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
Mar 26, 2015
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
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