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Investigating the contribution of DNA methylation to autism phenotypes in disorders of 7q11.23

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Strong, Emma

Osborne, Lucy

University of Toronto


2 years

Weatherstone Predoctoral Fellowship






Williams Syndrome (WS) and 7q11.23 Duplication Syndrome (Dup7) are rare neurodevelopmental disorders caused by deletion and duplication respectively, of 26 genes on chromosome 7q11.23. Individuals with WS and Dup7 show a range of cognitive and behavioral phenotypes, including intellectual disability and features of autism spectrum disorder (ASD). However, the underlying molecular mechanisms of these disorders are unknown. Five genes within 7q11.23 have been associated with epigenetic regulation. Therefore, the hypothesis driving this work is that deletion or duplication of 7q11.23 alters epigenetic regulation, specifically DNA methylation, and these alterations play an important role in the phenotypic presentation of WS and Dup7. Genome-wide DNA methylation in whole blood samples from a cohort of 20 WS, 10 Dup7 and 15 age- and sex-matched controls have been analyzed and over 1000 differentially methylated probes have been identified, corresponding to approximately 700 genes. Many genes have been linked to neuronal development or associated with abnormal brain development. The first objective is to identify the gene(s) within 7q11.23 that alter DNA methylation when deleted or duplicated. Specifically, genome-wide DNA methylation will be assessed in blood from families with smaller deletions or duplications of 7q11.23, and in available mouse models of WS and Dup7. This will allow the assessment of the contribution of a small number of genes to altered DNA methylation. The second objective is to assess DNA methylation and gene expression in neural tissue. Specifically, DNA methylation will be assayed in neural tissue from WS and Dup7 mouse models and neurons created from human WS and Dup7 induced pluripotent stem cells lines. In parallel, genome-wide expression will be examined using RNA sequencing, to determine the effect of aberrant DNA methylation on gene expression. These methods will allow the identification of novel genes and pathways disrupted by DNA methylation in the brain. Striking differences have been identified in methylation profiles in WS and Dup7; suggesting epigenetic pathways may be involved in the phenotypic presentation of these disorders. This project will identify a novel gene that is associated with aberrant DNA methylation, and identify novel pathways altered by DNA methylation in a biologically relevant tissue. The results will lay the foundation for a correlative analysis of DNA methylation profiles with ASD symptoms, and may identify new pathways involved in ASD pathogenesis.

Genetics, Biomarkers, Epigenetics, Gene Knock-Out/ Knock-In Models, Neurobiology, Broader Autism Phenotype, In-Vitro Models, Biology, Screening/ Diagnosis/ Phenotyping, Etiology/ Risk Factors, Infants (0-17 Months), Toddlers (18 Months-3 Years), Children (3-12 Years), Adolescents/ Young Adults (13-25 Years), Adults (>25 Years), Individuals At Risk For ASD, Low-Functioning/ Non-Verbal Individuals With ASD, Other Identifiable Genetic Disorder, Mice, Cultured Neurons, Brain Tissue

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