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Chapter 3.caro
Chapter 3.caro
Methodology
1.1. Introduction
Solving the CME, which is an infinite set of differential equations leads us to ob-
taining expressions for the probabilities in terms of parameters. Real systems are
represented by large and more complex models but it is hard to analytically solve
the resultant CMEs. This is the reason why the model used in this study is simple,
and represents those genes which switch “on” and “off”. Larger and more realis-
tic models are studied through simulations but, unfortunately, one may not obtain
expressions for the probability functions from the simulation method. Analytical
methods tend to enable researchers to focus on the content of a model, as opposed
to its implementation through a simulation.Compared to simulation, there are a
number of advantages that we get by using an exact approach. For instance, knowl-
edge about model parameters, i.e. the biochemical rate constants of the underlying
biochemical reactions, is something quite rare. In analytical methods, expressions
for the probability distributions are obtained in terms of the parameters. Thus, an
analytical approach leads to equations and allows one to be able to select parame-
ters and try them easily and quickly.
Methodology ii
dP (1, t)
= kon P (0, t) − kof f P (1, t).
dt
Knowing that P (0, t) + P (1, t) = 1, the master equation reduces to the first order
linear differential equation,
dP (1, t)
+ (kon + kof f )P (1, t) = kon .
dt
This equation is solved by use of an integrating factor which in this case is defined
R
as exp (kon + kof f )dt. Multiplying both sides of the differential equation by the
intergrating factor,
dP (1, t)
exp(kon + kof f )t + exp(kon + kof f )t(kon + kof f )P (1, t) = exp(kon + kof f )tkon .
dt
kon
P (1, t) = [1 − exp(−(kon + kof f )t)]
kon + kof f
after using the initial conditions that at time t=0, the gene is “off”. From the above
equation we observe that
kon
lim P (1, t) = .
x→∞ kon + kof f
There is a special case where P (1) = 1. This is for the genes that are responsible
for providing energy to the body for the pumping of blood throughout the body of
any organism. These genes are always “on” at any time in the organism’s life time
and when they switch “off” the organism dies.
Methodology iii
Similarly, the master equation involving the probability rate for evolution of the
“off ” state where 0 is the probability of the gene being “off” can be written as
dP (0, t)
= kof f P (1, t) − konP (0, t).
dt
This also reduces to the first order linear differential equation,
dP (0, t)
+ (kof f + kon )P (0, t) = kof f .
dt
solved by use of the integrating factor, exp(kof f + kon )t. Multiplying the differential
equation through by the intergrating factor,
dP (0, t)
exp(kof f + kon )t + exp(kof f + kon )t(kof f + kon )P (0, t) = exp(kof f + kon )tkof .
dt
kof f
P (0, t) = [1 − exp(−(kof f + kon )t)]
kof f + kon
after using the initial conditions that at time t=0, the gene is “on”. we also observe
that
kof f
lim P (0, t) = .
x→∞ kon + kof f
Both probability distributions are dependent on the probability rate constants
kon and kof f . These constants can be changed by injecting a drug either to enhance
or inhibit transcription leading to the change in the probability distribution. Even-
tually, one will know when to inject a drug to switch the gene to a certain mode.
We are also going to obtain two chemical master equations for the evolution of
mRNA molecules depending on the state of the gene.
dP (1, m, t) −
= kon P (0, m, t) + km (m + 1)P (1, m + 1, t) + km P (1, m − 1, t)
dt
−
−(kof f + km + km m)P (1, m, t), m ≥ 1. (1.1)
P(1,m,t) is the probability of the gene being “on” having m mRNA molecules at
a time t. As shown by the schematic diagram above, there are three probabilities
of going into this state. The first one is is the probability of the reaction rate con-
stant kon switching “on” the gene from the “off ” state i.e P(0,m,t). The second one
is the probability of the gene being “on” and there are m − 1 mRNA molecules in
the system and allowing 1 reaction at a time, the gene transcribes once at a re-
action rate constant of km . The last one is the probability of the gene being “on”
and there are m + 1 mRNA molecules ,again allowing one reaction at a time the
−
mRNA molecules degrade at a reaction rate constant of km which is a function of
the mRNA molecules initially present before degradation.
Likewise, there three probabilities of going out of this state. The first is the proba-
bility of the gene being “on” with m mRNA molecules and the reaction rate constant
kof f switches it to the “off” state. The second is the probability of the gene being
Methodology v
“on” with m mRNA molecules and transcription takes place. Finally there is the
probability of the gene being “on” with m mRNA molecules and degradation takes
place at a rate proportional to the mRNA molecules present in the system.
dP (0, m, t) − −
= kof f P (1, m, t) + km (m + 1)P (0, m + 1, t) − (kof f + km m)P (0, m, t), m ≥ 1.
dt
(1.2)
P(0,m,t) is the probability of the gene being “off” having m mRNA molecules at
a time t. As shown by the schematic diagram above, there are two probabilities of
going into this state. The first one is is the probability of the reaction rate constant
kof f switching “off” the gene from the “on” state i.e from P(1,m,t). The other one
is the probability of the gene being “off” and there are m + 1 mRNA molecules,
allowing one reaction at a time the mRNA molecules degrade at a reaction rate
−
constant of km which is a function of the mRNA molecules initially present before
degradation. No transcription takes place when the gene is “off”.
