WMS

MA256
Introduction to Systems
Biology

Revision Guide

Written by Eu Meng Chong

WMS
ii MA256 Intro to Systems Biology

Contents

I Introduction iii

II Clock Switches and Signals iii

1 Review of differential equations considered as dynamical systems iii
1.1 Bifurcation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iv

2 Biological Model v
2.1 Ultrasensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
2.2 Positive Feedback . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi
2.3 Nullclines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi

3 Oscillation vi
3.1 Goodwin Oscillator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii

III Oscillations in Biological Systems vii

4 Law of Mass Action vii

5 Periodic Orbits & Limit Cycles viii

6 Existence of Periodic Orbits ix

6.1 Brusselator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
6.2 Hopf Bifurcation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x

IV Mathematical Neuroscience x
7 The Leaky-Integrator Neuron x
7.1 Circuit for Non-Leaky Neuron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x
7.2 Leaky Neuron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

8 Voltage-Gated Currents xi
8.1 Linearisation Near Fixed Point . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xii

9 Leaky Integrate and Fire Model xii

9.1 Low Rate Limit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
9.2 High Rate Limit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
9.3 Non-Linear Integrate and Fire (IF) Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . xiii

V Introduction to Bioinformatics xiii

10 Regulatory Codes xiii
10.1 Concept of Dynamical Programming . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiv

11 Sequence Alignment xv

VI Biological Systems in Space and Time xvi

MA256 Intro to Systems Biology iii

12 Turing Systems xvi

12.1 Turing Instability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvi
12.2 Codimension-Two Turing-Hopf Bifurcation . . . . . . . . . . . . . . . . . . . . . . . . . . xvii
12.3 Traveling Wave Solution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii

Part I
Introduction
This revision guide is split into 5 sections, one for each lecturer of the course. This is a module where
it is possible to only learn 4 sections and get 100% on the exam! There is no crossover between each
section, so don’t be put off by skipping alignment of DNA completely- everyone does. It is possible to
score very very high on this module but similarly very badly. Only a small proportion of students take
it, so it is unlikely that it will be scaled at all. This is the first proper applied module that you will
come across at Warwick, so it is important to note that the exam will be less bookwork (ie there will be
hardly any of ”state a theorem and then prove said theorem”). The exam will be made up of applying
biological models and working through seen and unseen examples.

Part II
Clock Switches and Signals
1 Review of differential equations considered as dynamical sys-
tems
Consider the system of differential equations:

dxi
= fi (x1 , . . . , xn ; t) , i = 1, . . . , n
dt
We can rewrite it to a vector form ẋ = f (x) ∈ Rn .

The solution we obtain from such ODE is a vector of functions x(t) = (x1 (t), . . . , xn (t)).

Theorem 1.1. Given any initial condition x0 = (x0,1 , . . . x0,n ), there exist a unique solution x(t) such
that x(0) = x0 .

Definition 1.2. The equilibria are x ∈ Rn which satisfy:

f (x) = 0 i.e., fi (x1 , . . . , xn ) = 0 ∀i

Definition 1.3. The equilibrium x∗ is said to be stable if x(t) is the solution to the differential equation
for a given initial condition and x(t) → x∗ as t → +∞.

Consider only for dimension n = 2, we have v(x, y) := (f (x, y), g(x, y)).

Suppose there exist equilibria (x∗ , y∗ ) such that v(x∗ , y∗ ) = 0. To investigate the stability of the equi-
librium point we consider the eigenvalues of the Jacobian Matrix A evaluated at (x∗ , y∗ ).
!
∂f ∂f 
∂x ∂y 
A = ∂g ∂g 
∂x ∂y

x=x∗ , y=y∗

Theorem 1.4. Let λj = αj + iβj , j = 1, 2 be the eigenvalues of A. If αj < 0 for j = 1 and 2, then
(x∗ , y∗ ) is a stable equilibrium.
iv MA256 Intro to Systems Biology

Remark. The cases where αj = 0 are said to be degenerate. All cases other than stable and degenerate
are unstable.

