1. Course Evaluation Form About The Course -Go more slowly (||) -More lectures (||) -Problem Sets, Class Projects (|||) -Software tools About The Instructor -Accessible out of class (Office Hours, Thursdays 2pm-5pm) -Course Discussion

2. Networks in Biology

3. Todays Lecture - The Cell as a Complex System -Types of Molecular Networks -Some Results on the Structure of Molecular Networks (Hierarchical Structure, Date and Party Hubs) - Disease Networks - Impacts of Social Networks in Biology

4. http://multimedia.mcb.harvard.edu/media.html Inner Life of the Cell

5. protein-gene interactions protein-protein interactions PROTEOME GENOME Citrate Cycle METABOLISM Bio-chemical reactions Bio-Map

6. Citrate Cycle METABOLISM Bio-chemical reactions

7. Boehring-Mennheim

8. Metabolic Network Nodes : chemicals (substrates) Links : bio-chemical reactions Metab-movie

9. Metabolic network Organisms from all three domains of life are scale-free networks! H. Jeong, B. Tombor, R. Albert, Z.N. Oltvai, and A.L. Barabasi, Nature, 407 651 (2000) ArchaeaBacteriaEukaryotes Meta-P(k)

10. Modular vs. Scale-free Topology Scale-free (a) Modular (b)

11. Global network properties A.-L. B. and Z.N. Oltvai, Nat. Rev. Gen.(2004)

12. Hierarchical Networks 3. Clustering coefficient scales C(k)= # links between k neighbors k(k-1)/2

13. Scaling of the clustering coefficient C(k) The metabolism forms a hierachical network. Ravasz, Somera, Mongru, Oltvai, A-L. B, Science 297, 1551 (2002).

14. Characterizing the links Metabolism: Flux Balance Analysis (Palsson) Metabolic flux for each reaction 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).

15. Global flux organization in the E. coli metabolic network E. Almaas, B. Kovács, T. Vicsek, Z. N. Oltvai, A.-L. B. Nature, 2004.

17. protein-gene interactions protein-protein interactions PROTEOME GENOME Citrate Cycle METABOLISM Bio-chemical reactions Bio-Map

18. protein-protein interactions PROTEOME

19. Topology of the protein network H. Jeong, S.P. Mason, A.-L. Barabasi, Z.N. Oltvai, Nature 411, 41-42 (2001) Prot P(k) Nodes : proteins Links : physical interactions (binding)

20. Origin of the scale-free topology: Gene Duplication Perfect copy Mistake: gene duplication Wagner (2001); Vazquez et al. 2003; Sole et al. 2001; Rzhetsky & Gomez (2001); Qian et al. (2001); Bhan et al. (2002). Proteins with more interactions are more likely to get a new link: Π(k)~k (preferential attachment).

21. Yeast protein network - lethality and topological position - Highly connected proteins are more essential (lethal)... Prot- robustness H. Jeong, S.P. Mason, A.-L. Barabasi, Z.N. Oltvai, Nature 411, 41-42 (2001)

22. Protein Network Dynamics

25. Disease Networks Genotypic Association Between Diseases

26. Gene network GENOME PHENOME DISEASOME Disease network

27. Disease Network Goh et al. PNAS 2007

28. Mental Diseases

29. p53 network (mammals) P53 P(k)

30. Lethal Genes Disease Genes Goh et al. PNAS 2007

31. Schematic functional organization Functional Core –Expressed in most tissues (housekeeping) –High degree –High coexpression –Lethal Functional Periphery –Tissue-specific expression –Low degree –Low coexpression –Low lethality Lack of disease genes Enrichment of disease genes

32. Phenotypic Association Between Diseases

34. Disease 1Disease 2 Affect Same Individuals Significantly more than Random

35. ~ 13039018 patients ~ 32341348 records (hospitalizations)

36. P2P2 N Building a Net C 12 P1P1

37. Word of Caution Perfectly correlated diseases, P 2 = C 12 1 2 1 2 ~1 ~N Underestimates overlap of Common Phenotypes Overestimate overlap of Rare Phenotypes

38. Sibling having multiple sclerosis 1 Sibling having rheumatoid arthritis 1 1 Harley JB. Nature Genetics 39(9) 1053 (2007) 2 Scott LJ et al, Science 316 1341 (2007) First Degree Relatives Having Diabetes 2

39. C 12 P1P1 P2P2 N Building a Net

40. Word of Caution Perfectly correlated diseases & P 1 = P 2 = C 12 Perfectly correlated diseases & P 1 >> P 2 = C 12 If N >> P 1, P 2 Example P 2 = 1/10,000 P1 =1/100 1 2 1 2

41. Positive Associations Diseases appear are more likely to be correlated than anti-correlated

42. Visualizing the Network

46. http://hudine.neu.edu