NETWORKS

Systems Biology. What Is It?

 A branch of science that seeks to integrate

different levels of information to understand
how biological systems function.

 L. Hood: “Systems biology defines and analyses

the interrelationships of all of the elements in a
functioning system in order to understand how the
system works.”

 It is not the number and properties of system

elements but their relations!!
 More on Systems Biology
Essence of living systems is flow of mass,
energy, and information in space and time.

The flow occurs along specific networks

 Flow of mass and energy (metabolic networks)

 Flow of information involving DNA (transcriptional

regulation networks)

 Flow of information not involving DNA (signaling networks)

The Goal of Systems Biology:

To understand the flow of mass, energy,
and information in living systems.
Networks and the Core Concepts
of Systems Biology
(i) Complexity emerges at all levels of the
hierarchy of life

(ii) System properties emerge from interactions

of components
(iii) The whole is more than the sum of the parts.

(iv) Applied mathematics provides approaches to

modeling biological systems.
How to Describe a System
As a Whole?

Networks - The Language

of Complex Systems
 What is a Network?
Network is a mathematical structure
composed of points connected by lines

Network Theory <-> Graph Theory

Network  Graph

Nodes  Vertices (points)

Links  Edges (Lines)

F. Harary, Graph Theory, Addison Wesley, Reading, MA, 1969

Gross & Yellen, Handbook of Graph Theory, CRC Press, Boca Raton, FL, 2004

A network can be build for any functional system

System vs. Parts = Networks vs. Nodes
 Networks As Graphs
 Networks can be undirected or directed, depending on whether
the interaction between two neighboring nodes proceeds in both
directions or in only one of them, respectively.

1 2 3 4 5 6

 The specificity of network nodes and links can be quantitatively

characterized by weights
2.5
7.3 3.3 12.7
5.4

8.1
2.5
Vertex-Weighted Edge-Weighted
 Networks As Graphs - 2
A network can be connected (presented by a single component) or
disconnected (presented by several disjoint components).

connected disconnected
Networks having no cycles are termed trees. The more cycles the
network has, the more complex it is.

trees

cyclic graphs
 Networks As Graphs - 3
Some Basic Types of Graphs

Paths

Stars

Cycles

Complete Graphs

Bipartite Graphs
Air Transportation Network
The World Wide Web
Fragment of a Social Network
(Melburn, 2004)
Biological Networks
A. Intra-Cellular Networks
Protein interaction networks
Metabolic Networks
Signaling Networks
Gene Regulatory Networks
Composite networks
Networks of Modules, Functional Networks
Disease networks
B. Inter-Cellular Networks
Neural Networks

C. Organ and Tissue Networks

D. Ecological Networks

E. Evolution Network
 GENOME

miRNA
_____________________ regulation?
-
- protein-gene
interactions
PROTEOME

protein-protein
interactions

METABOLISM

Bio-chemical
reactions
Citrate Cycle
The Protein Network of Drosophila
Metabolic Networks
 Apoptosis Pathway - 1
Apoptosis is a mechanism of controlled cell death
critically important in many biological processes

Cleavage of Caspase
CASP6 Substrates
DISC

CASP10

Heterodimer DFF

FAS-L FAS-R FADD CASP3

Membrane
Death protein DFF45 DFF40
CASP8
activator

Death-Inducing Signaling Complex

CASP7
Initiator
Caspases Start DNA
Executor Fragmentation
Caspases
Gene Regulation Networks
The Longevity Gene-Protein Network (LGPN)
C. elegans
Network of Interacting Pathways (NIP)

381 organisms
 Functional Networks
Yeast: 1400 proteins, 232 complexes, nine functional groups of complexes
Cell Cycle Cell Polarity & Structure
13 7 8 Number of protein complexes
111 25 40 61 Number of proteins
Transcription/DNA
77 15 19 Number of shared proteins
Maintenance/Chromatin 14 11
Structure 30 16 27 7 22 Intermediate
55 187 43
740 94 33 221 and Energy
73 Metabolism
83 37 103
65
Signaling 11
20 13 20 Membrane
125 53 147 Biogenesis &
Turnover
35
41 321 19 299 49
97 75
5
RNA 28 9 33 Protein Synthesis
24 260
Metabolism 692 6 419 and Turnover
172 12 75
160
Protein RNA / Transport
All Complex Dynamic Networks
Have Similar Structure and
Common Properties

 Hubs

 Scale-Freeness

 Small-Worldness

 Centrality
 Robustness/Fragility
How To Characterize
a Network?
 Quantifying Networks
A. Graph-Theoretical (Topological) Descriptors

A1. Connectivity-based:

