在GitHub上以R包（github.com/kostkalab/aenmd.git）和容器化命令行界面（github.com/kostkalab/aenmd_cli.git）的形式提供。
DNA changes that cause premature termination codons (PTCs) represent a large fraction of clinically relevant pathogenic genomic variation. Typically, PTCs induce transcript degradation by nonsense-mediated mRNA decay (NMD) and render such changes loss-of-function alleles. However, certain PTC-containing transcripts escape NMD and can exert dominant-negative or gain-of-function (DN/GOF) effects. Therefore, systematic identification of human PTC-causing variants and their susceptibility to NMD contributes to the investigation of the role of DN/GOF alleles in human disease. Here we present aenmd, a software for annotating PTC-containing transcript-variant pairs for predicted escape from NMD. aenmd is user-friendly and self-contained. It offers functionality not currently available in other methods and is based on established and experimentally validated rules for NMD escape; the software is designed to work at scale, and to integrate seamlessly with existing analysis workflows. We applied aenmd to variants in the gnomAD, Clinvar, and GWAS catalog databases and report the prevalence of human PTC-causing variants in these databases, and the subset of these variants that could exert DN/GOF effects via NMD escape. aenmd is implemented in the R programming language. Code is available on GitHub as an R-package (github.com/kostkalab/aenmd.git), and as a containerized command-line interface (github.com/kostkalab/aenmd_cli.git).
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