We can summarise all the characteristics of equilibrium points in the following figure,

Figure 1: Graphical representation of the stability properties of linear systems ẋ = Ax where A is

a 2 × 2 matrix. The trace and determinant are plotted on the x-axis and y-axis respectively. The
eigenvalues in the coloured region are complex, and real elsewhere. These two regions are separated by
tr(A)2
the parabola det(A) = . Seven regions with various degrees of stability are indicated by the sign
4
of the eigenvalues.

Figure 2: Phase portraits for equilibria of two-dimensional systems

1.1 Bifurcation

Definition 1.5. Consider a system of differential equations depending on a parameter, λ, then we write
ẋ = f (x(t), λ). A system has a bifurcation at λ = λc if there is a change in stability of the equilibrium
point (x∗, y∗).

√
Example. This is a Fold Bifurcation. f (x, θ) = x2 − θ. Then f (x, θ) = 0 ⇔ x∗ = ± θ.

Note, as θ is changed from a positive to negative value, the stability of x∗ changes. In this case θc = 0
as this is the point where the equilibrium disappears.
MA256 Intro to Systems Biology v

Figure 3: (left) The graph of f for θ positive, negative and zero. (right) The equilibria x∗ plotted against
θ.

2 Biological Model
Let S, E and P be the substrate, enzyme and the product respectively and assume the E and S given
are constant independent of t. Now, let’s consider an enzymatic reaction:
kon ν
S + E
S : E→ P + E
koff

We define E0 := [E] + [S : E], when the total amount of E0 is smaller than the amount of S, the E0 is
kon
no longer constant. We assume S + E
S : E are in equilibrium. We call this the rapid equilibrium
koff
assumption, then,
kon [S][E] = koff [S : E]
. We can rearrange this to get,
kon (E0 − [S : E]) = koff [S : E]
[S]E0 koff
[S : E] = , ,K =
K + [S] kon
From here, we get an ODE of:

d[P ] [S] [S] kon

= ν[S : E] = νE0 =: ν1 ,K=
dt K + [S] K + [S] koff

David does not need you to show how this was derived but if you are interested, read ahead to Annabelle’s
section on the ’Michaelis-Menton Model’.

2.1 Ultrasensitivity
Assuming that [S] + [P ] is constant and consider the following reaction:
K,Kinase
S Ph,Phosphatase
P

We get the ODE of:

y x
ẋ = f (x) = Va + Vi
ka + y ki + x
where:
[P ]
x= , y =1−x
[S] + [P ]
Here, we consider the equilibrium of the ODE. By graphing equilibrium point x∗ with respect to λ = VVai .
There exists a critical point λ∗ such that when there is a small perturbation from λ∗ there is a large
change in x∗ . This is known as ultrasensitivity.
vi MA256 Intro to Systems Biology

2.2 Positive Feedback

Consider the following reactions:
k1R
P
P∗
k1F

k2R
Q
Q∗
k2F

Define y1 := [P ∗] , y2 = [Q∗] and E1 = [P ] + [P ∗], E2 = [Q] + [Q∗]. Then the forward rate from P → P ∗
is k1R y1 . Using this we obtain the following ODEs known as the Cascade System,

dy1
= k1F (E1 − y1 )y2 − k1R y1
dt

dy2
= k2F (E2 − y2 )y1 − k2R y2
dt
kiR
Now we want to consider the system at equilibrium. For simplicity we define Ki = kiF for i = 1, 2.

dy1 1 K1 y1
=0⇔ (E1 − y1 )y2 = y1 ⇒ y2 =
dt K1 E1 − y1

and,
dy2 K 2 y2
= 0 ⇔ y1 =
dt E2 − y2
. We can now do some rearranging to show equilibrium occurs when

E1 E2 − K1 K2 E1 E2 − K1 K2
y1 = , y2 =
E1 + K1 E1 + K2

By fixing E1 or E2 we obtain a Transcritical bifurcation diagram

Figure 4: (left) This is Transcritical bifurcation

2.3 Nullclines
Definition 2.1. Nullclines are the curves ẋ = f (x, y) = 0 and ẏ = g(x, y) = 0. The intersection of the
x-nullcline with the y-nullcline gives the equilibria points of the system v(x, y) = (f (x, y), g(x, y)). We
say ”y-nullcline is horizontal, x-nullcline is vertical”

