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

Shinya Yamamoto, Manish Jaiswal, Wu Lin Charng, Tomasz Gambin, Ender Karaca, Ghayda Mirzaa, Wojciech Wiszniewski, Hector Sandoval, Nele A. Haelterman, Bo Xiong, Ke Zhang, Vafa Bayat, Gabriela David, Tongchao Li, Kuchuan Chen, Upasana Gala, Tamar Harel, Davut Pehlivan, Samantha Penney, Lisenka E.L.M. VissersJoep De Ligt, Shalini N. Jhangiani, Yajing Xie, Stephen H. Tsang, Yesim Parman, Merve Sivaci, Esra Battaloglu, Donna Muzny, Ying Wooi Wan, Zhandong Liu, Alexander T. Lin-Moore, Robin D. Clark, Cynthia J. Curry, Nichole Link, Karen L. Schulze, Eric Boerwinkle, William B. Dobyns, Rando Allikmets, Richard A. Gibbs, Rui Chen, James R. Lupski, Michael F. Wangler, Hugo J. Bellen

Research output: Contribution to journalArticlepeer-review

241 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)200-214
Number of pages15
Issue number1
StatePublished - Sep 25 2014
Externally publishedYes

Bibliographical note

Funding Information:
We thank Y. Chen, C. Benitez, X. Shi, S. Gibbs, A. Jawaid, H. Wang, Y.Q. Lin, D. Bei, L. Wang, Y. He, and H. Pan for technical support; Y-N. Jan, T. Kaufman, C. Doe, U. Banergee, J. Olson, K. Cook, and D. Bilder for reagents; and J. Shulman, J. Zallen, E. Seto, and H.Y. Zoghbi for critical reading of this manuscript. This study was supported by the National Institutes of Health (NIH) 1RC4GM096355-01 (H.J.B. and R. Chen), U54HG006542 (BHCMG), R01NBS058529 (J.R.L.), 5P30HD024064 (Confocal microscopy at the Intellectual and Developmental Disabilities Research Center), K23NS078056 (W.W.) 5R01GM067858 (H.S.), T32 NS043124-11(H.S.), and 5K12GM084897 (H.S.), K08NS076547(M.F.W.), EY021163 (R.A.), EY019861 (R.A.), and EY019007 (R.A. and S.H.T.). Additional support: Nakajima Foundation and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital (S.Y.) National Science Centre Poland (DEC-2012/06/M/NZ2/00101) (W.W.), Houston Laboratory and Population Science Training Program in Gene-Environment Interaction from the Burroughs Wellcome Fund (Grant No. 1008200) (B.X.), NSF DMS# 1263932 (Z.L.), Bogazici University Research Foundation (09B101P) (E. Battaloglu), Research to Prevent Blindness to the Department of Ophthalmology, Columbia University (R.A., S.H.T.). H.J.B. is a Howard Hughes Medical Institute Investigator and received funds from the Robert and Renee Belfer Family Foundation, the Huffington Foundation, and Target ALS.

Publisher Copyright:
© 2014 Elsevier Inc.


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