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title title. Robustness, clustering & evolutionary conservation. Stefan Wuchty Center of Network Research Department of Physics University of Notre Dame. New York Times. Complex systems. Made of many non-identical elements connected by diverse interactions. NETWORK. Bio-Map. GENOME.

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Title title


Robustness, clustering &evolutionary conservation

Stefan Wuchty

Center of Network Research

Department of Physics

University of Notre Dame

New york times

New York Times

Complex systems

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


Bio map



protein-gene interactions




Bio-chemical reactions

Citrate Cycle

Bio map1




Prot interaction map

Prot Interaction map

Yeast protein network

Nodes: proteins

Links: physical interactions (binding)

P. Uetz, et al. Nature, 2000; Ito et al., PNAS, 2001; …

Prot p k

Prot P(k)

Topology of the protein network

H. Jeong, S.P. Mason, A.-L. Barabasi & Z.N. Oltvai, Nature, 2001




node failure





Fraction of removed nodes, f


Complex systems maintain their basic functions even under errors and failures (cell  mutations; Internet  router breakdowns)

Robust sf



Topological error tolerance

  3 : fc=1

(R. Cohen et. al., PRL, 2000)



Robustness of scale-free networks


R. Albert et.al.

Nature, 2000





Prot robustness

Prot- robustness

Yeast protein network

- lethality and topological position -

Highly connected proteins are more essential (lethal)...

H. Jeong et al., Nature, 2001

Title title

Metabolic networks

Protein networks

Modules in biological systems

E. Ravasz et al.,Science, 2002

Can we identify the modules

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

Title title

Metabolism: E. Ravasz et al.,Science, 2002

Protein interactions: Rives and Galitski, PNAS, 2003

Spirin and Mirny, PNAS, 2003

Open questions

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




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

From theparticularto theuniversal

A.-L- Barabasi & Z. Oltvai, Science, 2002

Topology and evolution

Topology and Evolution

Topology and evolution1

Topology and Evolution

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

Title title

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

Clustering in protein interaction networks

high clustering = high quality of interaction

Goldberg and Roth, PNAS, 2003

Does that also hold for evolutionary conservation

Does that also hold for evolutionary conservation?

Title title

Protein-protein interaction data

are highly flawed:

90% false positives, 50% false negatives

Von Mering et al., Nature, 2002

How stable are these results?

Something else

Something else?

Eisen et al., PNAS, 1998

Open question

Open question



Wuchty et al., submitted, 2004

Plasmodium falciparum

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., PloS, 2003, LeRoch et al., Science, 2003)

  • 868 orthologs with Yeast (InParanoid, Remm et al. J. Mol. Biol., 2001)

Title title

Plasmodium falciparum

Title title

Plasmodium falciparum

Inferred protein interaction network in p falciparum

  • Iteratively pruning edges starting with the least weighted link

  • Quality of clusters is assessed by their modularity

until a maximum is reached.

Inferred protein interaction networkin P. falciparum

  • 667 nodes, 3,564 weighted interactions

  • Clustering

Title title

All edges shown with Cvw > 1.

Colorcode red: Cvw > 4, yellow: Cvw > 3,

green: Cvw > 2, blue: Cvw > 1

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Co-expression patterns

Bozdech et al. PLoS, 2003

What does that mean?

Validation of results?

Title title


RNA processing


DNA processing



Wuchty, Barabasi, Ferdig and Adams, in preperation

What s next

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.

T h x

T H X !

http:[email protected]

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