3 Oscillation
Let’s consider 3 biological entities, which are [X1 ], [X2 ] and [X3 ].
MA256 Intro to Systems Biology vii

3.1 Goodwin Oscillator

Consider a system of ODEs:

d[X1 ] ν0 d[X2 ] d[X3 ]

= − k1 [X1 ] , = ν[X1 ] − k2 [X2 ] , = ν2 [X2 ] − k3 [X3 ]
dt 1 + ([X3 ]/km )p dt dt
Remark. This is known as negative feedback loop with delay (indicated with term km ).
0
Now, by substituting xi = ci [Xi ] and t = αt for some ci and α, we get:

dx1 ν0
 = − b1 x 1 = f 1
1 + xp3

dt





dx2
= b2 (x1 − x2 ) = f2


 dt
 dx3

= b3 (x2 − x3 ) = f3


dt
With c1 = k2νk13νk2m , c2 = k3νk2m , c3 = k1m and α = kνm0 νk12νk23 .
By setting b1 = b2 = b3 = b, we have unique equilibrium (ξ, ξ, ξ). The Jacobian matrix given by
 
−b 0 −φ
 b −b 0 
0 b −b

∂f1
where φ = − ∂x 3
> 0. By considering the Jacobian matrix at (ξ, ξ, ξ) (and a bit of extra work) we
can deduce φ = pn(bξ − 1) and we get that:

Re(λ) > 0 ⇔ p(1 − bξ)1/3 cos(pi/3) > 1

We get the result that,

p−8
bξ <
p
If p ≥ 8, the equibrium will get more unstable as b decreases, which is visualised below:

Figure 5: Bifurcation of Goodwin Equation with parameter b. This is known as Hopf Bifurcation. We
will go into more depth with this in Part II.

Part III
Oscillations in Biological Systems
4 Law of Mass Action
Definition 4.1. Mass - Action Law Speed of the reaction is proportional to the products of the reactants
states. We say ”forward reaction is equal to backward reaction”.
viii MA256 Intro to Systems Biology

Suppose [A], [B] and [C] are compounds in some solution.

Example. Stoichiometry: How many molecules produced in the following reaction
k1
2A + B
C
k2

• The stoichiometry of A in k1 is −2 - ”you are losing two A’s”

• The stoichiometry of A in k2 is 2 - ”you are gaining two A’s”
• The speed of reaction in the k1 direction is k1 A2 B - ”consider all the molecules and take the number
of molecules of A and raise it to the power”
• The speed of reaction in the k2 direction is k2 C - ”there is only the C molecule to consider”
Now we use the Mass-Action Law principle and consider the speed of reaction - ”the stoichiometry of
molecule you are considering multiplied by the speed of reaction”
dA
= −2k1 A2 B + 2k2 C
dt
dB
= −k1 A2 B + k2 C
dt
dC
= k1 A2 B − k2 C
dt
Then we can simply write this in matrix form,
 dA   
dt −2 2  2

 dB  = −1 1  k1 A B
dt k2 C
dC 1 −1
dt
k0
Definition 4.2 (Zero Order Reaction). Suppose ∅ is a source for producing compound X, i.e., ∅
d[X]
X, then = k0 .
dt
k1
Definition 4.3 (First Order Reaction). Suppose ∅ is an endpoint for compound X, i.e., X ∅,
d[X]
then = −k1 .
dt
Example. Michaelis - Menton Model, this is also discussed in David’s chapter
k1 k
2S + E
C →2 E + 2P
k−1

Then,

−2k1 S 2 E + 2k−1 C
     
Ṡ −2 2 0  2

Ė  −1 k1 S E 2
1 1  k−1 C  = −k1 S2 E + k−1 C + k2 C 
 
 =
Ċ   1 −1 −1  k1 S E − k−1 C − k2 C 
k2 C
Ṗ 0 0 2 2k2 C

5 Periodic Orbits & Limit Cycles

Let’s consider the ODE ẋi = fi (x1 , . . . , xn ) to be autonomous.
Definition 5.1. A non-constant solution x(t) is a periodic orbit if there exist T > 0 such that x(t + T ) =
x(t) for all t. The minimum T is called the period of x(t).
Definition 5.2. A periodic orbit is called a limit cycle if nearby points approach it when t → +∞ or
t → −∞.

