Drosophila Models of Rare Mendelian Disorders of Chromatin Modification

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PROJECT SUMMARY Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS) and Cornelia de Lange syndrome (CdLS) are rare genetic disorders of chromatin modification characterized by varying degrees of intellectual disability, seizures, hypotonia, and facial and digit abnormalities. CSS-associated mutations in the same gene do not necessarily present with identical phenotypes, suggesting that there exists naturally occurring genetic variants within the genetic background of the patient that modify disease presentation. This proposal tests the hypothesis that candidate genetic modifiers are responsible for the varied severity of CSS, NCBRS, and CdLS and seeks to identify such modifiers using D. melanogaster. There are not enough CSS patients to provide adequate statistical power to identify these modifiers using human data. However, genes associated with CSS and related disorders are highly conserved across taxa, facilitating the use of model organisms, such as the fruit fly Drosophila melanogaster, to elucidate possible genetic modifiers and mechanisms of pathogenesis. Flies can be economically reared in large numbers within a controlled genetic background and exhibit quantifiable changes in behavior upon perturbation of fly orthologs of CSS-, NCBRS-, and CdLS-associated genes. Flies with decreased expression of genes co-regulated upon perturbation of CSS-, NCBRS-, and CdLS-associated fly orthologs will be assessed for behavioral changes and the presence of epistatic genetic interactions. Resulting genetic interactions or changes in behavior indicate that gene may be a candidate genetic modifier. The impact of genetic background on CSS fly phenotypes will be assessed on transgenic flies with normal or mutant copies of human ARID1B, the most commonly mutated gene in CSS, as well as on flies with decreased expression of osa, the fly ortholog for ARID1B. Genome-wide association analysis will be used to identify potential genetic modifiers, and subsequent functional validation will provide evidence that these candidate modifiers likely play a role in CSS disease development. These genetic modifiers will serve as plausible targets for further study on the pathogenesis, diagnosis, treatment and management of CSS and related disorders. This proposal provides the opportunity for the candidate to receive training in areas related to her long-term career goals, including bioinformatics, statistical analyses, and a complex-trait approach to characterize Mendelian diseases through the use of animal models. In addition to laboratory training, the environment and resources available at the Clemson Center for Human Genetics will provide the candidate with additional opportunities to engage with clinicians and participate in genetics education and outreach activities.