Similarly, there two probabilities of going out of this state. The first is the probabil-
Methodology vi
ity of the gene being “off ” with m mRNA molecules and the reaction rate constant
kon switches it to the “on” state. Finally there is the probability of the gene being
“off ” with m mRNA molecules and degradation takes place at a rate proportional
to the mRNA molecules present in the system. It is important to note that degra-
dation takes places in both states.
Since m can take any nonnegative value, equations (3.1) and (3.2) are infinite sets
of ODEs. A special case of eqaution (3.1) arises when the gene is “on” and there are
no mRNA molecules. Taking m=0 in equation (3.1) gives
dP (1, 0, t) −
= kon P (0, 0, t) + km P (1, 1, t) + km P (1, −1, t) − (kof f + km )P (1, 0, t).
dt
dP (1, 0, t) −
= kon P (0, 0, t) + km P (1, 1, t) − (kof f + km )P (1, 0, t).
dt
− −
0 = kon P (0, m) + km (m + 1)P (1, m + 1) + km P (1, m − 1) − (kof f + km + km m)P (1, m).
1 − −
P (0, m) = (kof f + km + km m)P (1, m) − km (m + 1)P (1, m + 1) − km P (1, m − 1) .
kon
(1.3)
where we have dropped the variable t since we aim to obtain the stationary prob-
ability distributions. Applying the same stationarity conditions to the special case
Methodology vii
1 −
P (0, 0) = [(kof f + km )P (1, 0) − km P (1, 1)]. (1.4)
kon
Equation (3.3) gives P(0,m) in terms of P(1,.) and hence P(0,m + 1) also in terms of
P(1,.). This enables us to eliminate P(0,.) from the problem of solving for stationary
states.
1 − −
P (0, m+1) = (kof f + km + km m + 1)P (1, m + 1) − km (m + 2)P (1, m + 2) − km P (1, m).
kon
(1.5)
Substituting P (0, m) and P (0, m + 1) in equation 3.2 gives
− − − 2 2
km (kon + km ) + km (2km + kon + kof f )m + (km ) m P (1, m)
− − − 2
− km (kon + km + kof f + km ) + 2(km ) m (m + 1)P (1, m + 1)
− 2 −
+(km ) (m + 1)(m + 2)P (1, m + 2) − km (kon + km m)P (1, m − 1) = 0.
Equation (3.6) can be soved for P (1, m) by first defining, respectively for the “on”
and “off” states the moment generating functions. LetX be a random variable. If
the expected value exists and is finite for all real numbers belonging to a closed
interval , with X , then we say that X possesses a moment generating function
and the function is called the moment generating function of X. For the “on” and
“off ” states states, the moment generating functions are defined as,
∞
X
F (s, z) = z m P (s, m), |z| ≤ 1. (1.6)
m=0
Methodology viii
∞
X
F (1, z) = z m P (1, m), |z| ≤ 1.
m=0
∞
dF (1, z) 1X
= mz m P (1, m).
dz z m=0
− 2 2 − 2 − 2
) F 00 (1, z)
(km ) z − 2(km ) z + (km
− − − − 2
z F 0 (1, z)
+ km (2km + kon + kof f )z − km (kon + km + kof f + km ) − km km
−
+ km (kon + km ) − km kon z F (1, z) = 0.
∞
X 1 ()n n
M (; Ψ; uz ) = u (1.9)
n=0
n! (Ψ)n z
and
∞
X 1 ()n n
F (1, z) = c1 u = c1 M (; Ψ; uz ). (1.12)
n=0
n! (Ψ)n z
Methodology x
1
P (1, 0) = F (1, z) = c1 M (; Ψ; u0 )
0! z=0
1 d
P (1, 1) = F (1, z) = c1 α M ( + 1; Ψ + 1; u0 )
1! dz z=0 Ψ
1 d2 α2 ()2
P (1, 2) = F (1, z) = c1 M ( + 2; Ψ + 2; u0 )
2! dz 2 z=0 2! (Ψ)2
and it is easy to show that
1 dm αm ()m
P (1, m) = F (1, z) = c1 M ( + m; Ψ + m; u0 )
m! dz m z=0 m! (Ψ)m
kon −1
c1 = = .