A limit cycle is stable if if it attracts all nearby trajectories when t → +∞. It’s unstable if it repels.
MA256 Intro to Systems Biology ix

6 Existence of Periodic Orbits

Definition 6.1. An invariant region D (or trapping region) is a connected domain where the flow is not
outward along its boundary.

Theorem 6.2 (Poincare-Bendixon Theorem). If for t ≥ t0 , a trajectory is bounded and it doesn’t contain
an equilibrium point or approach one as t → +∞, then it is either a periodic orbit or it approaches one
for t → +∞.

To apply the Poincare-Bendixion Theorem we will construct and invariant region that doesn’t contain
any stable equilibrium points.
∂f ∂g
Theorem 6.3 (Bendixon Negative Criterion). Suppose that Ω is a simply connected domain. If +
∂x ∂y
is not identically zero and doesn’t change sign in Ω, then there are no periodic orbits in Ω.

Theorem 6.4 (Dulac’s Negative Criterion). Suppose Ω is a simply connected domain and consider a
∂Bf ∂Bg
scalar real function B(x, y) that is continuously differentiable on Ω. If + is not identically
∂x ∂y
zero and doesn’t change sign in Ω, then there is no periodic orbit.

6.1 Brusselator
The following is an important example which incorporates everything taught in this section of the module.
Consider the following series of reactions:
k
A→1 X
k
B + X →2 Y + C
k
2X + Y →3 3X
k
X →4 D
Then by the Mass-Action Law,

Ẋ = k1 A − k2 BX + k3 X 2 Y − k4 X

Ẏ = k2 BX − k3 X 2 Y
We will now use the following scaling to get dimensionless equations: x = Kx X, y = Ky Y and τ = Kt t.
k3 (k1 [A]) k2 [B]
By using the chain rule and choosing k4 = Kt , Ky = Kx = kK1 A
t
and letting a = 3 and b = ,
k4 k4
we get the simplified ODEs of:

dx


 = 1 − (b + 1)x + ax2 y
dτ
 dy = bx − ax2 y

dτ
By drawing the graph of x-nullcline (ẋ = 0) and y-nullcline (ẏ = 0) onto the x-y axis, we can then
construct an invariant region D on the graph, as illustrated below.
Now, to study the stability of our steady state (1, ab ) unstable, we need to investigate the trace and
determinant of the Jacobian matrix at the steady state.

Re(λ± ) > 0 ⇔ tr(J) > 0 ⇔ b − a − 1 > 0

The steady state (1, ab ) is unstable if b − a − 1 > 0. Then in this case by Poincare-Bendixon Theorem
there exists a periodic orbit.
x MA256 Intro to Systems Biology

Figure 6: The invariant region for Brusselator is the area shaded in cyan.

6.2 Hopf Bifurcation

In general, let’s consider a model based on a system of ODEs with p as a model parameter:

dx


 = f (x, y; p)
dt
 dy = g(x, y; p)

dt
Assume the system is at equilibrium at (x ∗ (p), y ∗ (p)) - ie equilibrium point depends on p.

Definition 6.5. A non-degenerate Hopf bifurcation in parameter p is a local bifurcation where the eigen-
valyes of the Jacobian transversely cross the imaginary axis in the complex plane at p0 . i.e.,

• λ± (p0 ) = ±µi

d
•

Re(λ± (p)) 6= 0
dp p=p0

Remark. When the limit cycle appears to be stable, then it is a supercritical Hopf bifurcation. If
otherwise, then it is a subcritical Hopf bifurcation.
Remark. For the Brusselator, the Jacobian patterns necessary for the Hopf Bifurcation are
   
+ + + −
and only.
− − + −

Part IV
Mathematical Neuroscience
7 The Leaky-Integrator Neuron
Let’s model our neurons as a capacitor with charge Q and voltage across the membrane V which follows
the equation of Q = CV , where C is a constant known as capacitance.

7.1 Circuit for Non-Leaky Neuron

dQ
Definition 7.1. The current I is the rate of change of charge, i.e., I = .
dt
dV
Hence the injection of current Iapp (t) is defined as a simple ODE of C = Iapp (t).
dt
MA256 Intro to Systems Biology xi

7.2 Leaky Neuron

Note that in neuron cells, there exist Na, K and Cl ion channels which allows the excess charge ’leak
away’ from it.

