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Topology, Functionality and Evolution of Metabolic Networks

Jing Zhao

Jzhao@scbit.org

Shanghai Center for Bioinformation and Technology

28, September, 2007

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I. Background

II. Modular Co-evolution of metabolic networks

III. Hierarchical modularity of nested bow-ties in metabolic networks

Outline

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Background

• Bow-tie pattern

• Hierarchical organization

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Csete M, Doyle J: Bow ties, metabolism and disease. Trends in Biotechnology 2004, 22:446-450.

Biological viewpoint of metabolic system: bow-tie

5E.coli metabolic network

Topological viewpoint of metabolic networks: bow tie

6Ma H-W, Zeng A-P: The connectivity structure, giant strong component and centrality of metabolic networks. Bioinformatics 2003, 19:1423-1430.

Topological viewpoint of metabolic networks: bow tie

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Bow-tie structure in the coarse-grained graph of the E.coli metabolic network

Zhao J, Yu H, Luo J, Cao Z, Li Y: Complex networks theory for analyzing metabolic networks. Chinese Science Bulletin 2006, 51(13):1529-1537.

Zhao J, Tao L, Yu H, Luo J-H, Cao ZW, Li Y: Bow-tie topological features of metabolic networks and the functional significance. Chinese Science Bulletin 2007, 52:1036 - 1045.

Topological viewpoint of metabolic networks: bow tie

Robust yet frangile

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Background

• Bow-tie pattern

• Hierarchical organization

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Life’s complex Pyramid

Oltvai, Z.N., Barabási, A.-L., Life’s Complexity Pyramid, SCIENCE, 2002, 298:763-764.

Biological viewpoint of biological systems: hierarchical organization

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Topological viewpoint of metabolic networks: hierarchical modularity

Ravasz E, Somera A L, Mongru D A, Oltvai Z N, Barabasi A L, Hierarchical organization of modularity in metabolic networks, Science,2002,297: 1551-1556

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Functional modules: protein complexes, signalling/metabolic pathways and transcriptional clusters

Network topological modules

Different viewpoint of modules

Har Hartwell LH, Hopfield JJ, Leibler S, Murray AW: From molecular to modular cell biology. Nature 1999, 402:C47-C52.

Newman MEJ, Girvan M: Finding and evaluating community structure in networks. Physical Review E 2004, 69:026113.

Protocols: the “rules” by which modules interact.

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Modular Co-evolution of metabolic networks

• Topological modules and their functions

• Phylogenetic profiles of enzymes within modules

• Evolutionary ages of modules

• Evolutionary rates of enzyme genes in modules

• Comparison the metabolic network with its random counterparts

• Conclusion

Zhao J, Ding G-H, Tao L, Yu H, Yu Z-H, Luo J-H, Cao Z-W, Li Y-X: Modular co-evolution of metabolic networks. BMC Bioinformatics 2007, 8:311.

13Core-periphery organization of modules Table 1

•Topological modules and their functions

Homo Sapiens metabolic network

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Phylogenetic profiles of enzymes within modules

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Spearman’s rank correlation is r= -0.3814,

P-value is 0.059

Phylogenetic profiles of enzymes within modules

05.0)66.0(

28.0

JCP

JC

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A module is regarded as an evolutionary module, if it satisfies all of the following three criteria:

(1)    Average JC of the module is bigger than 0.28.

(2)    The fraction of enzyme pairs with JC>0.66 in the module is significantly bigger than 0.05. We set the cutoff to 0.1.

(3)    The P-value is smaller than 0.05.

17Totally 12 of the 25 modules (module 7,3,25,9,16,4,6,22,12,15,19,21) were found to be evolutionary modules, most of which are periphery modules.

Phylogenetic profiles of enzymes within modules

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Evolutionary ages of enzymes:

(1) Prokaryota; (2) Protists; (3) Fungi;( 4) Nematodes;(5) Arthropods;(6)

Mammalian and (7) Human

Evolutionary ages of modules

Evolutionary age of a module:

The biggest value of the evolutionary age of enzymes included in this module, which satisfies all of the two criteria:(1)    More than 1/3 enzymes of this module belong to the evolutionary age;(2)    The corresponding P-value is smaller than 0.05.

 

19Table 2

Evolutionary ages of modules

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Spearman’s rank correlation is r= -0.4983, P-value= 0.011.

Evolutionary rates of enzyme genes in modules

s

a

K

Kr

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(1) topological null model

Z-score=19

•Comparison the metabolic network with its random counterparts

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(2) biological null model

•Comparison the metabolic network with its random counterparts

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Conclusions

From Topology: metabolic networks exhibit highly modular core-periphery organization pattern.

From Function: The core modules perform housekeeping functions, the periphery modules accomplish relatively specific functions.

From Evolution: The core modules are more evolutionarily conserved, the periphery modules appear later in evolution history.

=>

The core-periphery modularity organization reflects the functional and evolutionary requirement of metabolic system.

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Hierarchical modularity of nested bow-ties in metabolic networks

• Topological features

• Relationship between topology and functionality

• Discussion

Zhao J, Yu H, Luo J, Cao Z, Li Y: Hierarchical modularity of nested bow-ties in metabolic networks. BMC Bioinformatics 2006:7:386.

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Topological feature: bow-tie modules

Decomposition of the E.coli metabolic network

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The connections among the GSC parts of the twelve bow-tie like modules.

Topological feature: hierarchically nested bow-tie organization

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Topological feature: Compared with randomized counterparts

Comparison of the Core of E.coli network with that of a randomized network.

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Hierarchical modularity of nested bow-ties in metabolic networks

• Topological features

• Relationship between topology and functionality

• Discussion

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Cartographic representation of the metabolic network for E.coli..

Topology vs. functionality: functional clustering of bow-tie modules

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Case 1: most modules are dominated by one major category of metabolisms

Topology vs. functionality: Are bow-tie modules also functional modules?

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Topology vs. functionality: Are bow-tie modules also functional modules?

Case 2 : Some modules are mixtures of pieces of

several conventional biochemical pathways.

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Topology vs. functionality: Are bow-tie modules also functional modules?

Case 3 : A standard textbook pathway can break into several modules.

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Topology vs. functionality: e Bow-tie topology of functional modules

1. Chemical modules: 75 organisms

carbohydrate metabolism: bow-tie

lipid metabolism: not bow-tie

amino acid metabolism: not bow-tie

2. Spatial modules: yeast

cytosol: bow-tie

mitochondrion: bow-tie

peroxisome: not bow-tie

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Hierarchical modularity of nested bow-ties in metabolic networks

• Topological features

• Relationship between topology and functionality

• Discussion

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Significance of nested bow-tie organization

• Bow-tie modules may act as another kind of building block of metabolic networks

• Nested bow-tie organization contributes to system robustness

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Guo-Hui Ding: Chinese Academy of Sciences

Lin Tao: SCBIT

Hong Yu: SCBIT

Zhong-Hao Yu: Shanghai Jiao Tong University

Jian-Hua Luo: Shanghai Jiao Tong University

Zhi-Wei Cao: SCBIT

Yi-Xue Li: SCBIT

Acknowledgement:

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Thanks!