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Approximation of a cell cycle model in Budding Yeast • Introduction • Cell Cycle Model of
Approximation of a cell cycle model in Budding Yeast • Introduction • Cell Cycle Model of

Approximation of a cell cycle model in Budding Yeast

• Introduction • Cell Cycle Model of Budding Yeast Constant Input Response (CIR) of the Full Model • Proposed Method • Preprocessing: Jacobian-based Local Refinement (JLR) • Initialization of the Genetic Algorithm (GA)

• Results and Discussions Comparison between 2 Scenarios for Substitution of Excluded States

Results of Substitution Excluded States with Mean Values • GA with Parameter Estimation

Results of the GA with Parameter Estimation • Conclusion and Future Works

Presented by Chaiyut Thanukaew

1

Introduction • Molecular mechanisms in biological systems are complex and have dynamic interactions. • To express
Introduction • Molecular mechanisms in biological systems are complex and have dynamic interactions. • To express

Introduction

• Molecular mechanisms in biological systems are complex and have dynamic interactions. • To express behaviors of a system, often a set of nonlinear ODEs is occupied. • Since normally huge models, mathematical model reduction is used to gain insight into the models and reduce computational cost.

There are 36 ODEs, 25 algebraic equations and 139 parameters in the cell cycle model of budding yeast.

• The reduced model must retain essential features of the full model, traditionally, the trajectories of certain state variables. Moreover, it must comply with viability criteria.

• For the cell cycle model of budding yeast, responses of the mass regarding external input is decided to be the preserved characteristic .

  • Objective: to minimize the number of states with preserving certain characteristics

of the model by using genetic algorithm.

Cell Cycle Model of Budding Yeast (1) S p indle Nuclear Formation Migration 4 phases of
Cell Cycle Model of Budding Yeast (1) S p indle Nuclear Formation Migration 4 phases of

Cell Cycle Model of Budding Yeast (1)

S p indle Nuclear Formation Migration 4 phases of eukaryotic* cell cycle; G1-, S-, G2- and
S
p
indle
Nuclear
Formation
Migration
4 phases of eukaryotic* cell cycle; G1-, S-, G2-
and M-phase.
• G1 or Gap1 phase: the cell grows.
G2
Chromosome
M
Segregation,
• S or DNA synthesis: the cell makes
copies of its chromosomes and get ready
to divide.
DNA
Nuclear
S
Replication
Division
• G2 or Gap2 phase: the cell check the
duplicated chromosomes.
Bud
G1
Emergence
Cytokinesis
(Cell Division)
• M or Mitosis phase: the cell separates the
copies chromosomes into 2 full sets and
the cell divides into 2 new cells
Spindle
Pole, Body
Duplication
Start
Growth
How to know which mechanisms of the cell cycle
take place at what time?
CDK-Cyclin** is a protein active in regulating
Figure 1: Cell Cycle of Budding Yeast
the cell cycle.

* Eukaryote is a cell with visible nucleus e.g. yeast and mammal. ** Cyclin Dependent Kinase and Cyclin

3

Cell Cycle Model of Budding Yeast (2) Viability Criteria • Correct sequences, i.e. Budding  DNA
Cell Cycle Model of Budding Yeast (2) Viability Criteria • Correct sequences, i.e. Budding  DNA

Cell Cycle Model of Budding Yeast (2)

Cell Cycle Model of Budding Yeast (2) Viability Criteria • Correct sequences, i.e. Budding  DNA

Viability Criteria • Correct sequences, i.e.

Budding DNA synthesis

  • Mitosis Chromosome

segregation Cell division. • [mass] <= 10 all time.

Figure 2: Consensus Model of Budding Yeast

Constant Input Response (CIR) of Full Model (1) CIR definition: “ For each added constant input,
Constant Input Response (CIR) of Full Model (1) CIR definition: “ For each added constant input,

Constant Input Response (CIR) of Full Model (1)

CIR definition: “For each added constant input, the CIR is the amplitude and time of the

mass state such that it becomes stable while, also, the whole model must comply the

viability criteria”.

