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Cell. 2014 Sep 25;159(1):200-214. doi: 10.1016/j.cell.2014.09.002.

A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases.

Author information

1
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.
2
Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Howard Hughes Medical Institute, Houston, TX 77030, USA.
3
Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
4
Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Institute of Computer Science, Warsaw University of Technology, 00-661 Warsaw, Poland.
5
Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
6
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
7
Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
8
Program in Developmental Biology, Baylor College of Medicine (BCM), Houston, TX 77030, USA.
9
Program in Structural and Computational Biology and Molecular Biophysics, BCM, Houston, TX 77030, USA.
10
Department of Human Genetics, Radboudumc, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
11
Human Genome Sequencing Center, BCM, Houston, TX 77030, USA.
12
Department of Ophthalmology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
13
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.
14
Neurology Department and Neuropathology Laboratory, Istanbul University Medical School, Istanbul 34390, Turkey.
15
Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, Turkey.
16
Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Human Genome Sequencing Center, BCM, Houston, TX 77030, USA.
17
Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA; Department of Obstetrics and Gynecology, BCM, Houston, TX 77030, USA.
18
Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA; Department of Pediatrics, BCM, Houston, TX 77030, USA.
19
Division of Medical Genetics, Department of Pediatrics, Loma Linda University Medical Center, Loma Linda, CA 92354, USA.
20
Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA; Genetic Medicine Central California, Fresno, CA 93701, USA.
21
Human Genome Sequencing Center, BCM, Houston, TX 77030, USA; Human Genetics Center, University of Texas, Health Science Center, Houston, TX 77030, USA.
22
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.
23
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.
24
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.
25
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.
26
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.

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.

Comment in

PMID:
25259927
PMCID:
PMC4298142
DOI:
10.1016/j.cell.2014.09.002
[Indexed for MEDLINE]
Free PMC Article

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