We have an improvement of the model:

dV
C + gK (V − EK ) + gCl (V − ECl ) + gN a (V − EN a ) = Iapp (t)
dt
where g· and E· are the conductance and electrical potential for the ion channels respectively.

To simplify the model, let:


gL = gK + gCl + gN a
g E + gCl ECl + gN aEN a
EL = K K
gK + gCl + gN a
dV
We get the ODE of C + gL (V − EL ) = Iapp (t).
dt
Remark. At time t = 0, the current will be zero, then

gL (V − EL ) = 0 ⇔ V = EL

. Then the initial condition is V (0) = EL .

We can then solve the ODE using the integrating factor method - recall the first year Differential
Equations module! We get
V (t) = IRL (1 − e−t/τL ) + EL
C
where the total leak resistance is given by RL = 1/gL and the membrane time is given by τL = gL .

8 Voltage-Gated Currents
Let n be the fraction of open channels. Note that n has their own dynamics (not constant).

The system of ODEs are:

dV

C
 + gL (EL − V ) + gn n(En − V ) = Iapp
dt
τ dn = n (V ) − n

n ∞
dt
where τn is the time delay and n∞ is the value of n as t → +∞.
Definition 8.1. n∞ is defined as:
1
n∞ = −(V −V1/2 )
1+ exp[ ∆V ]
where V1/2 is the voltage where half of the channels are open and ∆V is the gradient of the n∞ at V1/2 .
Definition 8.2. A voltage-gated channel is said to be hyperpolarised-activated if ∆V < 0. If ∆V > 0,
then the channel is depolarised-activated.
Definition 8.3. The current is said to be a hyperolarising current if En < EL . If En > EL then the
current is depolarising current.
We can split Voltage-Gated Currents into four cases, in each case we sketch the nullclines V̇ = 0 and
ṅ = 0 on the V -n axes and call the nullclines n1 and n2 respectively.
Definition 8.4. Feedback from Nullclines:
xii MA256 Intro to Systems Biology

• Positive Feedback: If the gradients of n1 and n2 have the same sign it is possible to have one or
three fixed points.
• Negative Feedback: If the gradients of n1 and n2 have a different sign then there is a counterhchange.
You should now go and sketch the four cases:
1. Hyperpolarising Activated, hyperpolarising current (positive feedback)
2. Depolarisating Activated, depolarising current (positive feedback)
3. Hyperpolarising Activated, depolarising current (negative feedback).The solution flows around the
fixed point in the clockwise direction.
4. Depolarising Activated, hyperpolarising current (negative feedback). The solutions flows around
the fixed point in the anticlockwise direction.

8.1 Linearisation Near Fixed Point

Let’s rewrite the system of ODEs in the following manner (with Iapp = 0):
dV

τV
 = V∞ (n) − V
dt
τ dn = n (V ) − n

n ∞
dt
C gL EL + gn nEn
where τV = and V∞ = .
gL + gn n gL + gn n
Assume a neighbourhood of a fixed point:
V = V∗ + δV , n = n∗ + δn
By taking
 the terms of the first order in Taylor’s Expansion, then by substituting δV = v and δn =
dn∞ 
y, we get a linear systems of ODEs of:
dv t
  
dv  dV∞  dn∞  
 τ
 V∗
 = y−v
dt dn ∗ dV ∗
τn∗ dy = v − y


dt
We can make t dimensionless by applying τn∗ s = t. Also, by rewriting:
 
τn∗ τn∗ dV∞  dn∞ 
P = ,Q=
τv∗ τv∗ dn ∗ dV ∗
we can find obtain the eigenvalue λ for the linear ODEs to study the stability of the equilibrium point(s):
1 p

λ= − (1 + P ) ± (P − 1)2 + 4Q
2

9 Leaky Integrate and Fire Model

Let Vre be the reset potential and Vthreshold = Vth be the threshold potential.
dV I
• Integrate Part: We use the simplified model of τ = E0 − V , where E0 = EL + .
dt gL
• Fire Part: If V ≥ Vth , then V → Vre where Vth > Vre and we register the spike.
Remark. This only works when E0 > Vth
Once again we can solve this ODE using techniques from Differential Equations and the initial
condition at t = 0, V = Vre .
V (t) = E0 + (Vre − E0 )e−t/τ
MA256 Intro to Systems Biology xiii

