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A system-level approach for discovery of phenotype specific genetic variation in ASD


A considerable obstacle to establishing a thorough understanding of the causes of Autism Spectrum Disorders (ASD) is that there many different genetic factors involved, and that different genetic factors may be present in different affected individuals. Current approaches for discovering genetic factors require the deployment of very large sample sizes to compensate for this heterogeneity. When attempting to discover genetic factors for specific aspects of ASD (such as language abilities or social responsiveness), this problem is even more pervasive, as the variability between individuals necessitate limiting the analyses to smaller subsets of the initial cohort. While there are many different genetic factors influencing autism risk, there may be shared functional aspects between them. The same can be claimed about genetic factors for specific aspects of ASD. This research project is based on this idea, and will look at the effect of a specific group of genes, involved in DNA packing, which have recently been identified as a strong candidate for association with ASD. To that end, the first step will be to determine the effect of these mutations on the cellular, behavioral and cognitive level. The second step will be to look at gene activity in the human brain. Post-mortem brain tissue from autistics and controls will be used to discover cellular effects related to DNA packing. Sequencing will then be used to discover mutations in genes involved in DNA packing which could explain these effects. Understanding how perturbation to this group of genes is related to specific molecular and behavioral phenotypes in ASD will provide an important step in understanding the molecular basis of ASD. Autism manifests differently in different affected individuals, and discovering the molecular basis for this variation may eventually allow the deployment of individual-specific interventions, where the brain functionality impaired in an individual will be targeted specifically. Thus, this research may have profound implications for autistic individuals, and our abilities to offer a more personalized approach to the treatment of ASD.