Identification and analysis of RNA structural disruptions induced by single nucleotide variants using Riprap and RiboSNitchDB.

Abstract

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.