Genome-wide association studies have given us many clues about the mutations that cause common genetic diseases, including autoimmune diseases like lupus and rheumatoid arthritis. However, many of the mutations implicated in disease lie outside of the genes themselves and instead lie in the regions controlling expression of the genes, and so probably contribute to disease by producing the wrong amount of the gene in the wrong tissue or at the wrong time. Mutations in regulatory regions are thought to cause disease by altering the binding of regulatory proteins to the DNA, changing the DNA sequence from one that the protein can bind to one that it cannot (or vice versa). However, the ways in which these regulatory proteins control gene expression remains incompletely understood and so it is presently difficult to understand which regulatory protein binds differently to a mutated regulatory region, or how that change in binding affects expression of the regulated genes. In fact, we still do not even know where the regulatory regions are in the tissues we think are dysfunctional in disease. This project aims to better understand how these mutations contribute to autoimmune disease by first increasing our understanding of how regulatory proteins and regulatory regions work to control when and where genes are expressed, and then applying this knowledge to understand genetic disease. First, regulatory regions will be identified in immune cells and their effects on gene expression measured so that mutations that are likely to contribute to disease (those in regulatory regions) can be identified. The relationship between regulatory proteins, regulatory sequence, and gene expression will be learned by creating millions of synthetic regulatory regions and measuring their effect on gene expression, providing many examples of binding sites for each regulatory protein from which to learn. Finally, our new understanding of gene regulation will be applied to determine which genetic mutations change regulatory protein binding and cause disease. This will help us better understand the underlying causes of disease so that new treatments can be developed that target the mutations within each person. The candidate's long term career goals are to better understand how gene regulation works in humans so that we can better understand how the sequence of the genome controls the expression of our genes. The candidate currently works at the Broad Institute, a leading institute in human genetics and genomics with the resources and personnel required of this project. In order to continue to develop as a scientist, the candidate will gain more experience teaching, publish and present his existing findings, gain the necessary skills to work with human cells, and secure a faculty position and funding so that he can continue to make a positive impact on our knowledge of the genome.
Certain genetic diseases are thought to be caused by mutations in the DNA that alter the expression of nearby genes. This project will help us to understand how DNA sequence regulates the expression of genes, and aims to apply this knowledge to predict how and why mutations change gene expression and contribute to disease. By better understanding the fundamental causes of disease, we can better design therapeutic interventions.