9.1 Low Rate Limit

Consider the fact that |E0 − Vth |  |Vth − Vre |. Let ε = E0 − Vth . The time period T is the period from
reset to Vth , which implies V (T ) = Vth . Then, we have the low rate limit, rlow of:
1 1 1 1
rlow = E − V + V − V  ' −  ε 
τ 0 th th re τ log
log Vth − Vre
ε

9.2 High Rate Limit

Let Θ = Vth − Vre and assume that E  Θ (i.e., Θ/E  1). By rewriting the rate as function of Θ and E,
we could form a small quantity Θ/E in equation. Lastly, we utilise the Taylor’s Expansion of log(1 + x)
to get a leading order result:

1 1 1 E0 − (Vth − Vre )/2

rate =
τ  E + (Θ/2)  ≈ τ Vth − Vre
log
E − (Θ/2)
Refractory Period: We can add the constant (dying time, τr ) to our period. Hence, our total period,
Tr = T0 + τr .

9.3 Non-Linear Integrate and Fire (IF) Neurons

dV
Example. Consider the Quadratic IF Model: = qV 2 + I, q > 0. Note that V → +∞ first, then
dt
V → −∞.

• If I < 0. We have 2 fixed points of V∗ = −I/q. Note that it is an excitable model.

p

π
• If I > 0. We have oscillations of period T = √ .
Iq

dV V − V 
τ
Example. Consider the Exponential IF Model: F = τ = E0 − V + ∆τ exp
dt ∆τ

• By letting F = 0 and F 0 (V ) = 0, we can find the critical values E0∗ and V ∗ respectively.

• By Taylor’s Expansion onto exp(·), we can simply the model to some nth order terms.

Part V
Introduction to Bioinformatics
10 Regulatory Codes
Definition 10.1 (Position Weight Matrix, PWM or Motif). For L ∈ N, we define a 4 × L matrix M as
Position Weight Matrix iff all entries of M are non-negative and the sum of each column equals 1.

Definition 10.2 (Likelihood under PWN Model). Let L ∈ N, 4 × L matrix M a PWM, and S ∈
{A, C, G, T }L . Then we define the likelihood of S under the PWM model as:
L
Y
P(S|M ) = MSi ,i
i=1

Definition 10.3 (Likelihood under the background model). Let L ∈ N and S ∈ {A, C, G, T }L . We
define P(S|B) = (1/4)L .
xiv MA256 Intro to Systems Biology

Definition 10.4 (Site). Let M be a set of motifs and S be a sequence. We call any (M, P ) ∈ M ×
{1, . . . , |S|} a site iff |M | ≤ P .

Definition 10.5 (Configuration). Let M be a set of motifs and S a nucleotide sequence. We call any
finite set c of sites on S a configuration of S, i.e.,

c = {(Mi , Pi ) : (Mi , Pi ) a site on S ; 1 ≤ i ≤ N }

Definition 10.6 (Valid Configuration). Let c be a configuration. We call c valid iff no sites of c overlap,
i.e., for (M, P ), (M 0 , P 0 ) ∈ c, P ≤ P 0 − |M 0 | or P 0 ≤ P − |M | holds.

From now on, only valid configurations are considered unless being told otherwise.

Definition 10.7 (Weight of Configuration). Let c be a configuration, we define:

|c|
Y P(Si |Mi )
w(c) =
i=1
P(Si |B)

where Si denotes the part of S from position Pi − |Mi | + 1.

Definition 10.8 (Probability of Configuration). Let c be a configuration, we define:

w(c)
P(c) = P
c∈C w(c)
P
where C denotes the space of all valid configurations. We also let Z = c∈C w(c) to denote partition
function.

Definition 10.9 (eSM ). Let M be a set of motifs and S a sequence. We define:

X
eSM = P(c) · IM (c)
c∈C

where IM (c) is the number of sites (M 0 , P 0 ) ∈ c with M 0 = M . analogous to expectations.

