Title: Introduction to
1Eivind Almaas Microbial Systems Division
Introduction to Biological Networks
2Biological network examples
- Gene-regulation
- Protein interaction
- Metabolism
- Cell signaling
- Cytoskeleton
-
- Neural network
- Lymphatic node system
- Circulatory system
3Cellular networks
GENOME
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7Protein interactions Yeast two-hybrid method
8P. Uetz et. al. Nature 403, 601 (2000) H. Jeong
et. al. Nature 411, 41 (2001)
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10PINs are scale-free
- Protein interaction networks are scale-free.
- is this because of preferential attachment?
- another mechanism?
- how can we determine the cause?
11Comparison of proteins through evolution
Use Protein-Protein BLAST (Basic Local Alignment
Search Tool) -check each yeast protein against
whole organism dataset -identify significant
matches (if any)
12Preferential Attachment!
For given ?t ?k ? ?(k)
k vs. ?k linear increase in the of links
13SF topology from duplication diversification
Wagner (2001) Vazquez et al. 2003 Sole et al.
2001 Rzhetsky Gomez (2001) Qian et al.
(2001) Bhan et al. (2002).
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15Network motifs
- Definition A motif is a recurrent network
module - Examples
- Can think of networks as constructed by
combining these - basic building blocks
- Do these motifs have special properties?
16PIN motifs and evolution
Protein BLAST against A. thaliana C.
elegans D. melanogaster M. musculus H.
sapiens
S. Wuchty, Z.N. Oltvai, A.-L.Barabasi, 2003.
17Network peeling
- Core decomposition method
- the k-core consists of all nodes with degree gt
k. - recursively remove nodes with degree lt k.
S. Wuchty and E. Almaas, Proteomics 5, 444
(2005).
18Local vs. global centrality
S. Wuchty and E. Almaas, Proteomics 5, 444
(2005).
19Properties of globally central proteins
S. Wuchty and E. Almaas, Proteomics 5, 444
(2005).
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22Metabolic Networks
Nodes chemicals (substrates) Links chem.
reaction
H. Jeong, B. Tombor, R. Albert, Z.N. Oltvai, and
A.L. Barabasi, Nature 407, 651 (2000).
23Scaling of clustering coefficient C(k)
The metabolism forms a hierarchical network!
(why?)
Ravasz, et al, Science 297, 1551 (2002).
24Hierarchical Networks
Remember definition of clustering In
hierarchical networks, hubs act as connectors
between modules! Why could this be beneficial?
Ravasz, et al, Science 297, 1551 (2002).
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26How can we simulate metabolic function?
Constraints Optimization for growth
J.S. Edwards B.O. Palsson, Proc. Natl. Acad.
Sci. USA 97, 5528 (2000) R.U. Ibarra, J.S.
Edwards B.O. Palsson, Nature 420, 186 (2002) D.
Segre, D. Vitkup G.M. Church, Proc. Natl. Acad.
Sci. USA 99, 15112 (2002)
27Simple example
Reaction network
1 2 6
3 4 5 7
- We need
- List of metabolic reactions
- Reaction stoichiometry
- Assume mass balance
- Assume steady state
Edwards, J. S. Palsson, B. O, PNAS 97, 5528
(2000). Edwards, J. S., Ibarra, R. U. Palsson,
B. O. Nat Biotechnol 19, 125 (2001). Ibarra, R.
U., Edwards, J. S. Palsson, B. O. Nature 420,
186 (2002).
28Optimal fluxes in E. coli
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30A. Barrat, M. Barthélemy, R. Pastor-Satorras, and
A. Vespignani, PNAS 101, 3747 (2004) P.J.
Macdonald, E. Almaas and A.-L. Barabasi, Europhys
Lett 72, 308 (2005)
31Single metabolite use patterns
Evaluate single metabolite use pattern by
calculating
Two possible scenarios (a) All fluxes approx
equal (b) One flux dominates
32Functional plasticity of metabolism
33Functional plasticity of metabolism
- There exists a group of reactions NOT subject to
structural - plasticity the metabolic core
- These reactions must play a key role in
maintaining the metabolisms - overall functional integrity
34Essential metabolic core
- The core is highly essential 75 lethal (only
20 in non-core) for E. coli. -
84 lethal (16 non-core) for S. cerevisiae. - The core is highly evolutionary conserved
- 72 of core enzymes (48 of
non-core) for E. coli.
E. Almaas, Z. N. Oltvai, A.-L. Barabási, PLoS
Comput. Biol. 1(7)e68 (2005)
35Metabolic core flux variations synchronized
E. Almaas, Z. N. Oltvai, A.-L. Barabási, PLoS
Comput. Biol. 1(7)e68 (2005)
36Summary
- Cellular networks are predominantly scale-free
- Network structure constrains dynamics
- Protein interaction network from preferential
attachment - Networks motifs and k-core decomposition
- Metabolic fluxes are scale-free
- Metabolic fluxes correlate with the network
topology - Fluxes predominantly flow along metabolic
super-highways - Synchronized essential metabolic core