The Genom of Homo sapiens.pdf

438 JORGENSEN ET AL.AArp2/3 ComplexRNaseComplexAnaphase PromotingTubulin Binding ComplexComplex26SProteasomeHistone DeacetylaseComplexTRAPPComplexBTAFIIDComplexSCFComplexEIF3 Complexv-SNARECOP IIVesicle CoatmRNAProcessingCDNA replicationFactor C ComplexMitochondrialRibosomeRNA SplicingPol II MediatorComplexRibosomeBiogenesisDEFFigure 5. Minimal overlap between protein and genetic interaction networks. (A–C) Yeast networks. (A) Complete protein interactionnetwork (12,379 interactions). (B) Genetic interaction network (3,404 interactions). (C) Overlap between protein and genetic networks(135 interactions). (D–F) Fly networks. (D) Protein interaction network derived from two-hybrid interaction data (Giot et al.2003). (E) Genetic interaction network (curated from FlyBase). (F) Overlap between protein and genetic networks (23 interactions).partially superimposable across distantly related species.To illustrate, the S. cerevisiae and D. melanogaster proteininteraction networks exhibit substantial overlap at ahigh stringency of >50% sequence identity (Fig. 6). Indeed,sequence-based comparison methods across theevolutionary spectrum also have a surprising degree ofpredictive power based on coevolution of interaction partners(Valencia and Pazos 2003). All told, model organisminteraction networks provide an informative scaffold forassembly of the corresponding human networks, which inturn will facilitate the dissection of human polygenic traitsand disorders (Hartwell et al. 1997).BIOLOGICAL DISCOVERY IN INTERACTIONNETWORKS: CRITICAL CELL SIZEWe have used the power of integrated functional genomicapproaches to uncover myriad new pathways thatinfluence the timing of cell cycle commitment, an eventcalled Start in yeast and the Restriction Point in mammaliancells (Jorgensen et al. 2002a). Because cell cyclecommitment in budding yeast requires that cells achievea minimum critical cell size in late G 1 phase to pass Start,growth and division are coupled at this point (Johnston etal. 1977). The coupling between growth and division ispoorly understood in metazoan species, but there is nowa general sentiment that oncogenic factors such as cyclinD, c-Myc, and the AKT/TOR signaling network primarilydictate cell growth, which in turn drives proliferation(Saucedo and Edgar 2002; Ruggero and Pandolfi 2003).In yeast, mutations that perturb the timing of Start havelittle or no growth defect, but instead affect cell size (Rupes2002). That is, a delay at Start increases cell size, andacceleration of Start reduces cell size. Because there is noeasily selectable growth phenotype for cell size mutants,and because such mutants arise spontaneously with veryhigh frequency, we and other investigators have foundthat this problem is largely refractory to conventional genetics.Thus, only a handful of genes that regulate Starthave been identified over the past two decades. Start iscurrently viewed as a largely transcriptional event, limitedby the activity of two key transcription factor com-