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Networks in Biology

Today’s 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

http://multimedia.mcb.harvard.edu/media.html

Inner Life of the Cell

protein-gene interactions

protein-protein interactions

PROTEOME

GENOME

Citrate Cycle

METABOLISM

Bio-chemical reactions

Citrate Cycle

METABOLISM

Bio-chemical reactions

Metabolic NetworkNodes: chemicals (substrates)

Links: bio-chemical reactions

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)

Archaea Bacteria Eukaryotes

Modular vs. Scale-free Topology

Scale-free

(a)

Modular

(b)

Global network properties

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

Hierarchical Networks3. Clustering coefficient scales

C(k)= # links between k neighborsk(k-1)/2

Scaling of the clustering coefficient C(k)

The metabolism forms a hierachical network.

Ravasz, Somera, Mongru, Oltvai, A-L. B, Science 297, 1551 (2002).

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).

Global flux organization in the E. coli metabolic network

E. Almaas, B. Kovács, T. Vicsek, Z. N. Oltvai, A.-L. B. Nature, 2004.

protein-gene interactions

protein-protein interactions

PROTEOME

GENOME

Citrate Cycle

METABOLISM

Bio-chemical reactions

protein-protein interactions

PROTEOME

Topology of the protein network

)exp()(~)( 00

k

kkkkkP

H. Jeong, S.P. Mason, A.-L. Barabasi, Z.N. Oltvai, Nature 411, 41-42 (2001)

Nodes: proteins

Links: physical interactions (binding)

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).

Yeast protein network- lethality and topological position -

Highly connected proteins are more essential (lethal)...

H. Jeong, S.P. Mason, A.-L. Barabasi, Z.N. Oltvai, Nature 411, 41-42 (2001)

Protein Network Dynamics

Disease Networks

Genotypic Association Between Diseases

Gene network

GENOME

PHENOMEDISEASOME

Disease network

Disease NetworkGoh et al. PNAS 2007

Mental Diseases

p53 network (mammals)

Lethal Genes Disease Genes

Goh et al. PNAS 2007

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

Phenotypic Association Between Diseases

Disease 1 Disease 2Affect Same Individuals

Significantly more than Random

~ 13’039’018 patients

~ 32’341’348 records (hospitalizations)

P2

N

jiijij PPNCR /

Building a Net

C12

P1

Word of Caution

PNPPNCR jiijij //

Perfectly correlated diseases, P2 = C12

~1

~N

Underestimates overlapof Common Phenotypes

Overestimate overlapof Rare Phenotypes

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 Diabetes2

C12

P1 P2

N

))(( jiji

jiijij

PNPNPP

PPNC

Building a Net

Word of Caution

1)(

)(

))((

PNP

PNP

PNPNPP

PPNC

jiji

jiijij

Perfectly correlated diseases & P1 = P2 = C12

)(

)(

))(( 21

12

PNP

PNP

PNPNPP

PPNC

jiji

jiijij

Perfectly correlated diseases & P1 >> P2 = C12

If N >> P1, P2

1

2

P

Pij

Example P2 = 1/10,000 P1 =1/100

1.0ij

-0.1 0 0.1 0.2 0.3 0.4 0.50

1

2

3

4

5

6

7

ij

log 1

0 Num

ber

of P

airs

66.8%-0.1 0 0.1 0.2 0.3 0.4 0.5

0

1

2

3

4

5

6

7

ij

log 1

0 Num

ber

of P

airs

66.8%

Positive Associations

Diseases appear are more likely to be correlated than anti-correlated

Visualizing the Network

http://hudine.neu.edu