Grant: Foundation Grant

We have shown that almost all human genes encode multiple protein products through a process known as alternative splicing. Each gene is transcribed into an RNA copy that contains coding and non-coding segments. RNA splicing joins the coding segments into a contiguous messenger RNA that can be translated into a functional protein product. Alternative splicing occurs when the coding segments are spliced in different combinations such that a single gene can produce multiple RNA and protein products. This process greatly diversifies the regulatory and functional capacity of genes, resulting in biological complexity. Alternative splicing is frequently disrupted by mutations that cause or contribute to human diseases and disorders. Moreover, some disease mutations can affect entire programs of alternative splicing by targeting the factors that regulate this process. However, we currently know nothing about the specific functions of most individual protein variants generated by alternative splicing, nor how these variants, when mis-regulated, contribute to human diseases. These questions represent key challenges for future biomedical research and form the main goals of this proposal. We will draw on our world-leading expertise in the areas of alternative splicing, functional genomics, and proteomics, to provide the first large-scale map of splice variant function in the context of both normal physiology and human disease. We will systematically dissect the regulatory pathways that control functionally important and disease-associated splicing events. Finally, we will use information generated by our project to develop new therapeutic strategies for correcting altered splicing programs that underlie human diseases and disorders, focusing on autism. Our research will yield unprecedented new insight into the multitasking functions of our genes, and it will further facilitate the development of a new generation of splicing-directed therapeutics.