and their Application to the Artificial Evolution of Genetic Regulatory Networks

Genetic Algorithms

Tutorial ICSB 2007

Johannes F. Knabe, Katja Wegner, and Maria J. Schilstra
University of Hertfordshire, UK

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Overview

Fundamentals

Biological evolution Evolutionary algorithms

Genetic algorithms

Modelling Gene Regulatory Networks (GRNs) Evolution of biological clocks with GRNs Evolution in NetBuilder
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Part 1: Fundamentals

Biological Evolution

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Biological Evolution

Evolution = change in the gene pool of a population over time Gene = hereditary unit - can be passed on unaltered for many generations Gene pool = set of all genes in a species or population

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Biological Evolution - Example

English moth, Biston betularia:

Two color morphs: light and dark 1848 dark moths <= 2% of the population Frequency of the dark morph increased:
industrialized areas

1898 95% were dark in Manchester and other highly Soot from factories darkened birch trees the moths landed on Birds could see the ligther colored moths better and
ate more of them more dark moths survived
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Why? natural selection

http://www.talkorigins.org/faqs/faq-intro-to-biology.html

Biological Evolution contd

Natural selection:

Favors those species for further survival and evolution that are best adapted to their environment see English moth

Population is evolving ratio of different genetic types is changing and new types are created

Not each individual !!

Darwin:

Evolution through random variations of heritable characteristics and natural selection

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Evolutionary cycle : Generation

Selection
Parents Recombination Population Mutation

Replacement

Offspring
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Dictionary 1

Gene smallest unit with genetic information Genotype collectivity of all genes Phenotype expression of genotype in environment Individual single member of a population with genotype and phenotype Population set of several individuals Generation one iteration of evaluation, selection and reproduction with variation
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Selection and Reproduction

Selection does not act on genotype at all but on the performance of the phenotype (fitness) There is differential reproduction phenotypes better adapted to the environment are likely to produce more offspring Slightly unfaithful reproduction creates genotypic variations affect traits of the phenotype, which in turn affect fitness These genotypic variations are heritable

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Recombination (crossover)

Choose two individuals from current population parents New combination of the genetic material of these individuals offspring No new genetic information, only reshuffling of existing information But can have strong effects on phenotype
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http://student.biology.arizona .edu/honors2001/group12/int roduction.html

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Duplication
http://en.wikipedia.org/wiki/Gene_duplication 11

Any doubling of a certain region, e.g. through unequal recombination If this region consists of a gene, it is called gene-duplication

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Mutation

http://www.biocrawler.com/encyclopedia/Mutation

Permanent changes to genetic material

Can be caused by errors during reproduction of DNA

Mutation rate: i.e. 1 in 10.000 bases is incorrectly reproduced

Brings variability into reproduction

Usually small changes at individual level but strongly depends on importance of mutated base to phenotype
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The Evolutionary Mechanisms

Selection and differential reproduction DECREASE diversity in population Genetic operators (mutation, recombination) INCREASE diversity of population

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Part 1: Fundamentals (2)

Evolutionary Computation Genetic Algorithms (GA)

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Evolutionary Computation

Evolutionary Computation

Exploitation of concepts of natural evolution for problem solving using computers Simulation of evolutionary processes (recombination, mutation, selection) for solving a desired problem Particularly well-suited to complex, multidimensional problems too big to search exhaustively (non-linear optimization problems) Cannot solve all problems perfectly, but has fewer restrictions than most problem-solving algorithms
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Optimization

Finding the best solution to a problem Mathematically: finding the minimum or maximum of a function (optimum)
Maximum

Minimum
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Optimization - Problems

Example: hill-climbing

Start with estimate of global maximum Try to improve by finding other solutions that have
a greater value than the current estimate (local search)

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Optimization - Problems

Example: hill-climbing

Start with estimate of global maximum Try to improve by finding other solutions that have
a greater value than the current estimate (local search)

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Optimization - Problems

Example: hill-climbing

Start with estimate of global maximum Try to improve by finding other solutions that have
a greater value than the current estimate (local search) Global
Local maximum maximum

Local maxima = hazards could converge to

local maximum instead of global
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Evolutionary cycle - revisited

(random) start population

Evaluation Population

End? Selection

Parents Recombination Mutation Offspring

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Replacement
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Dictionary 2

Individual - one candidate solution Population - set of individuals Genotype - encoded representation of individual Phenotype - decoded representation of individual Mapping - decodes the phenotype Mutation - variability operator that modifies a genotype Recombination/Crossover - variability operator mixing genotypes Fitness - performance of a phenotype with regard to objective Iteration - Generation
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EC - General properties

