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. Vissers; Joep 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

doi:10.1016/j.cell.2014.09.002

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 journal › Article › peer-review

189 Scopus citations

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.

Original language	English (US)
Pages (from-to)	200-214
Number of pages	15
Journal	Cell
Volume	159
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2014.09.002
State	Published - Sep 25 2014
Externally published	Yes

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.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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Yamamoto, S., Jaiswal, M., Charng, W. L., Gambin, T., Karaca, E., Mirzaa, G., Wiszniewski, W., Sandoval, H., Haelterman, N. A., Xiong, B., Zhang, K., Bayat, V., David, G., Li, T., Chen, K., Gala, U., Harel, T., Pehlivan, D., Penney, S., ... Bellen, H. J. (2014). A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases. Cell, 159(1), 200-214. https://doi.org/10.1016/j.cell.2014.09.002

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

In: Cell, Vol. 159, No. 1, 25.09.2014, p. 200-214.

Research output: Contribution to journal › Article › peer-review

Yamamoto, S, Jaiswal, M, Charng, WL, Gambin, T, Karaca, E, Mirzaa, G, Wiszniewski, W, Sandoval, H, Haelterman, NA, Xiong, B, Zhang, K, Bayat, V, David, G, Li, T, Chen, K, Gala, U, Harel, T, Pehlivan, D, Penney, S, Vissers, LELM, De Ligt, J, Jhangiani, SN, Xie, Y, Tsang, SH, Parman, Y, Sivaci, M, Battaloglu, E, Muzny, D, Wan, YW, Liu, Z, Lin-Moore, AT, Clark, RD, Curry, CJ, Link, N, Schulze, KL, Boerwinkle, E, Dobyns, WB, Allikmets, R, Gibbs, RA, Chen, R, Lupski, JR, Wangler, MF & Bellen, HJ 2014, 'A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases', Cell, vol. 159, no. 1, pp. 200-214. https://doi.org/10.1016/j.cell.2014.09.002

Yamamoto, Shinya ; Jaiswal, Manish ; Charng, Wu Lin ; Gambin, Tomasz ; Karaca, Ender ; Mirzaa, Ghayda ; Wiszniewski, Wojciech ; Sandoval, Hector ; Haelterman, Nele A. ; Xiong, Bo ; Zhang, Ke ; Bayat, Vafa ; David, Gabriela ; Li, Tongchao ; Chen, Kuchuan ; Gala, Upasana ; Harel, Tamar ; Pehlivan, Davut ; Penney, Samantha ; Vissers, Lisenka E.L.M. ; De Ligt, Joep ; Jhangiani, Shalini N. ; Xie, Yajing ; Tsang, Stephen H. ; Parman, Yesim ; Sivaci, Merve ; Battaloglu, Esra ; Muzny, Donna ; Wan, Ying Wooi ; Liu, Zhandong ; Lin-Moore, Alexander T. ; Clark, Robin D. ; Curry, Cynthia J. ; Link, Nichole ; Schulze, Karen L. ; Boerwinkle, Eric ; Dobyns, William B. ; Allikmets, Rando ; Gibbs, Richard A. ; Chen, Rui ; Lupski, James R. ; Wangler, Michael F. ; Bellen, Hugo J. / A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases. In: Cell. 2014 ; Vol. 159, No. 1. pp. 200-214.

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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.",

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

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{\textquoteright}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: {\textcopyright} 2014 Elsevier Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2014",

month = sep,

day = "25",

doi = "10.1016/j.cell.2014.09.002",

language = "English (US)",

volume = "159",

pages = "200--214",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases

AU - Yamamoto, Shinya

AU - Jaiswal, Manish

AU - Charng, Wu Lin

AU - Gambin, Tomasz

AU - Karaca, Ender

AU - Mirzaa, Ghayda

AU - Wiszniewski, Wojciech

AU - Sandoval, Hector

AU - Haelterman, Nele A.

AU - Xiong, Bo

AU - Zhang, Ke

AU - Bayat, Vafa

AU - David, Gabriela

AU - Li, Tongchao

AU - Chen, Kuchuan

AU - Gala, Upasana

AU - Harel, Tamar

AU - Pehlivan, Davut

AU - Penney, Samantha

AU - Vissers, Lisenka E.L.M.

AU - De Ligt, Joep

AU - Jhangiani, Shalini N.

AU - Xie, Yajing

AU - Tsang, Stephen H.

AU - Parman, Yesim

AU - Sivaci, Merve

AU - Battaloglu, Esra

AU - Muzny, Donna

AU - Wan, Ying Wooi

AU - Liu, Zhandong

AU - Lin-Moore, Alexander T.

AU - Clark, Robin D.

AU - Curry, Cynthia J.

AU - Link, Nichole

AU - Schulze, Karen L.

AU - Boerwinkle, Eric

AU - Dobyns, William B.

AU - Allikmets, Rando

AU - Gibbs, Richard A.

AU - Chen, Rui

AU - Lupski, James R.

AU - Wangler, Michael F.

AU - Bellen, Hugo J.

N1 - 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. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2014/9/25

Y1 - 2014/9/25

N2 - 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.

AB - 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.

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JO - Cell

JF - Cell

SN - 0092-8674

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

Abstract

Bibliographical note

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