The Duke FUNCTION Center: Pioneering the comprehensive identification of combinatorial noncoding causes of disease

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ABSTRACT: Noncoding genetic variation that alters gene regulatory element activity has major impacts on health, disease, and evolution. Because measuring regulatory element activity has long been a major challenge, the mechanisms underlying thousands of genetic associations with disease remain unknown. Recent advances in high-throughput technologies have disruptively advanced the ability to measure the activity of individual regulatory elements, and the first population- and genome-scale uses of those methods are now underway. However, regulatory elements do not act alone. They interact with promoters, other regulatory elements, and the surrounding chromatin, all in ways that are complex and difficult to predict. Though there are now a plethora of technologies to measure the activity of individual regulatory elements, the ability to recapitulate the effects of combinations of regulatory elements is woefully inadequate and severely hinders efforts to establish the gene regulatory contributions to traits and diseases. The goal of the Duke FUNCTION Center of Excellence in Genomic Science is to make the study of the combinatorial activity of regulatory elements routine. Aim 1 is to develop a suite of new technologies to measure the combinatorial effects of regulatory elements in their endogenous genomic contexts. Those technologies will leverage very recent discoveries of CRISPR enzymes other than Cas9 that greatly expand the ability to manipulate the human genome. Aim 2 is to develop the matched computational, statistical, and evolutionary models needed to interpret and predict the measured effects of combinations of regulatory variants on human traits and diseases. Aim 3 is to demonstrate the broad applicability of the technologies developed through case studies of human diseases with prevalence ranging from common to ultra rare. Example case studies will include studies of schizophrenia, rare recessive disorders, and undiagnosed genetic disorders. We will also use a nationwide request for applications to identify Pilot Projects that will expand applications to other disease areas. Aim 4 is to create an electronic platform for distributing results from functional studies of the noncoding genome to the broad research community. The platform will integrate our results with those from studies in other labs and consortia, such as ENCODE; and will enable researchers with diverse expertise to benefit from the Center. Finally, our Education and Outreach Aim is to expand genomics capacity locally and nationally, and with a particular emphasis on increasing use of our new technologies for translational research. The expected outcome of this project will be a paradigm shift in human genetic and genomics in which it will become possible to finally understand the full regulatory complexity that controls the expression of human genes. We anticipate that ability will be particularly powerful for translating genetic associations into disease mechanisms, thus creating a windfall of new knowledge about which genes contribute most to disease, and how to manipulate those genes for therapeutic benefit. Long term, we envision this work being critical to realizing the full potential of whole genome sequencing to detect causes of disease.