Grant: Operating Grant

In previous research we have shown that almost all human genes encode multiple protein products through a process known as alternative splicing. Each gene is first transcribed into an RNA copy that contains coding and non-coding segments. RNA splicing serves to join the coding segments into a contiguous messenger RNA that it can then 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 serves to greatly diversify the regulatory and functional capacity of genes, and is a major driver of biological complexity. Furthermore, alternative splicing is frequently disrupted by mutations that cause or contribute to human diseases, including many neurological disorders and cancers. In some cases, disease mutations affect entire programs of alternative splicing by targeting the RNA binding proteins that regulate this process. Despite this knowledge, we know nothing about the specific functions of the vast majority of individual protein variants generated by alternative splicing, nor how most of these variants, when misregulated, 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. The information generated by our project 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.