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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
titletitle

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.

NETWORK

bio map
Bio-Map

GENOME

protein-gene interactions

PROTEOME

protein-proteininteractions

METABOLISM

Bio-chemical reactions

Citrate Cycle

bio map1
Bio-Map

PROTEOME

protein-proteininteractions

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

robustness
Robustness

1

node failure

S

fc

0

1

Fraction of removed nodes, f

Robustness

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

robust sf
Robust-SF

Failures

Topological error tolerance

  3 : fc=1

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

fc

Attacks

Robustness of scale-free networks

1

R. Albert et.al.

Nature, 2000

S

0

f

1

prot robustness
Prot- robustness

Yeast protein network

- lethality and topological position -

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

H. Jeong et al., Nature, 2001

slide10

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

slide12

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

results.

motifs
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
From theparticularto theuniversal

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

topology and evolution1
Topology and Evolution

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

slide18

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

slide22

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)
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
slide29

All edges shown with Cvw > 1.

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

green: Cvw > 2, blue: Cvw > 1

slide30

Co-expression patterns

Bozdech et al. PLoS, 2003

What does that mean?

Validation of results?

slide31

ribososome

RNA processing

translation

DNA processing

exo/protesome

replication

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://www.nd.edu/[email protected]

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