A Drosophila model for 16p11.2 deletion shows differential sensitivity to gene dosage. J. Iyer, L. Pizzo, T. Le, P. Patel, L. Thomas, K. Vadodaria, S. Girirajan Departments of Biochemistry and Molecular Biology and Anthropology, The Pennsylvania State University, University Park, PA 16802.

   Recent studies have suggested a significant role for rare copy number variants (CNVs) towards a wide range of phenotypes, such as intellectual disability, autism, and schizophrenia. This has posed challenges in the diagnosis and management of affected individuals carrying these CNVs; lack of functional candidate genes within the region has impaired our understanding of the mechanisms of disease. We tested dosage sensitivity of Drosophila melanogaster orthologs of human genes within the autism-associated 16p11.2 region. Taking advantage of the tissue-specific expression system conferred by the UAS-Gal4 system, we used RNA interference (RNAi) to achieve eye-specific (GMR-Gal4) and neuron-specific (Elav-Gal4) knockdown of 18 fly lines representing eight fly orthologs of human genes within 16p11.2. We developed novel quantitative methods to accurately assess the severity of neurodevelopmental phenotypes and to identify candidates that are sensitive to gene-dosage alteration. Combining data from gene expression using qPCR with phenotypic measurements of fly RNAi lines enabled us to correlate the effect of gene dosage alterations to severity. Seven out of eight genes within 16p11.2 showed dosage-dependent change in severity including C16ORF53, CDIPT, KCTD13, FAM57B, ALDOA, PP419C, and MAPK3. In aggregate, male flies with reduced dosage of 16p11.2 genes were more severe (p=0.0015) than female flies suggesting a potential biological component to the observed male bias in neurodevelopmental disorders. Neuron-specific reduction of gene expression resulted in lethality for ALDOA and PP419C. Further, to assess the impact of gene dosage on fly head size, we measured the distance between conserved bristle landmarks for six genes. Three genes, KCTD13 (5.4 sd units), MAPK3 (6.6 sd units) and C16ORF53 (5.6 sd units) showed significant (p<0.001) macrocephaly at 50% expression levels and reflect the macrocephaly phenotypes observed in individuals with 16p11.2 deletions and autism. Interestingly, significant (p<0.001) microcephaly phenotypes were observed when the dosage of CDIPT (12.3 sd units) and CORO1A (11.2 sd units) was further reduced (expression <30%). We propose that conserved genes within rare CNVs associated with genomic disorders are involved in differential roles, sensitive to gene dosage alteration, and this complex interaction between cis and trans genetic variants contribute to the observed phenotypic variability.

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