Exploit collective learning process of a population (each individual = one solution = one search point) Evaluation of individuals in their environment = measure of quality = fitness comparison of individuals Selection favors better individuals who reproduce more often than those that are worse Offspring is generated by random recombination and mutation of selected parents
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Main trends

Genetic algorithms (GAs) Genetic programming (subform of GAs) Evolutionary strategies (ES) Evolutionary programming (EP)

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Genetic Algorithms

GAs - Simple Example

Simple example f(x) = x

Finding the maximum of a function:

f(x) = x Range [0, 31] Goal: find max (31 = 961) Binary representation: string length 5 = 32 numbers (0-31)

= f(x)
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F(x) = x - Start Population

binary String 1 00110 value 6 fitness 36

String 2
String 3 String 4

00011
01010 10101

3
10 21

9
100 441

String 5

00001

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F(x) = x - Selection
binary String 1 00110 value 6 fitness 36

String 2
String 3 String 4

00011
01010 10101

3
10 21

9
100 441

String 5

00001

Worst one removed

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F(x) = x - Selection
binary String 1 00110 value 6 fitness 36

String 2
String 3 String 4

00011
01010 10101

3
10 21

9
100 441

String 5

00001

Best individual: reproduces twice keep population size constant

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F(x) = x - Selection
binary String 1 00110 value 6 fitness 36

String 2
String 3 String 4

00011
01010 10101

3
10 21

9
100 441

String 5

00001

All others are reproduced once

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F(x) = x - Recombination

Parents and x-position randomly selected (equal recombination)

String 1 String 3

partner String 2 String 4

x-position 4 2

String 1:

0 0 1 1 0
0 0 0 1 1

0 0 1 1 1 0 0 0 1 0

String 2:

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F(x) = x - Recombination

Parents and x-position randomly selected (equal recombination)

String 1 String 3

partner String 2 String 4

x-position 4 2

String 3:

0 1 0 1 0
1 0 1 0 1

0 1 1 0 1 1 0 0 1 0

String 4:

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F(x) = x - Mutation
bit-flip:

Offspring -String 1: String 4:

00111 (7) 10111 (23)

10101 (21) 10001 (17)

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F(x) = x
All individuals in the parent population are replaced by offspring in the new generation
(generations are discrete!)

New population (Offspring):

String 1 String 2 String 3 String 4 String 5 binary 10111 00010 01101 10000 10001 value 23 2 13 16 17 fitness 529 4 169 256 289
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F(x) = x - End

Iterate until termination condition reached, e.g.:

Number of generations Best fitness Process time No improvements after a number of generations Best individual: 10111 (23) fitness 529
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Result after one generation:

F(x) = x - Animation

Java-Applet (html page) with examples

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GAs - General

Genetic algorithms

Differences to other search and optimization algorithms:

GAs search from a population of points

(possible solutions), not from a single point GAs use probabilistic, not deterministic rules

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History

In 1960s John H. Holland, University of Michigan:

Abstraction and generalisation of the

population concept with genetic coding and operators

Use in Bioinformatics, e.g.:

motif discovery, sequence alignment, protein structure prediction etc.

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Coding and Mapping

Genetic coding

Finite strings (= genome, represents genotype) Strings consists of units with information (unit = gene) One string ( individual) = one possible solution of the problem Genotype often real numbers or bit string:

1.853

0.492

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Genetic coding and mapping

What should the phenotype look like and how to encode it as a genotype? How does one map from genotype to phenotype, considering the sources of variation (mutation and recombination)?

Highly problem dependent! Hint: small changes to genotype should often result in small changes to phenotype, i.e. similar performance: heritability of traits! heritability of traits is important otherwise GA becomes only random search
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Mapping Example

Binary coding versus Gray coding of a number

Hamming distance:

Number of bits that have to be changed to map one string into another one E.g. 000 and 001 distance = 1

Remember: small changes in genotype should cause small changes in phenotype

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Mapping Example contd

Binary coding of 0-7 (phenotype):
0 1 2 3 4 5 6 7 000 001 010 011 100 101 110 111
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Mapping Example contd

Binary coding of 0-7 (phenotype):
0 1 2 3 4 5 6 7 000 001 010 011 100 101 110 111

Hamming distance, e.g.:

000 (0) and 001 (1)
Distance = 1 (optimal)

011 (3) and 100 (4)

Distance = 3 (max possible)

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Mapping Example contd

Gray coding of 0-7:
0 1 2 3 4 5 6 7 000 001 011 010 110 111 101 100
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Mapping Example contd

