Genomic and epigenomic dysregulation in Autism Spectrum Disorders
Berko, Esther R.
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Autism Spectrum Disorders (ASDs) encompass a heterogeneous group of diseases characterized by impairments in communication and social interaction. Rates of ASD rise with parental age, with fathers older than 40 and mothers older than 35 each possessing greater independent risk of having a child with an ASD. Advanced maternal age could contribute to ASD pathogenesis via two biologic mechanisms. First, older oocytes have greater risk of chromosomal non-disjunction and resultant aneuploidy, which can result in mosaic trisomy in surviving offspring. Second, older oocytes possess greater risk of undergoing epigenetic dysregulation, which could lead to aberrant DNA methylation patterns in the offspring. The goal of this study was to assess if individuals with an ASD, born to mothers 35 and older, demonstrated greater rates of mosaic trisomy, or showed dysregulation of DNA methylation, when compared to typically developing controls also born to older mothers.;This study did not show increased prevalence of mosaic trisomy in affected individuals, potentially due to limitations of array-based technology to detect mosaicism of less than 20%. The epigenome-wide association study on an homogeneous ectodermal cell type showed that DNA methylation patterns were distinctive in ASD subjects, after stringently accounting for confounding effects of subject age, sex and ancestral haplotype. The loci with distinctive DNA methylation in ASD were located adjacent to genes whose protein products were found to be significantly enriched for interactions with those encoded by known ASD genes.;The study also included development of an innovative technique to use sequencing based technology to detect chromosomal mosaicism. This sequence capture based approach discriminates less than 1% mosaicism in cell lines and performs well on human clinical samples.;In summary, this thesis reveals that DNA methylation may play a role in ASD pathogenesis, and may serve as another mechanism in regulating known ASDassociated genomic pathways. While our patient cohort failed to reveal detectable chromosomal mosaicism, the possibility remains that low-level mosaicism may still be present in ASD, a prospect that can now be explored with the development of the new sequence capture assay.