Constant In ut added to the state 5 (Sic1)

p

;

d Sic

[

1]

dt

(

k

'

s c

,

1

k

"

s c

,

1

.[

Swi

5]) (

V

d b

,

2

k

di b

,

2

).[ 2] (

C

V

d b

,

5

k

di b

,

5

).[ 5]

C

k

pp c

,

1

.[

Cdc

14].[ 1 ]

Sic P

k

( as, b 2.[

Clb

2

k

] as, b 5.[

Clb

5

] Vkp, c1).[

Si

c 1 ]

K

added

Constant Input Response (CIR) of Full Model (1) CIR definition: “ For each added constant input,

Added constant input

Why adding at [Sic1]?

  • As Sic1 is a regular cyclin subunit called st oichiometric CDK inhibitor, directly adding

a constant signal, physically, would mean putting some substances to boost up some

activities of the cell cycle, e.g. going faster into the G1-phase.

How to notice the response of the budding yeast model after adding up the constant

signal to the Sic1 state?

  • The easiest answer is to measure how the mass physically reacts to this

perturbation.

Constant Input Response (CIR) of Full Model (2) Response of the mass to different constant inputs
Constant Input Response (CIR) of Full Model (2) Response of the mass to different constant inputs

Constant Input Response (CIR) of Full Model (2)

Response of the mass to different constant inputs

Constant Input Response (CIR) of Full Model (2) Response of the mass to different constant inputs
 

Mass Stable

K added

Time

Amplitude

0.035

~ 520

~ 3

0.15

~ 190

~ 5

0.245

~ 460

~ 8

0.30

 

Inviable

6

Figure 3: The mass state when different constant inputs are applied

Proposed Method (1) The full model is written as;  x  f ( x ,
Proposed Method (1) The full model is written as;  x  f ( x ,

Proposed Method (1)

The full model is written as;

x f ( x , p )

We rewrite the full model as;

x f ( x , s , p )

Where;

x: the vector of states

p: the vector of parameters, and

s: a vector where s i is “1” when the i-th state is included in the model

(“0” if excluded).

Objective

The reduced model

*

x f x s p

(

,

,

)

is defined such that its solution x

*

minimizes

the cost function

, i.e.

reduction

( x ) min

sS

reduction

( x )

Where;

: the cost function, and

S : the set of all vectors of length N f (Number of states of the full model)

whose entries are “0” or “1”.

7

Proposed Method (2) Cost Function The cost function  is defined as;    
Proposed Method (2) Cost Function The cost function  is defined as;    

Proposed Method (2)

Cost Function

The cost function

is defined as;

 

1

1. 1.

CIR

X is not oscillatory or inviable.

X is oscillatory and viable.

  • Not count reduced models with negative cost as feasible solutions.

Where;

The relative model size is,

N

r

N

f

the number of states in the reduced model the number of states in the full model
the number of states in the reduced model
the number of states in the full model
Proposed Method (3) Where (continued); The CIR error is computed as the least square distance between
Proposed Method (3) Where (continued); The CIR error is computed as the least square distance between

Proposed Method (3)

Where (continued);

The CIR error is computed as the least square distance between one of the

full and one of the reduced model as following;

CIR

N per 2 2  ( x ( ) i  x ( )) i 
N
per
2
2
(
x
( )
i
x
( ))
i
(
y
( )
i
y
( ))
i
F
R
F
R
i  1
N
per
2
2
x
( ) 
i
y
( )
i
F
F
  • i 1

x F and y F represent the positions of the CIR of the full model when

different constant inputs are applied,

N per is the maximum number of different constant inputs for which the

full model is still oscillatory and viable, and

x R and y R represent the positions of the CIR for the reduced model

regarding different constant inputs added.

