Robustness clustering evolutionary conservation Stefan Wuchty Center of

Robustness, clustering & evolutionary conservation Stefan Wuchty Center of Network Research Department of Physics University of Notre Dame

Complex systems Made of many non-identical elements connected by diverse interactions. NETWORK

GENOME proteingene interactions PROTEOME protein interactions METABOLISM Citrate Cycle Biochemical reactions

PROTEOME protein interactions

Yeast protein network Nodes: proteins Links: physical interactions (binding) P. Uetz, et al. Nature, 2000; Ito et al. , PNAS, 2001; …

Topology of the protein network H. Jeong, S. P. Mason, A. -L. Barabasi & Z. N. Oltvai, Nature, 2001

Robustness Complex systems maintain their basic functions even under errors and failures (cell mutations; Internet router breakdowns) 1 S fc 0 1 Fraction of removed nodes, f node failure

Robustness of scale-free networks Failures Topological error tolerance 1 R. Albert et. al. Nature, 2000 S 0 Attacks 3 : fc=1 (R. Cohen et. al. , PRL, 2000) fc f 1

Yeast protein network - lethality and topological position - Highly connected proteins are more essential (lethal). . . H. Jeong et al. , Nature, 2001

Modules in biological systems Metabolic networks E. Ravasz et al. , Science, 2002 Protein networks

Can we identify the modules? J(i, j): # of nodes both i and j link to; +1 if there is a direct (i, j) link

Metabolism: E. Ravasz et al. , Science, 2002 Protein interactions: Rives and Galitski, PNAS, 2003 Spirin and Mirny, PNAS, 2003

Open questions Does the application of standart clustering algorithms reflect real modules well? Since e. g. one protein can be part of more than one protein complex overlapping clustering algorithms should give better results.

Motifs Small subnetworks that appear in real world networks significantly more often than in random graphs. (Milo et al. , Science, 2002; Conant and Wagner, Nature Gen. , 2003, Shen-Orr et al. , Nature Gen. , 2002, Milo et al, Science, 2004)

From the particular to the universal A. -L- Barabasi & Z. Oltvai, Science, 2002

Topology and Evolution

Topology and Evolution S. Wuchty, Z. Oltvai & A. -L. Barabasi, Nature Genetics, 2003

Topology and evolution - General distribution of orthologs: E = N(o)/N(p) - degree-dependent distribution of orthologs ek = Nk(o)/Nk Orthologous Excess Retention: ERk = ek/E S. Wuchty, Genome Res. , 2004

Clustering in protein interaction networks high clustering = high quality of interaction Goldberg and Roth, PNAS, 2003

Does that also hold for evolutionary conservation?

Protein-protein interaction data are highly flawed: 0% false positives, 50% false negative Von Mering et al. , Nature, 2002 How stable are these results?

Something else? Eisen et al. , PNAS, 1998

Open question ? ? Wuchty et al. , submitted, 2004

Plasmodium falciparum • • Eukaryotic organism Malaria parasite Genome size 23 MB, 14 chromosomes 5300 genes (estimated, Hall et al. , Nature 2002, Gardner et al. , Nature, 2002) • No protein interaction data available • Co-expression data available (Bozdech et al. , Plo. S, 2003, Le. Roch et al. , Science, 2003) • 868 orthologs with Yeast (In. Paranoid, Remm et al. J. Mol. Biol. , 2001)

Plasmodium falciparum

Plasmodium falciparum

Inferred protein interaction network in P. falciparum • 667 nodes, 3, 564 weighted interactions • Clustering - Iteratively pruning edges starting with the least weighted link - Quality of clusters is assessed by their modularity until a maximum is reached.

All edges shown with Cvw > 1. Colorcode red: Cvw > 4, yellow: Cvw > 3, green: Cvw > 2, blue: Cvw > 1

What does that mean? Validation of results? Co-expression patterns Bozdech et al. PLo. S, 2003

re pli cat ion ex o/ pr ot es o me tr DNA processing an sla R tio NA n pr oc rib es os sin os g o me Wuchty, Barabasi, Ferdig and Adams, in preperation

What‘s next? • Uncovering evolutionary cores of interactions in other organisms. • Application of a Maximum Set Cover Algorithm to predict protein interactions (Huang, Kaanan, Wuchty, Izaguirre and Cheng, submitted) to unfold the interactome using the evolutionary cores and experimentally derived interactions.

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