genome biology and biotechnology the next frontier: systems biology prof. m. zabeau department of...
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Genome Biology and BiotechnologyThe next frontier: Systems biologyProf. M. ZabeauDepartment of Plant Systems Biology Flanders Interuniversity Institute for Biotechnology (VIB)University of Gent International course 2005
From genes to networksgenepathwaynetworkMolecular Biology60s to mid 80sMolecular Geneticssince mid 80sSystems Biologysince mid 90s
The large-scale organisation of metabolic networksStudy of the design principles underlying the structure of biological systemsDissection of integrated pathway-genome databases providing complex connectivity mapsJeong et al (2000) Nature 407: 651
Case studyAnalyses of core cellular metabolisms as described in the `Intermediate metabolism and bioenergetics' portions of the WIT databasePrediction of metabolic pathways in organisms on the basis of its annotated genome (presence of presumed open reading frame for enzymes that catalyse a given metabolic reaction)in combination with firmly established data from the biochemical literature.6 archaea, 32 bacteria and 5 eukaryotesReprinted from: Jeong et al (2000) Nature 407: 651
Graph theoretic representationReprinted from: Jeong et al (2000) Nature 407: 651Nodes are substratesLinks are metabolic reactions (with EC enzyme numbers)
Theoretical Network ArchitecturesReprinted from: Jeong et al (2000) Nature 407: 651Probability thata node has k linksrandomuniformscale-freeheterogeneousThe World Wide Web and social networks have a scale-free structure
Connectivity distributionReprinted from: Jeong et al (2000) Nature 407: 651Metabolic networks are scale-free as shown by the distribution of incoming and outgoing links for each substrate.
This is a general rule applying to all organisms studied.Archaeglobus fulgidusE. coliC. elegansAll 43
Network diameterReprinted from: Jeong et al (2000) Nature 407: 651Definition: the shortest pathwayaveraged over all pairs of substratesBiochemical pathway length in E. coliAverage path length (43)ArchaeBacteriaEukaryaincoming linksoutgoing linksUnexpectedly, network diameter does not increase with complexity. Therefore interconnectivity grows with the addition of substrates.
Hub propertiesReprinted from: Jeong et al (2000) Nature 407: 651A few hubs dominate the overall connectivityThe sequential (mutations) removal of the most connected hubs dramatically increases the network diameter until disintegrationthe metabolic networks seem highly robust in computer simulations (cf. lethal mutation rate observed in vivo)
ConclusionsThe structure of biological networks are far from randomTheir contemporary topology reflects a long evolutionary processThey show a robust response towards internal defectsContrary to other scale-free networks, metabolic ones do not grow in diameter with increasing complexitywhich may be represent an additional (necessary?) survival and growth advantage Reprinted from: Jeong et al (2000) Nature 407: 651
Extension of the conceptProtein-protein interaction networks are also scale-free yeast Y2H dataThe probability for a gene to be essential increases with the connectedness of the encoded protein93% of proteins have 5 links or less21% of their genes are essential7% of have more than 15 links62 % of their genes are essentialJeong et al (2001) Nature 411: 41
Reprinted from: Jeong et al (2001) Nature 411: 41
A long way to goList of biological componentscells, genes, proteins, metabolitesDescription of local relationshipsexpression clusterprotein-protein interactionmolecule traffickingcell-cell crosstalkWhole system architectureDynamic regulatory mechanismsSystem behaviour predictionSystem manipulation, de novo designneedmoredata!
Recommended readingLarge-scale organisation of biological networksJeong et al (2000) Nature 407: 651Oltvai and Barabasi (2002) Science 298: 763 Modelling at different levelsIdeker and Lauffenburger (2003) TIB 21, 255Synthetic biologyElowitz and Leibner (2000) Nature 403: 335
Further readingLarge-scale organisation of biological networksJeong et al (2001) Nature 411: 41Han et al (2004) Nature 430: 88 Oltvai and Barabasi (2002) Science 298: 763Modelling at different levelsMaere et al (2005) Bioinformatics 21: 3448Vercruysse and Kuiper (2005) Bioinformatics 21: 269Synthetic biologyGuet et al. (2002) Science 296: 1466
Genoom BiologieAcademiejaar 2004 - 2005Genoom BiologieSystem can be organism, can also be defined as specific mechanisms such as cell cycle or root developmentAcademiejaar 2004 - 2005