Proposed Method (4) Generation “n” Generation “0” Randomly generate an individual Do linear ranking of all
Proposed Method (4) Generation “n” Generation “0” Randomly generate an individual Do linear ranking of all

Proposed Method (4)

Generation “n” Generation “0” Randomly generate an individual Do linear ranking of all individuals Jacobian-based local
Generation “n”
Generation “0”
Randomly generate an
individual
Do linear ranking of all
individuals
Jacobian-based local
refinement (JLR)
Copy 2 best individuals
from the previous
generation (Elitism)
Calculate cost of each
individual
Random selection 2
parents acc. to their ranks
Crossover and mutation
Total N i individuals
Jacobian-based local
refinement (JLR)
Figure 4: Flowchart of the GA
Calculate cost of each
offspring
Applying to Reduce the Model
Total N i individuals

Replacement

(till reaching

setting “n” or

satisfied cost

value or no

improvement

after some time)

10

Preprocessing : JLR (1) Jacobian matrix and JLR  The matrix of all first-order partial derivat
Preprocessing : JLR (1) Jacobian matrix and JLR  The matrix of all first-order partial derivat

Preprocessing : JLR (1)

Jacobian matrix and JLR

  • The matrix of all first-order partial derivatives of a vector-valued function returning

relationship between equations in a system regarding that vector-valued function.

  • JLR uses information from Jacobian matrix for local refinement.

Considering the following equation;

~

J J diag ( J )

Where,

J: the Jacobian matrix, and

diag(J): all diagonal elements of the Jacobian matrix.

If there is any row in

~

J

such that all elements are zeros input-only state, and

 

~

If there is any column in

J

such that all elements are zeros output-only state.

  • Can leave out the input- and output-only states because of redundancy, e.g. the input-

only state can be substituted by a constant and the output-only state can be indirectly

obtained by some other states.

Preprocessing : JLR (2) Index table of the original cell cycle model Input-only states ~ Table
Preprocessing : JLR (2) Index table of the original cell cycle model Input-only states ~ Table

Preprocessing : JLR (2)

Index table of the original cell cycle model

Input-only states ~ Table 1: Index Table J  J  diag ( J ) of
Input-only
states
~
Table 1: Index Table
J  J  diag ( J )
of the Cell Cycle Model
Output-only
12
states
Initialization of the GA (1) Problem: Very hard to obtain individuals being oscillatory and viable in
Initialization of the GA (1) Problem: Very hard to obtain individuals being oscillatory and viable in

Initialization of the GA (1)

Problem: Very hard to obtain individuals being oscillatory and viable in the gen. “0”.

Reasons would be as following;

Generating individuals by rounding a random number of uniform distribution

causing that half of the number of bits is “0” in average (18 from 36 bits). There is

the problem, e.g. assume that oscillatory individuals must comprise of at least 26

states, thus it is hard to obtain this number.

The generated individuals lack of some crucial states, e.g. mass and some states of

cyclins. Thus, leaving out only one of these states causes the reduced models non-

oscillatory or inviable.

Solution introduce preconditions to generates the individuals in the initial generation

of the GA.

Initialization of the GA (3) Example: Feasible individual generated in gen. “0” with preconditions bit 1
Initialization of the GA (3) Example: Feasible individual generated in gen. “0” with preconditions bit 1

Initialization of the GA (3)

Example: Feasible individual generated in gen. “0” with preconditions

bit 1

bit 2

bit

3

bit 4

bit

5

bit 26

bi t 27

bi t

33

bit

34

bit

35

bit

36

1

R

R

  • 1  

  • 1  

  • State 1: set to “1” (mass)

  • State 3 and 4: randomly generated

  • State 4: set to “1” (viability concerned)

  • State 5: set to “1” (constant input added)

  • L  

  • State 26, 27: likely set to “1s” (only missing

  • L one state, non-oscillatory)

  • 1

  • 1  

  • 1  

1

State 33, 34, 35 and 36: set to “1s”

(viability concerned)

Figure 5: Example of Generating a Feasible Individual in Gen. “0”

14

Comparison between Zero VS Mean-valued Sub. 2 scenarios of substitution an excluded state; • Substitution with
Comparison between Zero VS Mean-valued Sub. 2 scenarios of substitution an excluded state; • Substitution with

Comparison between Zero VS Mean-valued Sub.

