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First published online April 20, 2007
Journal of Experimental Biology 210, 1559-1566 (2007)
Published by The Company of Biologists 2007
doi: 10.1242/jeb.002311

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Modelling genotype–phenotype relationships and human disease with genetic interaction networks

Ben Lehner

EMBL/CRG Systems Biology Unit, Centre for Genomic Regulation (CRG), UPF, C/Dr Aiguader 88, Barcelona 08003, Spain

View larger version (13K): [in this window] [in a new window]   Fig. 1. Synthetic genetic interactions. A synthetic lethal interaction between two genes is defined when the survival of the combined mutation is less than the product of the survival of the two single mutations. In yeast, genetic interactions are defined by combining mutant strains using systematic mating protocols (A), and synthetic lethal or sick phenotypes are defined where a double mutant strain displays a phenotype that is not seen with either single mutant strain. In C. elegans, genetic interations are defined by combining genetic mutations with RNAi to target a second gene (B), or by using combinatorial RNAi to target two genes simultaneously (C) (Tischler et al., 2006). Synthetic aggravating phenotypes can be similarly defined for other phenotypes such as sterility or growth (Lehner et al., 2006b), and many more possible combinations of aggravating or alleviating interactions are also possible (Drees et al., 2005).

View larger version (5K): [in this window] [in a new window]   Fig. 2. Within- and between-pathway models for genetic interactions. Synthetic lethal interactions (broken lines) can occur both between two components of a single biochemical pathway (A), or between components of two parallel pathways that can functionally compensate for each other (B). Kelley and Ideker found that the combination of within- and between-pathway models could explain about 40% of synthetic lethal or sick interactions in yeast, with between-pathway models predominating. Examples of within-pathway interactions include interactions among components of the spliceosome, and interactions among components of the casein kinase 2 complex. Between-pathway interactions include extensive interactions between components of the Dynactin complex and components of the Prefoldin complex (Kelley and Ideker, 2005). For interactions between partial loss-of-function mutations, however, within-pathway models may predominate. Genes/proteins are shown as nodes, protein interactions as solid edges, and genetic interactions as broken edges.

View larger version (8K): [in this window] [in a new window]   Fig. 3. Genetic hubs and genetic disease in humans. Genetic hubs are genes that when inactivated can enhance the phenotypic consequence of mutations in many different genes. Often hub genes can enhance the consequences of mutations in genes acting in diverse functionally unrelated pathways. Examples include a set of chromatin-modifying genes in C. elegans (the genes mys-1, trr-1, dpy-22, hmg-1.2, din-1, and egl-27) (Lehner et al., 2006b), the Prefoldin complex in S. cerevisiae (Tong et al., 2004), and the gene hsp90 in yeast (Zhao et al., 2005), flies (Rutherford and Lindquist, 1998) and plants (Queitsch et al., 2002). Here the red node represents a hub gene, and the remaining nodes are coloured according to their function. Protein–protein interactions are shown as solid lines and genetic interactions as broken lines.