Yeast genetic interaction screen of human genes associated with amyotrophic lateral sclerosis: identification of MAP2K5 kinase as a potential drug target
- Myungjin Jo1,7,
- Ah Young Chung2,7,
- Nozomu Yachie3,7,8,
- Minchul Seo1,
- Hyejin Jeon1,
- Youngpyo Nam1,
- Yeojin Seo1,
- Eunmi Kim2,
- Quan Zhong4,
- Marc Vidal5,
- Hae Chul Park2,
- Frederick P. Roth3,6 and
- Kyoungho Suk1
- 1Department of Pharmacology, Brain Science and Engineering Institute, and Department of Biomedical Sciences, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, 41944, Korea;
- 2Department of Biomedical Sciences, Korea University Ansan Hospital, Ansan-si, Gyeonggi-do, 425-707, Korea;
- 3Donnelly Centre and Departments of Molecular Genetics and Computer Science, University of Toronto and Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada;
- 4Department of Biological Sciences, Wright State University, Dayton, Ohio 45435, USA;
- 5Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
- 6Canadian Institute for Advanced Research, Toronto, Ontario M5G 1Z8, Canada
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↵7 These authors contributed equally to this work.
Abstract
To understand disease mechanisms, a large-scale analysis of human–yeast genetic interactions was performed. Of 1305 human disease genes assayed, 20 genes exhibited strong toxicity in yeast. Human–yeast genetic interactions were identified by en masse transformation of the human disease genes into a pool of 4653 homozygous diploid yeast deletion mutants with unique barcode sequences, followed by multiplexed barcode sequencing to identify yeast toxicity modifiers. Subsequent network analyses focusing on amyotrophic lateral sclerosis (ALS)-associated genes, such as optineurin (OPTN) and angiogenin (ANG), showed that the human orthologs of the yeast toxicity modifiers of these ALS genes are enriched for several biological processes, such as cell death, lipid metabolism, and molecular transport. When yeast genetic interaction partners held in common between human OPTN and ANG were validated in mammalian cells and zebrafish, MAP2K5 kinase emerged as a potential drug target for ALS therapy. The toxicity modifiers identified in this study may deepen our understanding of the pathogenic mechanisms of ALS and other devastating diseases.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.211649.116.
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Freely available online through the Genome Research Open Access option.
- Received June 29, 2016.
- Accepted June 6, 2017.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