An approach to Comparing Regulatory Sequence:

INPUT: Sequences S, T ; set of motif M.

STEP 1: Compute eSM and eTM ∀M ∈ M.
STEP 2: Compare vector (eSM )M ∈M and (eSM )M ∈M statistically.
OUTPUT: Similarity score for S and T .

10.1 Concept of Dynamical Programming

Solve the problem for small input sizes and adaptively derive solutions for larger input sizes.
M
Definition 10.10 (Ci,j , PM
i,j ). Let S be a sequence, M a set of motifs, M ∈ M, i ≥ 1, j ≥ 0. We define
M
Ci,j as the space of all valid configuration which:

• Do not occupy the part of S after position i and

• Have exactly j sites for motif M , i.e.,

M
Ci,j := {c ∈ C : ∀(M 0 , P 0 ) ∈ c : P 0 ≤ i ; |{(M 0 , P 0 ) ∈ c : M 0 = M }| = j}

and PM
P
i,j := M
c∈Ci,j P(c).
MA256 Intro to Systems Biology xv

Lemma 10.11. Let S be a sequence and M a set of motifs. The following holds for M ∈ M:
J  
X |S|
eSM = [j · PM
|S|,j ] where J = .
j=0
|M |

Definition 10.12 (o(c, i)). Let c be a configuration and i ∈ {1, . . . , |S|}. We define the occupants of
base i by:
o(c, i) := {M : ∃(M, P ) ∈ c ; P − |M | + 1 ≤ i ≤ P }

Lemma 10.13. Let S be a sequence, M a set of motifs, M ∈ M, i ≥ 1, j ≥ 0. Then,

P(Si,M |M ) X P(Si,M 0 |M 0 )
PM M M
i,j = Pi−1,j + Pi−|M |,j−1 + PM 0
i−|M |,j .
P(Si,M |B) 0
P(Si,M 0 |B)
M ∈M
M 0 6=M

The Comparison of (eSM )M ∈M and (eSM )M ∈M (Under Step 2):

1. Pick sequences randomly from the genome and compute e·· -values for these sequences.
2. For each Mi ∈ M = {M1 , . . . Mn }, record the mean and the standard deviation of e·Mi on
random sequences: µR R
i , σi . (The probability distribution was found to be approximately a
normal distribution.)
3. If a set of sequences is available which is functionally similar to T , then compute e·Mi -values
for these and record results as µTi , σiT .

4. Using the normal distribution, we compute sequence similarity as:

n
P(eS· |µT· , σ·T ) Y P(eSMi |µTi , σiT )
Similarity(S, T ) = =
P(eS· |µR R
· , σ· ) i=1
P(eSMi |µR R
i , σi )

11 Sequence Alignment
Definition 11.1 (Γ∗ ). Let Γ be a finite set (alphabet). We define Γ0 = {∅}, Γ1 = Γ, Γn = Γ × Γn−1
for n > 1 and Γ∗ = ∪i≥0 Γi .

Definition 11.2 (Pairwise Alignment). Let Γ be an alphabet and u, v ∈ Γ∗ . Let ”−” denote a new
character that is not in Γ and let u0 , v 0 ∈ (Γ ∪ {−})∗ . We call (u0 , v 0 ) a pairwise alignment of (u, v) iff
the following conditions hold:

• |u0 | = |v 0 |.

• Removing occurrences of ”−” from u0 and v 0 yield u and v respectively.

We call ”−” a gap character.

Definition 11.3 (Score Matrix). Let Γ be an alphabet and Γ0 = Γ ∪ {−}. We call any function δ :
Γ0 × Γ0 ⇒ R a score matrix.

Definition 11.4 (Alignment Score). Let u, v ∈ Γ∗ be sequences and (u0 , v 0 ) be alignment of (u, v). Let
δ be score matrix. we define the score of (u0 , v 0 ) as:
0
|u |
X
δ(u0i , vi0 )
i=1
xvi MA256 Intro to Systems Biology

Definition 11.5 (Needleman-Wunsets Algorithm, NWA). Let Γ be an alphabet; u, v ∈ Γ∗ and δ be a

score matrix. For ı ∈ {0, . . . , |u|} and j ∈ {0, . . . , |v|}, the NWA computes S(i, j) ∈ R as follows:

• S(0, 0) = 0

• For i = 1, . . . , |u|: S(i, 0) = S(i − 1, 0) + δ(ui , −)

• For j = 1, . . . , |v|: S(0, j) = S(0, j − 1) + δ(−, vj )

• For i = 1, . . . , |u| and j = 1, . . . , |v|:

S(i, j) = max{S(i − 1, j − 1) + δ(ui , vj ) , S(i, j − 1) + δ(−, vj )} , S(i − 1, j) + δ(ui , −)}.