A2. Distance-based

B. Information-Theoretic Descriptors
B1, Compositional

B2. Structural

C. Complexity Measures
C1. Subgraph Count
C2. Overall Connectivity
C3. Walk Count
C4. Small-World Connectivity
Connectivity-Based Topological
Descriptors
Adjacency Matrix

Adjacency relation, aij

1
aij = 1 (neighbors)
V=5
aij = 0 (otherwise) G
E=4
2 3 4 5
random node numbering
Adjacency Matrix

1 2 3 4 5 ai
1
1 0 0 1 0 0 1
2 0 0 1 0 0 1
A(G) = 3 1 1 0 1 0 3
4 0 0 1 0 1 2
1 3 2 1
node degrees
5 0 0 0 1 0 1

ai – node degree
 Connectivity Descriptors
Local (node) descriptors: vertex (node) degrees, ai

V
ai   aij   j  neighborsaij
j 1

Global (Network) descriptors: total adjacency, A

V V V
A(G)   ai   aij
i 1 i 1 j 1
 Connectivity Descriptors-2
Average and Normalized Descriptors

Average vertex (node) degree:

 ai  A(G) / V

Network connectedness (density)

A 2E A
Conn(G )   ; Conn (G )  2
V (V  1) V (V  1) V
Example
1 A = 1+1+3+2+1 = 8

<ai> = 8/5 = 1.6

1 3 2 1
Adjacency in Directed Graphs
Adjacency relation, aij
aij = -1 (incoming edge(arc))
aij = +1 (outgoing edge(arc))
aij = 0 (otherwise)

In-degree = -1 Out-degree = +1

1 2 3 4 5 ai(out)

2 3 4 5 1 0 0 1 0 0 +1
2 0 0 1 0 0 +1
A(DG) = 3 1 0 0 0 0 +1
-1,1 4 0 0 1 0 0 +1
5 0 0 0 1 0 +1
ai(in) -1 0 -3 -1 0

0,1 -3,1 -1,1 0,1

Distance-Based Topological
Descriptors
Distance Matrix
Distance relation: dij = 1 for i,j - neighbors

The distance between two non-neighboring nodes is equal to the

number of edges along the shortest path that connects them.

1 1 2 3 4 5 di 6 7
1 0 2 1 2 3 8
D(G) =
2 2 0 1 2 3 8 2 3
3 1 1 0 1 2 5 4
2 3 4 5 4 2 2 1 0 1 6
5 3 3 2 1 0 9
5

di – node distance d26 = ? d57 =?

(node distance degree)
 Distance Descriptors
Node descriptors:
V

node distance, di d i   d ij
j 1

Node eccentricity, eei ei = Max(dij)

Network descriptors:
V V V

Network distance, D(G) D(G)   d i   d ij

i 1 i 1 j 1

Network diameter, Diam(G)

Diam (G )  Max(d ij )

Network radius, Rad(G) Rad (G )  Min (ei )  Min ( Max (d ij ))

 Distance Descriptors-2
Average and Normalized Descriptors

Average node distance, <di>

 d i   D(G) / V
Average network distance, <d>
(average degree of separation, average path length)

 d   D / V (V  1)
Example
8 D = 8+8+5+6+9 = 36

<di> = 36/5 = 7.2

8 5 6 9
<d > = 36/5.4 = 1.8
 Distances in Directed
Networks
 In-distances and out-distances

0,3 D(in) = D(out) = 6

1
<d> = 6/(4x3) = 0.5 ???
2 -2,1
d21=? d13=?
3 4 0, 2 -4, 0

 Some distances in directed graphs are equal to infinity !!

How to calculate D and <d>?

 Distances in Directed
Networks - 2
 Network Node Accessibility Acc (G) = Nd(DG)/Nd

d 
 Adjusted Average Network Distance AD( DG ) 
Acc

Example: 9 9

8
7 1 0
6 8 12
G DG
9 9
D = 52, <d(G)> = 52/(6x5) = 1.73 D = 34, <d(DG)> = 34/20 = 1.70 < D(G)??

AC = 20/30 = 0.667 AD = 1.70/0.667 = 2.55 > D(G)

 Shannon’s Information Theory
What Is Information?
Wiener: Information is neither matter, nor energy.

How to Measure Information?

Forget about meaning!
Information is contained in any system, the elements of which can be
grouped according to one or more criteria.

The more diverse the distribution of system elements, the larger its
information content.

Information is a measure of system’s diversity

The more complex the system, the larger its information content.

