Long-read RNA-seq demarcates cis - and trans -directed alternative RNA splicing.

Genetic regulation of alternative splicing constitutes an important link between genetic variation and disease. Nonetheless, RNA splicing is regulated by both cis -acting elements and trans -acting splicing factors. Determining splicing events that are directed primarily by the cis - or trans -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 of cis - and trans -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 of cis -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 novel cis -directed splicing events in Alzheimer's disease-relevant genes such as MAPT and BIN1 . Together, the clear demarcation of cis - and trans -directed splicing paves ways for future studies of the genetic basis of disease.