Part VI
Biological Systems in Space and Time
12 Turing Systems
Definition 12.1 (Turing System). Turing System is defined as a reaction diffusion system that is stable
against spatial perturbations when there is no diffusion (D = 0) but becomes unstable when D > 0. Let
f , g be non-linear functions, then the Turing system is:

∂A ∂2A
= f (A, I) + DA 2



∂t ∂x
2
 ∂I ∂ I

 = g(A, I) + DI 2
∂t ∂x

12.1 Turing Instability

Ignoring the diffusion terms, consider the fixed points (A∗ , I ∗ ) and Jacobian J to study the stability of
those points:  
fA fI
J=
gA gI
We linearise about the steady states a = A − A∗ and i = I − I ∗ . We should get:
 2
 ∂a = fA a + fI i + DA a

∂x2

∂t
2
 ∂i = g a + g i + D ∂ i

 A I I
∂t ∂x2
We should be able to get the solution from here. Let’s substitute into the linearised system. Note that
k is the wavenumber obtained from the solutions a(x, t) and i(x, t).

∂A


 = a11 A + a12 I − k 2 ∇2 A
∂t
 ∂I = a A + a I − k 2 ∇2 I

21 22
∂t
We shall take the Jacobian, JD from this linearised system. Then by considering the trace of the system
with diffusion τ (JD ) and letting det(JD ) < 0 for the instability of the system, we get the Turing
conditions of:

a11 + a22 < 0

a11 a22 − a12 a21 > 0
 p
Da a22 + Di a11 > 2 Da Di (a11 a22 − a12 a21 )

MA256 Intro to Systems Biology xvii

and the wavelength k, which is: r

Da a22 + Di a11
k := kmin =
2Da Di
By convention, we let a11 > 0; a22 < 0. Moreover, we can soften condition 3 of Turing conditions to get
Di > Da . Also, note that det(JD ) = Da Di k 4 − (Da a22 + Di a11 )k 2 + det(J).
Di
Definition 12.2. We define dcrit = . Note that d is just the ratio between Da and Di .
Da
By plotting the graph of det(JD ) against k 2 , Note that if d > dcrit , the parabola crosses the k 2 -axis.
Definition 12.3. The characteristics equation is defined to be:

det(JD − λU ) = λ2 − λτ (JD ) + det(JD ) = 0

where U is a 2 × 2 identity matrix.

12.2 Codimension-Two Turing-Hopf Bifurcation

Consider the model of semiconducter charge transport:

∂2a

∂a u−a

 = − T a +
∂t (u − a)2 + 1 ∂x2

 ∂u 2
∂ u
= α[j0 − (u − a)] + D 2


∂t ∂x
Let’s consider the trace and determinant of JD in respect to wavenumber k:

τ (k) = γ − T − α − (D + 1)k 2 , det(k) = αT + (α + γD + DT )k 2 + Dk 4

j02 − 1
where γ := .
(j02 + 1)2
Now, let’s consider the instabilisation around:

k=0 (Hopf Mode)

k = kcrit (Turing Mode)
γH = α + T (Hopf Threshold)
√ r 
α 2
T
γ = T+ (Turing Threshold)
D

Definition 12.4. A codimensional-2 Turing-Hopf point is the point which satisfies γ H = γ T .

12.3 Traveling Wave Solution

Let’s consider the Fisher’s Equation:

∂u ∂2u
= ku(1 − u) + D 2
∂t ∂x
r
τ D
First: Make it dimensionless by using t = and x = ξ.
k k
Second: Change it to a new coordinate of z = ξ − cτ .

Lastly: From here, investigate the steady state by using the Jacobian J.

THE END FOR MA256.