title: A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases.
abstract: Invertebrate model systems are powerful tools for studying human disease owing to their genetic tractability and ease of screening. We conducted a mosaic genetic screen of lethal mutations on the Drosophila X chromosome to identify genes required for the development, function, and maintenance of the nervous system. We identified 165 genes, most of whose function has not been studied in vivo. In parallel, we investigated rare variant alleles in 1,929 human exomes from families with unsolved Mendelian disease. Genes that are essential in flies and have multiple human homologs were found to be likely to be associated with human diseases. Merging the human data sets with the fly genes allowed us to identify disease-associated mutations in six families and to provide insights into microcephaly associated with brain dysgenesis. This bidirectional synergism between fly genetics and human genomics facilitates the functional annotation of evolutionarily conserved genes involved in human health.
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Howard Hughes Medical Institute, Houston, TX 77030, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Jaiswal
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
authors.forename: Wu-Lin
authors.initials: WL
authors.lastname: Charng
authors.affiliation: Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Institute of Computer Science, Warsaw University of Technology, 00-661 Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
authors.forename: Ender
authors.initials: E
authors.lastname: Karaca
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Ghayda
authors.initials: G
authors.lastname: Mirzaa
authors.affiliation: Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wiszniewski
authors.affiliation: Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
authors.forename: Hector
authors.initials: H
authors.lastname: Sandoval
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA.
authors.forename: Nele A
authors.initials: NA
authors.lastname: Haelterman
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiong
authors.affiliation: Program in Structural and Computational Biology and Molecular Biophysics, BCM, Houston, TX 77030, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA.
authors.forename: Vafa
authors.initials: V
authors.lastname: Bayat
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: David
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA.
authors.forename: Tongchao
authors.initials: T
authors.lastname: Li
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA.
authors.forename: Kuchuan
authors.initials: K
authors.lastname: Chen
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA.
authors.forename: Upasana
authors.initials: U
authors.lastname: Gala
authors.affiliation: Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Harel
authors.affiliation: Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
authors.forename: Davut
authors.initials: D
authors.lastname: Pehlivan
authors.affiliation: Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Penney
authors.affiliation: Department of Human Genetics, Radboudumc, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Lisenka E L M
authors.initials: LELM
authors.lastname: Vissers
authors.affiliation: Department of Human Genetics, Radboudumc, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: de Ligt
authors.affiliation: Human Genome Sequencing Center, BCM, Houston, TX 77030, USA.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Department of Ophthalmology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Ophthalmology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Tsang
authors.affiliation: Neurology Department and Neuropathology Laboratory, Istanbul University Medical School, Istanbul 34390, Turkey.
authors.forename: Yesim
authors.initials: Y
authors.lastname: Parman
authors.affiliation: Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, Turkey.
authors.forename: Merve
authors.initials: M
authors.lastname: Sivaci
authors.affiliation: Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, Turkey.
authors.forename: Esra
authors.initials: E
authors.lastname: Battaloglu
authors.affiliation: Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Human Genome Sequencing Center, BCM, Houston, TX 77030, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA; Department of Obstetrics and Gynecology, BCM, Houston, TX 77030, USA.
authors.forename: Ying-Wooi
authors.initials: YW
authors.lastname: Wan
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA; Department of Pediatrics, BCM, Houston, TX 77030, USA.
authors.forename: Zhandong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Lin-Moore
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Loma Linda University Medical Center, Loma Linda, CA 92354, USA.
authors.forename: Robin D
authors.initials: RD
authors.lastname: Clark
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA; Genetic Medicine Central California, Fresno, CA 93701, USA.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Curry
authors.affiliation: Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
authors.forename: Nichole
authors.initials: N
authors.lastname: Link
authors.affiliation: Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Howard Hughes Medical Institute, Houston, TX 77030, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Schulze
authors.affiliation: Human Genome Sequencing Center, BCM, Houston, TX 77030, USA; Human Genetics Center, University of Texas, Health Science Center, Houston, TX 77030, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Neurology, University of Washington, Seattle WA 98195, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: Department of Ophthalmology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Rando
authors.initials: R
authors.lastname: Allikmets
authors.affiliation: Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Human Genome Sequencing Center, BCM, Houston, TX 77030, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Human Genome Sequencing Center, BCM, Houston, TX 77030, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Human Genome Sequencing Center, BCM, Houston, TX 77030, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: michael.wangler@bcm.edu.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wangler
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA; Howard Hughes Medical Institute, Houston, TX 77030, USA; Program in Structural and Computational Biology and Molecular Biophysics, BCM, Houston, TX 77030, USA; Department of Neuroscience, BCM, Houston, TX 77030, USA. Electronic address: hbellen@bcm.edu.
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
mesh_terms: D000818:Animals; D004194:Disease / Q000235:genetics*; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D040582:Inheritance Patterns; D034622:RNA Interference; D014960:X Chromosome