Grant: Operating Grant

Twenty years after the proposal of the double helix, it was discovered that DNA does not directly encode messenger RNA, but that a process called splicing assembles each mRNA based on carefully selected DNA subsequences. Because of this, a gene can encode many different mRNAs and which mRNAs are generated can depend on cell type, age and disease. There are 22,000 human genes, but there are over 1,000,000 different mRNAs produced by splicing. For example, one fruit fly gene encodes 38,000 mRNAs that control wiring in the brain. Roberts and Sharp received the Nobel Prize for their work in 1993, but the genetic information that controls splicing in general has remained a mystery. Unraveling this mystery is important for fundamental science, but also for medicine, since many diseases are associated with errors in splicing. Recently, my group proposed a new approach whereby hundreds of new and known RNA features are assembled into a "splicing code" that accounts for tissue-dependent changes in alternative splicing (Nature, accepted subject to minor revisions). In this project, my group will use this approach to develop the first every, comprehensive human splicing code. This code will elucidate new classes of tissue-regulated alternative splicing patterns, identify distinct regulatory programs in different tissues, correctly predict splicing patterns in healthy tissues and find associations between disease-associated mutations and the codes needed for normal splicing. I anticipate that these results will provide a foundation for understanding and predicting the complicated, genome-wide regulation of splicing, and how diseases can cause this process to go wrong.