Information is a measure of system complexity

 Shannon’s Information Theory
Basic Equations
Finite Probability Scheme:

System of N elements and k equivalence classes with equivalence criterion α:

class number of elements probability

1 N1 p1
2 N2 p2
………………………………………………………………...
k Nk I
pk

where pi = Ni / N, and Σ pi = 1.
k
Mean Information: I ( )   p i log 2 p i , bits/element
i 1

k
Total Information: I tot ( )  N log N   N i log N i , bits
i 1

Normalized Information: I tot ( )  N i log 2 N i

0  I norm ( )  1
I norm ( )   1  i 1
N log 2 N N log 2 N
 Network Information Descriptors
Information on the system elements equivalence, eI

Vertex degree equivalence distribution: 6{3, 1, 1, 1}

2
degrees 4
eI(deg) = -(3/6)2log(3/6) – 3x(1/6)log2(1/6) = 1.79 bits/node
3 eI
tot(deg) = 6log26 – 3log23 – 3x1log1 = 10.75 bits
2 1
eI
2 norm(deg) = 10.75/(6log26) = 0.693

9 Vertex distance equivalence distribution: 6{ 2, 2, 1, 1}

distances
8
eI(deg) = - 2x(2/6)log2(2/6) – 2x(1/6)log2(1/6) = 1.92 bits/node
6 8 12
9 eI
tot(dist) = 6log26 – 2x2log22 – 2x1log1 = 11.51 bits
eI (deg) = 11.51/(6log26) = 0.742

Composition distribution: 6{2,2,1,1}

Network Information Descriptors - 2
Information on the system elements weight (or magnitude) , mI
weighted information descriptors (indices)

Vertex degree distribution: 14 {4, 3, 3x2, 1}

2
degrees 4
mI(deg) = -(4/14)log2(4/14) –(3/14)log2(3/14) –
3x(2/14)log2(2/14) – (1/14)log2(1/14) = 2.47 bits/node
3
2 1
mI
A = 14 tot(deg) = 14log214 – 4log24 – 3log23 -3x2log22 -1log21 = 34.55 bits
2
mI
norm(deg) = 34.55/(14log214) = 0.648

Distance magnitude distribution: 52 {12, 2x9, 2x8, 6}

9
distances mI(deg) = -(12/52)log2(12/52) – 2x(9/52)log2(9/52) –
2x(8/52)log2(8/52) – (6/52)log2(6/52) = 2.55 bits/node
8
6 8 12 mI(dist) = 52log252–12log212–2x9log29–2x8log28-6log26 = 132.83 bits
9 D = 52
mI
norm(deg) = 132.83/(52log252) = 0.448
 Network Complexity Descriptors - 1
Subgraph Count, eSC
Overall Connectivity, eOC
1
Example V = 5, E = 4 e = number of edges
1 3 2 1

e=0 0SC =5 0OC =8

e=1 1SC =4 1OC = 16
1 3 1 3 3 2 2 1
1 1

e=2 2SC =4 2OC = 23

1 3 2 1 3 3 2 3 2 1
1 1
3SC =3 3OC = 21
e=3
1 3 2 1 3 2 1 1 3 2
1
4SC=1 4OC =8
e=4
1 3 2 1
SC = 17 (5, 4, 4, 3, 1)
OC = 76 ( 8, 16, 23, 21, 8)
Network Complexity Descriptors - 2
Walk Count, WC
2

Example
1 3 4 5

l = 1 l=2 l=2 WC = 106 ( 8, 16, 28, 54)

1 3 1 3 1 3 4

The three complexity measures, SC, OC, and WC,

can discriminate very subtle complexity features.

1 2
SC 28(5,8,9,5,1) 30(5,9,10,5,1)

OC(in) 111(12,28,41,25,5) 135(16,40,49,25,5)

WC 15(5,5,5) 21(5,7,9)

For networks use only complexity measures with e = 1, 2, and 3!!

Network Complexity Descriptors - 3
Small-World Connectivity

Network complexity increases with connectivity

Network complexity increases with the decrease in its radius

Can one unite the two patterns into a single complexity measure?

A V
ai V
B1  B2     bi
D i 1 d i i 1

bi is a measure for node centrality

Examples of Increasing Complexity: N = 5

6
3 4 5
SC = 11 17 20 26
OC = 32 76 100 160
WC = 58 106 140 150
B1 = 0.2 0.222 0.250 0.333
B2 = 1.105 1.294 1.571 1.6667

7 9
8 10
SC = 29 31 54 57
OC = 190 212 482 522
WC = 178 214 300 350
B1 = 0.313 0.313 0.429 0.400
B2 = 1.6774 1.783 2.200 2.211

11 13 14 15
12
SC = 61 114 119 477 973
OC = 566 1316 1396 7806 18180
WC = 337 538 638 1200 1700
A/D = 0.429 0.538 0.538 0.818 1
B2 = 2.410 2.867 2.943 4.200 5