2 scenarios of substitution an excluded state;

• Substitution with zero: the excluded states is completely cut away, and

• Substitution with mean value: the excluded state still has influence, but not

dynamic behavior.

 

Case #1

Case #2

Case #3

Representation

Binary bit string

Binary bit string

Binary bit string

Population Size

80

100

80

Fitness Assignment

Linear ranking

Linear ranking

Linear ranking

Selection

Fitness-based

Fitness-based

Fitness-based

Crossover

Uniform

Uniform

2-point

Mutation

Bit mutation prob.=0.1

Bit mutation prob.=0.1

Bit mutation prob.=0.1

Replacement Scheme

Whole population replacement with elitist

Whole population replacement with elitist

Whole population replacement with elitist

no.=2

no.=2

no.=2

Table 2: Parameter Setting of 2 Substitution Scenarios

15

Results : Comparison between Zero VS Mean-valued Sub. The best result re garding Table 3 comes
Results : Comparison between Zero VS Mean-valued Sub. The best result re garding Table 3 comes

Results : Comparison between Zero VS Mean-valued Sub.

The best result regarding Table 3 comes from the mean-valued substitution

 

2. Reduced model with mean-valued substitution

Case #1

Case #2

Case #3

Total State No.

23

24

25

Total Cost

0.7244

0.7521

0.7754

Table 3: Results of Mean-valued Substitution

  • Model reduction with mean-valued substitution is accredited for further

simulations since it returns the better cost value (the lower value).

  • The total state number can be subtracted 3 because the states 34, 35, 36 are

output-only states added to determine the viability (see slide 12).

  • Not obvious seen difference between eac h case of the same substitution

scenario even population size and crossover strategy are varied.

Results : Mean-valued Substitution (1) Table 4: Results of Mean-valued Substitution from Several Simulations Purpose: 
Results : Mean-valued Substitution (1) Table 4: Results of Mean-valued Substitution from Several Simulations Purpose: 

Results : Mean-valued Substitution (1)

Results : Mean-valued Substitution (1) Table 4: Results of Mean-valued Substitution from Several Simulations Purpose: 

Table 4: Results of Mean-valued

Substitution from Several Simulations

Purpose: to prove that the results

do not come from local minima .

• The best reduced models “S1” and

“S2” contains 23 states.

• Although, different number of

states for each result, all results are

somehow in the same pattern (blue

highlight).

• If fixing highlight areas, the best

result can be obtained from varying

of 10 bits in non-highlighted areas

(search space is reduced).

• Further test “S1” and “S2”

comparing their responses to one of

the full model .

17

Results : Mean-valued Substitution (2) The cell cycle of the full model VS the cell cycle
Results : Mean-valued Substitution (2) The cell cycle of the full model VS the cell cycle

Results : Mean-valued Substitution (2)

The cell cycle of the full model VS the cell cycle of the reduced model

Results : Mean-valued Substitution (2) The cell cycle of the full model VS the cell cycle
“ ”

S1

in Table 4

Figure 6: Cell Cycle of the Full Model VS Cell Cycle of

  • Cell cycle of “S2” is very similar to “S1” except that Clb2T is higher (max. nearly 1.5).

18

Results : Mean-valued Substitution (4) Reduced model “S1” as t he Jacobian index table : Excluded
Results : Mean-valued Substitution (4) Reduced model “S1” as t he Jacobian index table : Excluded

Results : Mean-valued Substitution (4)

Reduced model “S1” as the Jacobian index table

: Excluded states (non- dinamic) : Substituted by constant : Non-zero Jacobian 19
: Excluded
states (non-
dinamic)
: Substituted
by constant
: Non-zero
Jacobian
19

Table 5: Reduced Model “S1” Substituting in the Jacobian Index Table

Results : Mean-valued Substitution (4) Reduced model “S1” as t he Jacobian index table Table 6:
Results : Mean-valued Substitution (4) Reduced model “S1” as t he Jacobian index table Table 6:

Results : Mean-valued Substitution (4)

Reduced model “S1” as the Jacobian index table

Results : Mean-valued Substitution (4) Reduced model “S1” as t he Jacobian index table Table 6:

Table 6: Jacobian Index Table of the Reduced Model “S1”

Note: State 24 (Tem1) is input-only state but cannot be left out since it

involves resetting parameters.