kon + kof f Ψ−1
Methodology xi
Substituting for c1 in the expression for P(1,m), we have the joint probability dis-
tribution of the “on” state and having m mRNA molecules as
αm ()m − 1
P (1, m) = M ( + m; Ψ + m; u0 )
m! (Ψ)m Ψ − 1
Deriving the expression for P(0,m), we substitute m by m+1 and m-1 in the
expression for P(1,m). This gives
αm+1 ()m+1 − 1
P (1, m + 1) = M ( + m + 1; Ψ + m + 1; u0 )
m + 1! (Ψ)m+1 Ψ − 1
and
αm−1 ()m−1 − 1
P (1, m − 1) = M ( + m − 1; Ψ + m − 1; u0 )
m − 1! (Ψ)m−1 Ψ − 1
respectively. Using the definition of the rising factorial we have that
()m+1 = ( + 1)...( + m) = ()m ( + m) and
()m
()m−1 = ( + 1)...( + m − 2) = +m−1
. Using these simplifications we have
αm+1 ()m + m − 1
P (1, m + 1) = M ( + m + 1; Ψ + m + 1; u0 )
m + 1! (Ψ)m Ψ + m Ψ − 1
and
αm−1 ()m Ψ + m − 1 − 1
P (1, m − 1) = M ( + m − 1; Ψ + m − 1; u0 ).
m − 1! (Ψ)m + m − 1 Ψ − 1
αm ()m − 1
1 −
P (0, m) = (kof f + km + km m) M ( + m; Ψ + m; u0 )
kon m! (Ψ)m Ψ − 1
− αm+1 ()m + m − 1
−km (m + 1) M ( + m + 1; Ψ + m + 1; u0 )
m + 1! (Ψ)m Ψ + m Ψ − 1
αm−1 ()m Ψ + m − 1 − 1
−km M ( + m − 1; Ψ + m − 1; u0 )
m − 1! (Ψ)m + m − 1 Ψ − 1
Methodology xii
which when simplified gives the expression for the joint probability distribution of
the “off” and having m mRNA molecules as
αm ()m 1
P (0, m) = [(Ψ − + α + m)M ( + m; Ψ + m; u0 )
m! (Ψ)m Ψ − 1
+m
−α M ( + m + 1; Ψ + m + 1; u0 )
Ψ+m
Ψ+m−1
−m M ( + m − 1; Ψ + m − 1; u0 )
+m−1
To derive the expression for the marginal distribution, we sum the joint probabil-
ity distributions over all s. This is the probability of having m mRNA molecules
regardless of the state of the gene. This will enable us to predict the distribution of
the number of mRNA molecules transcribed by a particular gene at any time. The
marginal distribution is given by
1
X
P (m) = P (s, m) = P (0, m) + P (1, m)
s=0
αm ()m 1
P (m) = [(Ψ − + α + m)M ( + m; Ψ + m; u0 )
m! (Ψ)m Ψ − 1
+m
−α M ( + m + 1; Ψ + m + 1; u0 )
Ψ+m
Ψ+m−1
−m M ( + m − 1; Ψ + m − 1; u0 )
+m−1
αm ()m − 1
+ M ( + m; Ψ + m; u0 )
m! (Ψ)m Ψ − 1
Simplifying gives
Methodology xiii
αm ()m 1
P (m) = [(Ψ + α + m − 1)M ( + m; Ψ + m; u0 )
m! (Ψ)m Ψ − 1
+m
−α M ( + m + 1; Ψ + m + 1; u0 )
Ψ+m
Ψ+m−1
−m M ( + m − 1; Ψ + m − 1; u0 )
+m−1
P (m) ∩ P (s)
P (m|s) = .
P (s)
The expressions we obtained for P (1, m) and P (0, m) are the probabities of being
in state s and having m mRNA molecules which can also be represented as the
intersection of two probabilities, P (m) ∩ P (s). The conditional probability can then
be found by
P (s, m)
P (m|s) = .
P (s)
In the first section of this chapter we found that
kon −1
P (1) = = = c1 .
kon + kof f Ψ−1
Therefore
αm ()m −1
P (1, m) m! (Ψ)m Ψ−1
M ( + m; Ψ + m; u0 )
P (m|1) = = −1
c1 Ψ−1
αm ()m
= M ( + m; Ψ + m; u0 )
m! (Ψ)m
Methodology xiv
and
P (0, m)
P (m|0) =
1 − c1
αm ()m 1
P (m|0) = [(Ψ − + α + m)M ( + m; Ψ + m; u0 )
m! (Ψ)m Ψ − 1
+m
−α M ( + m + 1; Ψ + m + 1; u0 )
Ψ+m
Ψ+m−1 Ψ−
−m M ( + m − 1; Ψ + m − 1; u0 )/
+m−1 Ψ−1
Simplifying gives
αm ()m 1
P (m|0) = [(Ψ − + α + m)M ( + m; Ψ + m; u0 )
m! (Ψ)m Ψ −
+m
−α M ( + m + 1; Ψ + m + 1; u0 )
Ψ+m
Ψ+m−1
−m M ( + m − 1; Ψ + m − 1; u0 )
+m−1