Increasingly, human neurological diseases are being mapped to genome regions shared between affected individuals, however current methods generally identify large genomic regions containing many genes. For example, Williams-Beuren Syndrome (WBS), results in learning deficits and cardiopulmonary phenotypes and is associated with deletion of at least 25 genes in the 1.5 Mb WBS critical region (WBSCR). Interestingly, those affected with WBS often have a 'hyper-gregarious'nature and enhanced language or music skills. Despite the small number of genes implicated, the lack of a social animal model has limited the study of how WBSCR genes affect social interaction and little is known about the WBSCR genes or how they contribute to the characteristic WBS symptoms. Social insects, including ants and bees, are a tractable experimental system to test the in vivo effects of WBSCR genes on complex social behaviors. We propose to perturb the expression level of genes from the WBSCR in the social insect, Linepithema humile (Argentine ant). We will: 1) Use comparative genomics to identify WBSCR gene orthologs in several genomes and annotate their exons, regulatory elements, and repeats. 2) Develop L. humile cDNA and fosmid resources to clone, sequence, and assess the methylation state of WBSCR gene regions. 3) Use RNA interference constructs to perturb expression of WBSCR genes in ants and observe changes in individual and group behaviors. In addition to these research objectives, the principal investigator will pursue the following developmental goals with the guidance of his mentor, Dr. Gary Karpen 4) establish an independent research group 5) enhance personal mentoring and teaching skills 6) improve the quality of research. Relevance to Public Health: Social interaction is a complex behavior that profoundly affects human health and well-being. Experimentation with behavior genes in humans is not feasible, making the development of a 'social behavior'animal model system desirable. The proposed studies will elucidate the conserved protein, cis-DNA regulatory features, and gene networks involved in Williams-Beuren Syndrome and will develop a social animal model system to test other gene-behavior interactions. This study of WBSCR genes promises to identify novel biomarkers and gene targets for therapeutic intervention of behavioral disorders.
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