1. 1 Modular Co-evolution of metabolic networks Zhao Jing

2. 2 Background Background Results/Discussion Topological modules and their functions The similarity between the phylogenetic profiles of enzymes within modules Determining the evolutionary ages of modules Evolutionary rates of enzyme genes in modules Comparison the Humo sapien network with its random counterparts Conclusion Outline

3. 3 Background Life’s complex Pyramid Oltvai, Z.N., Barabási, A.-L., Life’s Complexity Pyramid, SCIENCE, 2002, 298:763-764.

4. 4 Functional modules: protein complexes, signalling/metabolic pathways and transcriptional clusters Evolutionary modules: cohesive evolutionary blocks in cellular systems Network topological modules Different aspects of modules:

5. 5 Functional modules => evolutionary modules Snel B, Huynen MA: Quantifying Modularity in the Evolution of Biomolecular Systems. Genome Res 2004 14:391-397. Work 1 1387 functional modules in total

6. 6 Phylogenic profiles

7. 7 Campillos M, von Mering C, Jensen LJ, Bork P: Identification and analysis of evolutionarily cohesive functional modules in protein networks. Genome Research 2006, 16:374-382. Evolutionary age Work 2

8. 8 Evolutionary rate CheChen Y, Dokholyan NV: The coordinated evolution of yeast proteins is constrained by functional modularity Trends in Genetics 2006, 22(8):416-419 Work 3

9. 9 Evolutionary modules => functional modules von Mering C, Zdobnov EM, Tsoka S, Ciccare FD, Pereira-Leal JB, Ouzounis CA, Bork P: Genome evolution reveals biochemical networks and functional modules. PNAS 2003, 100:15428-15433. Network: E.coli PPI network predicted by STRING ; each node is a COG Modules: topological modules got by network clustering Reference functional modules: 144 e.coli metabolic pathways from EcoCyc Result: 74% of the known metabolic enzymes clustering together in modules Work 1

10. 10 Yamada T, Kanehisa M, Goto S: Extraction of phylogenetic network modules from the metabolic network. BMC Bioinformatics 2006, 7(1):130. Yamada T, Goto S, Kanehisa M: Extraction of Phylogenetic Network Modules from Prokayrote Metabolic Pathways. Genome Informatics 2004, 15:249-258 Network: enzyme graph including all the organisms in KEGG Work 2

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12. 12 Topological modules = > functional modules Guimera R, Nunes Amaral LA: Functional cartography of complex metabolic networks. Nature 2005, 433(7028):895-900.

13. 13 Zhao J, Yu H, Luo J, Cao Z, Li Y: Hierarchical modularity of nested bow-ties in metabolic networks. BMC Bioinformatics 2006:7:386.

14. 14 Fraser H, Hirsh A, Steinmetz L, Scharfe C, Feldman M: Evolutionary Rate in the Protein Interaction Network. Science 2002, 296:750-752. Work 1 How network topology affect protein evolution?

15. 15 Work 2 Vitkup D, Kharchenko P, Wagner A: Influence of metabolic network structure and function on enzyme evolution. Genome Biology 2006, 7(5):R39.

16. 16 Work 3 Light S, Kraulis P, Elofsson A: Preferential attachment in the evolution of metabolic networks. BMC Bioinformatics 2005, 6:159. The average connectivity for enzymes in phylogenetic groups 1–5

17. 17 Work 4 Fraser H: Modularity and evolutionary constraint on proteins. Nature Genetics 2005, 37(4):351-352. Protein interaction hubs situated within modules are more evolutionarily constrained(have lower mean evolutionary rate)than those bridging different modules.

18. 18 My question: Topological modules => Evolutionary modules?

19. 19 Identifying topological modules and their functions Core-periphery organization of modules Table 1

20. 20 The similarity between the phylogenetic profiles of enzymes within modules

21. 21 Spearman’s rank correlation is r= -0.3814, P-value is 0.059

22. 22 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.

23. 23 The evolutionary ages of modules We classified enzymes in the Homo sapiens network into seven evolutionary ages: (1) Prokaryota; (2) Protists; (3) Fungi;( 4) Nematodes;(5) Arthropods;(6) Mammalian and (7) Human Table 2

24. 24 Evolutionary rates of enzyme genes in modules Spearman’s rank correlation is r= -0.4983, P-value= 0.011.

25. 25 Comparison the Humo sapien network with its random counterparts (1) topological null model Z-score=19

26. 26 (2) biological null model

27. 27

28. 28 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.

29. 29 Thanks!