Article abstract
Nature Genetics 40, 181 - 188 (2008)
Published online: 27 January 2008 | doi:10.1038/ng.2007.70
A single gene network accurately predicts phenotypic effects of gene perturbation in Caenorhabditis elegans
Insuk Lee1,4, Ben Lehner2,3,4, Catriona Crombie2, Wendy Wong2, Andrew G Fraser2 & Edward M Marcotte1
Abstract
The fundamental aim of genetics is to understand how an organism's phenotype is determined by its genotype, and implicit in this is predicting how changes in DNA sequence alter phenotypes. A single network covering all the genes of an organism might guide such predictions down to the level of individual cells and tissues. To validate this approach, we computationally generated a network covering most C. elegans genes and tested its predictive capacity. Connectivity within this network predicts essentiality, identifying this relationship as an evolutionarily conserved biological principle. Critically, the network makes tissue-specific predictions—we accurately identify genes for most systematically assayed loss-of-function phenotypes, which span diverse cellular and developmental processes. Using the network, we identify 16 genes whose inactivation suppresses defects in the retinoblastoma tumor suppressor pathway, and we successfully predict that the dystrophin complex modulates EGF signaling. We conclude that an analogous network for human genes might be similarly predictive and thus facilitate identification of disease genes and rational therapeutic targets.
- Center for Systems and Synthetic Biology, Department of Chemistry and Biochemistry, Institute for Cellular and Molecular Biology, University of Texas, 2500 Speedway, MBB 3.210, Austin, Texas 78712, USA.
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
- European Molecular Biology Laboratory-Centre for Genomic Regulation (EMBL-CRG) Systems Biology Unit and Institució Catalana de Recerca i Estudis Avançats (ICREA), Center for Genomic Regulation, Universitat Pompeu Fabra, C/ Dr. Aiguader 88, 08003 Barcelona, Spain.
- These authors contributed equally to this work.
Correspondence to: Andrew G Fraser2 e-mail: agf@sanger.ac.uk
Correspondence to: Edward M Marcotte1 e-mail: marcotte@icmb.utexas.edu
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