Variability of phenotypes resulting from similar genotypes is a major challenge in medical genetics. Even closely related carriers of the same mutation often have drastically distinct phenotypes. Molecular and genetic mechanisms contributing to such variability are poorly understood. We identified a copy number variant (CNV) in 16p11.2 region which accounts for one percent of ASDs. Across the genome, CNVs are associated with gene expression level, which is thought to be the mechanism of pathogenicity. Accordingly, the 16p11.2 genomic deletion/duplication was shown in blood to be correlated with lower/higher expression across the genes in the region. However, the penetrance for this major disruption of >25 genes is incomplete and the expression is extremely variable. We recently uncovered a widespread epigenetic mechanism that has major impact on gene expression and its variability. This mechanism, monoallelic expression or epigenetic loss of heterozygosity (eLOH), affects more than a quarter of human autosomal genes, including several genes in the 16p11.2 region. We hypothesize that eLOH has a significant yet underappreciated contribution to molecular and thus phenotypic variation. The interaction of copy number variation with eLOH is a completely uncharted territory and understanding how genomic copy number influences eLOH could lead to mechanistic insight into the regulation of eLOH as well as a source of expression and phenotypic variability that might be magnified or diminished for genes undergoing eLOH during neurodevelopment. The purpose of this project is to establish an experimental platform for understanding the interaction between an epigenetic mechanism affecting gene expression (eLOH) and genetic copy number variation in the context of a neurodevelopmental CNV. We will combine expertise and unique reagents of two leading laboratories in order to start addressing this fundamental question of gene regulation.
A number of human neurodevelopmental diseases, such as autism spectrum disorders, are associated with heritable genetic changes;however, individuals with the same risk variant can present very different clinical pictures - from normal development to severe disease. Understanding mechanisms of this variability is important for diagnosis and treatment of these disorders, and can offer clues for prevention of disease in at-risk individuals. This project aims to understand the role of a recently discovered mechanism of epigenetic loss of heterozygosity in affecting variation in gene expression.