A Drosophila genetic resource to study human disease genes and its use for gene discovery in human exome data. M. F. Wangler1,2, S. Yamamoto1,3,4, M. Jaiswal1,5, W. L. Charng1,4, T. Gambin1,6, E. Karaca1, G. Mirzaa7,8, W. Wiszniewski1,2, H. Sandoval1, N. Haelterman4, V. Bayat4, D. Pehlivan1, S. Penney1,2, L. Vissers10, S. Jhangiani11, S. Tsang12,13, Y. Xie12, Y. Parman14, E. Battaloglu15, D. Muzny1,11, Z. Liu3,16, R. Clark17, C. Curry18, E. Boerwinkle11,19, W. Dobyns7,8,20, R. Allikmets12,13, R. Gibbs1,11, R. Chen1,4,11, J. R. Lupski1,2,11,16, H. Bellen1,2,3,4,9,21 1) Department of Molecular and Human Genetics, BCM, Houston, TX, 77030; 2) Texas Childrens Hospital, Houston, TX, 77030; 3) Jan and Dan Duncan Neurological Research Institute, Texas Childrens Hospital (TCH), Houston, TX, 77030; 4) Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX, 77030; 5) Howard Hughes Medical Institute, Houston, TX, 77030; 6) Institute of Computer Science, Warsaw University of Technology, 00-661 Warsaw, Poland; 7) Department of Pediatrics, University of Washington, Seattle, WA, 98195; 8) Center for Integrative Brain Research, Seattle Childrens Research Institute, Seattle, WA, 98101; 9) Program in Structural and Computational Biology and Molecular Biophysics, BCM, Houston, TX, 77030; 10) Department of Human Genetics, Radboudumc, PO Box 9101, 6500 HB, Nijmegen, The Netherlands; 11) Human Genome Sequencing Center, BCM, Houston, TX, 77030; 12) Department of Ophthalmology, Columbia University College of Physicians and Surgeons, New York, NY, 10032; 13) Department of Pathology & Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY, 10032; 14) Neurology Department and Neuropathology Laboratory, Istanbul University Medical School, Istanbul, Turkey; 15) Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey; 16) Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030; 17) Division of Medical Genetics, Department of Pediatrics, Loma Linda University Medical Center, Loma Linda, CA, 92354; 18) Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, and Genetic Medicine Central California, Fresno, CA, 93701Division of Medical Genetics, Department of Pediatrics, Loma Linda University Medical Center, Loma Linda,; 19) Human Genetics Center, University of Texas, Health Science Center at Houston, Houston, TX, 77030; 20) Department of Neurology, University of Washington, 98195; 21) Department of Neuroscience, BCM, Houston, TX, 77030Department of Neurology, University of Washington, 98195.

   Exploring the genetic mechanisms of disease in model organisms such as Drosophila has traditionally relied primarily upon gene discovery in humans followed by reverse genetic studies of the disease gene in the model system. While forward genetic screens in Drosophila have provided numerous fundamental contributions to basic biology, technical limitations have made it more difficult to quickly use these screens for disease discovery. The widespread use of exome sequencing now allows for more rapid application of Drosophila screens to personal genomes of patients with rare disease. In order to provide functional information about many genes, we conducted a large forward-genetic mutagenesis screen of the Drosophila X-chromosome and selected lethal mutations. Numerous phenotypes were tested in these lethal stocks to capture genes required for development, function, and maintenance of the nervous system. We mapped, and rescued the phenotypes associated with mutations in 165 fly genes. We then undertook a systematic study of the 250 human homologues. We observed that the human homologues of lethal fly genes were enriched for association with Mendelian disease compared to the whole genome. In addition we made a surprising observation, that genes that are 1) essential in flies and 2) have multiple human homologs are the most likely to be associated with Mendelian disease. We then undertook a systematic study of these human homologues within 1,929 human exomes from families with unsolved rare disease from the Baylor Hopkins Center for Mendelian Genomics study. We extracted all the variants in these genes under dominant and recessive models, and by sequencing family members we identified disease-associated, co-segregating mutations in six independent families. These families provided some examples of findings consistent with what has been previously reported (DNM2 and Charcot-Marie Tooth disease), examples of phenotypic expansion for a known disease gene (CRX and Bulls Eye Maculopathy), and potential novel disease gene discoveries, namely mutations in ANKLE2 associated with severe microcephaly. This latter family and the resulting Drosophila and human studies are described in additional abstracts from this project (see Charng et al, and Clark et al). Our approach provides an example of the use of forward genetic screens in Drosophila and human genomic data in order to facilitate gene discovery and unbiased functional studies of Mendelian disease.

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