1 Topology, Functionality and Evolution of Metabolic Networks Jing Zhao Shanghai Center for Bioinformation and Technology 28, September, 2007

2 I. Background II. Modular Co-evolution of metabolic networks III. Hierarchical modularity of nested bow-ties in metabolic networks Outline

3 Background Bow-tie pattern Hierarchical organization

4 Csete M, Doyle J: Bow ties, metabolism and disease. Trends in Biotechnology 2004, 22: Biological viewpoint of metabolic system: bow-tie

5 E.coli metabolic network Topological viewpoint of metabolic networks: bow tie

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

7 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): 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: Topological viewpoint of metabolic networks: bow tie Robust yet frangile

8 Background Bow-tie pattern Hierarchical organization

9 Life’s complex Pyramid Oltvai, Z.N., Barabási, A.-L., Life’s Complexity Pyramid, SCIENCE, 2002, 298: Biological viewpoint of biological systems: hierarchical organization

10 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:

11 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: Protocols: the “rules” by which modules interact.

12 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.

13 Core-periphery organization of modules Table 1 Topological modules and their functions Homo Sapiens metabolic network

14 Phylogenetic profiles of enzymes within modules

15 Spearman’s rank correlation is r= , P-value is Phylogenetic profiles of enzymes within modules

16 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 (2) The fraction of enzyme pairs with JC>0.66 in the module is significantly bigger than We set the cutoff to 0.1. (3) The P-value is smaller than 0.05.

17 Totally 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

18 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.

19 Table 2 Evolutionary ages of modules

20 Spearman’s rank correlation is r= , P-value= Evolutionary rates of enzyme genes in modules

21 (1) topological null model Z-score=19 Comparison the metabolic network with its random counterparts

22 (2) biological null model Comparison the metabolic network with its random counterparts

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24 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.

25 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.

26 Topological feature: bow-tie modules Decomposition of the E.coli metabolic network

27 The connections among the GSC parts of the twelve bow-tie like modules. Topological feature: hierarchically nested bow-tie organization

28 Topological feature: Compared with randomized counterparts Comparison of the Core of E.coli network with that of a randomized network.

29 Hierarchical modularity of nested bow-ties in metabolic networks Topological features Relationship between topology and functionality Discussion

30 Cartographic representation of the metabolic network for E.coli.. Topology vs. functionality: functional clustering of bow-tie modules

31 Case 1: most modules are dominated by one major category of metabolisms Topology vs. functionality: Are bow-tie modules also functional modules?

32 Topology vs. functionality: Are bow-tie modules also functional modules? Case 2 : Some modules are mixtures of pieces of several conventional biochemical pathways.

33 Topology vs. functionality: Are bow-tie modules also functional modules? Case 3 : A standard textbook pathway can break into several modules.

34 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

35 Hierarchical modularity of nested bow-ties in metabolic networks Topological features Relationship between topology and functionality Discussion

36 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

37 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:

38 Thanks!