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Induced pluripotent stem cells and the impact of genomic variation on psychiatric disorders

Wednesday, February 19, 2014

Speaker

Flora M. Vaccarino, M.D.
Harris Professor of Child Psychiatry and Neurobiology
Yale University

Dr. Vaccarino directs a multidisciplinary research group, which integrates knowledge from developmental neurobiology, genetics, human brain neuroanatomy, and animal model systems to elucidate the pathophysiology of childhood neuropsychiatric disorders, notably autism spectrum disorders and Tourette syndrome. She has been studying the cerebral cortex, basal ganglia, and connected forebrain regions in both animal models and human brains for more than 15 years, with a focus on how genetic and environmental factors regulate neural stem cells. In 2009, she founded the “Program in Neurodevelopment and Regeneration,” which is a collaborative interdepartmental program at Yale. The program is leading interdisciplinary studies on human iPSCs, human neural stem cells, and somatic mosaicism during brain development. Her laboratory uses deep sequencing and advanced neurobiological techniques to characterize the genome, transcriptome, and biological phenotypes of iPSC-derived neurons from patients—and their families—with developmental disorders. Her laboratory is also studying somatic genomic mosaicism in the brain and its implications for human development and disease.

Summary

It has been difficult to establish a link between mutations in the human genome and common disorders of complex etiology. By allowing the direct study of gene expression and function as neural cells divide and differentiate, the induced pluripotent stem cell (iPSC) model promises to bridge the gap between genomic variation and its effects on neuronal circuitry and function. The genome of iPSCs is relatively stable, but reflects the genomic mosaicism (genomic variation in the cells of a single individual) present in the somatic cells of origin. Dr. Vaccarino’s laboratory studies of the iPSC genome suggest that there is a surprisingly large amount of genomic variation in normal skin fibroblasts. To investigate whether the iPSC model can be used to illuminate the pathophysiology of neurodevelopmental disorders of complex etiology, her laboratory generated neural organoids from iPSC lines derived from 15 individuals in five families encompassing probands (first affected family members who seek medical attention for a genetic disorder) with autism and macrocephaly. Weighted gene co-expression network analysis (WGCNA) of transcriptome data and biological validations suggests that cells from probands have a shorter cell cycle and a significant imbalance in inhibitory/excitatory neurons in early brain development driven by a set of key transcription factors. She concludes that hiPSCs can be useful as a model to elucidate the etiology and pathophysiology of complex human disorders and represent a promising model for diagnostics, drug discovery, therapeutics, and personalized medicine.


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