Resolving complex alternative splicing of psychiatric disease genes using single-cell approaches

PROJECT SUMMARY Schizophrenia (SZ), bipolar disorder (BD) and autism spectrum disorder (ASD) are common and debilitating neurodevelopmental disorders that together affect more than 5 million Americans. Despite more than fifty years of research, no cures exist and the standard of treatment remains unsatisfactory. Dysregulation of alternative splicing in the human brain has been implicated in SZ. Among genes with critical brain functions, many have a large number of exons, resulting in complex splicing patterns that can vary between neuronal subtypes; however, the isoform repertoires of most of these complex genes have not been resolved in a cell-type specific manner. Recent advances in long read sequencing have provided an unprecedented opportunity to resolve complex alternative splicing. Thus, to better understand the clinical impact of changes of alternative splicing in psychiatric diseases, it is critical to evaluate how isoform repertoire impact neuronal maturation and synaptic function in a cell-type specific manner. Here, we propose to catalog and functionally characterize the complexity of human isoform repertoires of SZ-associated genes using a single-cell long-read sequencing based approach, and to study how genetic variations influence alternative splicing and impact neuronal maturation and synaptic function in a subtype specific manner. This project will provide comprehensive catalogs of cell-specific full isoform repertoires of SZ genes that will broadly facilitate SZ research. It will also deepen the understanding of how genetic variations and alternative splicing contribute to SZ, help better predict the clinical outcome and identify novel therapeutic interventions. The single cell approach used in this project is generally applicable to study other mental disorders such as BD and ASD.