Functional Genomics of Human Brain Development

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DESCRIPTION (provided by applicant): Understanding the molecular processes involved in the development and functional organization of biological systems, as well as their alterations in disease states, requires precise measurements of nucleic acid- and protein-level properties of cellular machinery across different cell types and developmental time points. This is particularly difficult to achieve in the human brain due to its cellular complexity and inaccessibility for experimentation. Here, we propose a Center with a multi-disciplinary group of investigators that will develop upon several cutting-edge genomics approaches in a unique and innovative way to elucidate molecular networks underlying human brain development and evolution. This will be achieved through the generation and exploration of integrated multi-dimensional genomic scale data generated from single cells and tissues of developing and adult human and non-human primate (NHP; chimpanzee and macaque) brains. We will also use these new sources of information to facilitate the identification of regulatory mutations in autism spectrum disorders (ASD) as well as to elucidate common and cell type specific molecular networks compromised in ASD. Finally, we implement approaches to model and functionally characterize of human-specific and ASD-associated regulatory mutations in the context of mouse brain development. Our proposed Center couples these research efforts with extensive training opportunities in human and comparative genomics. This organizational structure combines the expertise of each individual key investigator and establishes a CEGS that is capable of much more than each individual working alone and whose resources will create capabilities that are much more than the sum of its parts. Our work will pave the way for reconstructing molecular networks in human development and disease states, and provide a clear path to new and more effective treatments of major disorders.