20

GA with Parameter Estimation (1) Idea: number of feasible solutions might be increased if the thresholds
GA with Parameter Estimation (1) Idea: number of feasible solutions might be increased if the thresholds

GA with Parameter Estimation (1)

Idea: number of feasible solutions might be increased if the thresholds of determination

the viability criteria are changed.

Implementation method: to put 4 more bits representing real value numbers used as the

thresholds of the viability determination.

Representation

Representation

36

Binary bit strings and 4 positive real values

Population size

Population size

80

Fitness assignment

Fitness

assignment

 

Linear ranking

Selection

Selection

 

Fitness-based

Crossover

Crossover

Uniform crossover with prob. = 0.5 (crossover in the parameter part is

substituted by the median values of the parents)

Mutation

Mutation

Bit mutation with prob. = 0.1 and normal distribution added with the

previous value in the parameter part

Replacement

Replacement

Whole population replacement with elitist no. = 2

Scheme

Scheme

Table 7: Parameter Setting of the GA with Parameter Estimation

21

Results: GA with Parameter Estimation Results of the GA with Parameter Estimation Reduced Model with Parameter
Results: GA with Parameter Estimation Results of the GA with Parameter Estimation Reduced Model with Parameter

Results: GA with Parameter Estimation

Results of the GA with Parameter Estimation

 

Reduced Model with

Parameter Estimation

Round#3

Round#3

Ind.1

Ind.2

Kez (0.3)

  • 0.4572 0.4242

 

Kez2 (0.2)

  • 0.1720 0.2485

 

Thres. 0.1

  • 0.1050 0.0806

 

Thres. 1

  • 0.6481 0.9425

 

Total State

24

25

No.

Total Cost

0.7765

0.7954

Discussions

The results are not better than the results with no

parameter estimation. The reasons would be as

following;

• Inappropriate estimation of “Thres. 1”

because it is used as the threshold for 3 states

[ORI], [BUD] and [SPN],

• Newly estimated parameters cannot lead

feasible individuals into optimal region in the

search space, and

• New parameters are generated by the normal

distribution with a small variance.

Table 8:The 2 Best Result of GA with Parameter

Estimation (from 3 times of simulation)

22

Conclusion and Further Works • The best result contains 23 states. 3 mo re states can
Conclusion and Further Works • The best result contains 23 states. 3 mo re states can

Conclusion and Further Works

• The best result contains 23 states. 3 more states can be ignored because of the

output-only states.

• Appropriate GA’s parameters might increase efficiency of the simulation, e.g. lessen

the computational time, explore the search space intelligently.

• The GA hybridizes with the Jacobian-based local refinement can reduce

unnecessary computation, e.g. the GA with JLR in this work.

• Although GA can be applied to resolve a given problem without prior knowledge of

such that problem, initialization of the GA is applied to this problem because of

physical reality and model constraints.

• Further works would be to study more about the GA with parameter estimation and to

combine other strategies of model reduction to the GA, e.g. to lump 2 continuous states

together.

1 2 3
1
2
3
Conclusion and Further Works • The best result contains 23 states. 3 mo re states can
1 2 3
1
2
3

Thank You

23

Appendix A : CIR of the Full Model Fi g ure A . 1: CIR of
Appendix A : CIR of the Full Model Fi g ure A . 1: CIR of

Appendix A : CIR of the Full Model

Appendix A : CIR of the Full Model Fi g ure A . 1: CIR of
Appendix A : CIR of the Full Model Fi g ure A . 1: CIR of

Figure A.1: CIR of the full model such

Fi

ure A 2: CIR of the full model such

 

g

.

that Kadded is increased 0.01 each

that Kadded is the median values of

time (from 0 to 0.28)

each group