Human brains exhibit dramatic anatomical and cognitive differences from those of closely related species. Identifying genomic contributors to primate neuroanatomy and development will allow us to hone in on features responsible for certain behavioral traits and disorders. To date, relatively few mutations have been found that contribute to neural differences among primates. Improved DNA sequencing technologies have provided access to previously unexplored complex regions of the genome that have classically remained recalcitrant to analyses such as genomic duplications that suffer from high sequence identity. Analysis of thousands of human and great ape genomes shows that segmental duplications (SDs, or regions >10 kbp with >90% sequence identity) account for greater euchromatic genetic differences between species than any other type of variant. Human-specific SDs (HSDs) are enriched for genes implicated in neurological function?relative to nonhuman great apes?and have the propensity to contribute to novel phenotypes by creating duplicate versions of themselves that may be truncated, fused with other genes, or expressed in alternative tissues. Further, most HSDs cluster at genomic ?hotspots??or regions prone to deletions and duplications?implicated in neurodevelopmental disorders such as autism, intellectual disability, and epilepsy. The primary goal of the proposed project is to systematically dissect the role that duplicated genes play in neurodevelopment and disease. Knowing that gene duplication is a well-established mode of species innovation and divergence, the project will test the hypothesis that certain novel paralogs are functional in humans today and contribute to innovative neurological features; indeed, evidence already exists for two duplicated genes SRGAP2C and ARHGAP11B using mouse models. Three fundamental questions will be addressed regarding each duplicated gene: (1) Are duplicate genes functional? (2) What is the function of ancestral and duplicate gene paralogs? (3) Do mutations of HSD genes cause disease? If successful, not only will this project provide important insight into what it means to be human, but also the methods proposed? genome sequencing of human cohorts coupled with parallelized screens of function? provide a roadmap to characterize other complex genes implicated in neurological function and disease.
Neurodevelopmental disorders are common in the population, representing a significant burden in all aspects of life and society. Studies aimed at discovering the causes of such disorders will lead to a better understanding of the underlying biological mechanisms and, in turn, facilitate development of improved diagnostic methods and potential treatments.