Many neuropsychiatric disorders, including schizophrenia, bipolar disorder, and autism show evidence of a strong genetic component, yet linkage and association study results have been inconclusive and contradictory. Thus a large component of their observed heritability remains unexplained. Recent genome wide association studies suggest the prominent involvement of noncoding genomic regions in a number of common diseases, including neuropsychiatric disorders. This proposal takes advantage of the systematic identification and characterization of cis-regulatory elements relevant to human neurological development using digital DNaseI mapping to analyze fetal brain tissues at different developmental time points (between 70 and 140 days), and further develops novel techniques to identify regulatory interaction in trans. This map of functional cis-regulatory elements will be used to analyze regions implicated in genetic studies of psychiatric disorders. Conversely, disease-associated variants in transcription factor coding sequence will be systematically evaluated for altered DNA sequence specificity, potentially leading to effects in trans on downstream regulatory elements. Finally, the trans effects of disease-associated regulatory variants will be validated and explored using site-specific genome editing of cultured human cells This work will provide a unique resource for understanding the molecular mechanisms of gene regulation in neural development, and will establish a baseline for interpreting genetic variation observed in association studies. These rapidly expanding catalogs of human genetic variation offer great promise for reducing the burden of mental disorders. This proposed resource will unlock the full advantage of these catalogs by generating high-resolution maps of cis-regulatory elements and trans-regulatory interactions likely relevant to neurological disease. The research training program combines the strengths of the applicant's host institution and sponsor, and offers an opportunity to translate thee results of large-scale regulatory mapping efforts such as the ENCODE project and the Roadmap Epigenomics program to a specific disease area.
Understanding the elements that turn genes on and off in brain development is critical to the future of psychiatric research and practice. This project take advantage of new technology made possible by the Human Genome Project to identify the regulatory machinery of the cell during brain development. Its methods are eventually applicable to the understanding of human disease and lends interpretation to a variety of genomics resources, particularly genome-wide association studies (GWAS).