Long-read RNA-seq demarcatescis- andtrans-directed alternative RNA splicing

Abstract

AbstractGenetic regulation of alternative splicing constitutes an important link between genetic variation and disease. Nonetheless, RNA splicing is regulated by bothcis-acting elements andtrans-acting splicing factors. Determining splicing events that are directed primarily by thecis- ortrans-acting mechanisms will greatly inform our understanding of the genetic basis of disease. Here, we show that long-read RNA-seq, combined with our new method isoLASER, enables a clear segregation ofcis- andtrans-directed splicing events for individual samples. The genetic linkage of splicing is largely individual-specific, in stark contrast to the tissue-specific pattern of splicing profiles. Analysis of long-read RNA-seq data from human and mouse revealed thousands ofcis-directed splicing events susceptible to genetic regulation. We highlight such events in the HLA genes whose analysis was challenging with short-read data. We also highlight novelcis-directed splicing events in Alzheimer’s disease-relevant genes such asMAPTandBIN1. Together, the clear demarcation ofcis- andtrans-directed splicing paves ways for future studies of the genetic basis of disease.