Gray coding of 0-7:
0 1 2 3 4 5 6 7 000 001 011 010 110 111 101 100

Hamming distance:
Two neighboring numbers (phenotypes) have always a genotype distance of 1 (all differ only by one bit flip) OPTIMAL mapping
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Mapping Example contd

Comparing kinship with distance = 1

Binary:

Gray:

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Selection

Selection

Based on fitness function:

Determines how good an individual is (fitness)

Better fitness, higher probability of selection

Selection of individuals for differential reproduction of offspring in next generation Favors better solutions Decreases diversity in population

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Selection - Roulette-Wheel

Each solution gets a region on a roulette wheel according to its fitness Spun wheel, select solution marked by roulette-wheel pointer stochastic selection (better fitness = higher chance of reproduction)
http://www.edc.ncl.ac.uk/highlight/rhjanuary2007g02.php

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Selection - Elitism

Individual(s) kept unchanged for next population Example:

Selection based on fitness values Keep the best individual of current population unrealistic but ensures best fitness of a
generation never decreases decrease of diversity
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Selection - Tournament

randomly select q individuals from current population Winner: individual(s) with best fitness among these q individuals Example:

select the best two individuals as parents for

recombination
q=6
selection

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Genetic variability operators

Mutation

Varies details, usually exploitive Changes one position in the string

each position same small probability of undergoing a mutation

Goal: search around existing good solution, possibly leave local optima
1.853 1.807

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Recombination/Crossover

Usually explorative Creates new strings by combining parts of two existing strings

Parents:

0 1 1

1 1 0

Offspring:

0
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Recombination
Unequal:
Crossover points independent for each string chosen

Parents:

0 1 1

1 1 0

Offspring:

1
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Fitness

Fitness function

Nature:

only survival and reproduction count how well do I do in my environment

Defined by kinship of genotypes and fitness function Advantage: visual representation can be useful when thinking about model design Limitation: ideas might be too simplistic when not working on toy-problems - complex spaces and movements (think crossover!)

Fitness space structure:

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Fitness space or landscape

0110
0100 0000

0010
0001

0011

1100

1000

1001

Schema of genetic kinship

How we move in that landscape over generations is defined by our variability operators, usually mutation and recombination Now add fitness
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Fitness space or landscape

0110
fitness

0010
0001

0011

0100

0000

1100

1000

1001

Schema of genetic kinship

How we move in that landscape over generations is defined by our variability operators, usually mutation and recombination Now add fitness
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Fitness landscapes contd.

Every snowflake one individual, search focuses on promising regions (due to differential reproduction)
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Animation adapted from Andy Keane, Uni. Of Southampton

x/y axes: kinship, i.e. the more genetic resemblance the closer together z axis: fitness

Fitness space Good design

Easy to find the optimum by local search neighboring genotypes have similar fitness (smooth curve high evolvability)

Fitness

Genotypes
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Fitness space - Bad design

Here we will have a hard time finding the optimum Low evolvability (fitness is right/wrong) Either problem not well suited for GA or bad design

Fitness

Genotypes
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Fitness space Mediocre design

Many local optima, so we are likely to find one However not much of a gradient to find global optimum, random search could do as well

Fitness

Genotypes
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Dynamic fitness landscape

Animation by Michael Herdy, TU Berlin

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Fitness does not need to be static over generations Can allow to reach regions otherwise uncovered Natural fitness certainly very dynamic
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Design issues

Integrating problem knowledge

Always to some degree in representation/ mapping Create more complex fitness function Start population chosen instead of a uniform random one

Useful e.g. if constraints on range of solutions Possible problems: Loss of diversity and bias
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Design decisions

GAs: high flexibility and adaptability because of many options:

Problem representation Genetic operators with parameters Mechanism of selection Size of the population Fitness function

Decisions are highly problem dependent Parameters not independent, you cannot optimize them one by one
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Hints for the parameter search

Find balance between:

Exploration (new search regions) Exploitation (exhaustive search in current region) Parameters can be adaptable, e.g. from high in the beginning (exploration) to low (exploitation), or even be subject to evolution themselves

Balance influenced by:

Mutation, recombination:

create indiviuals that are in new regions (diversity!!) fine tuning in current regions
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Selection: focus on interesting regions

Keep in mind

Start population has a lot of diversity Invest search time in areas that have proven good in the past Loss of diversity over evolutionary time Premature convergence: quick loss of diversity poses high risk of getting stuck in local optima Evolvability:

Fitness landscape should not be too rugged Heredity of traits Small genetic changes should be mapped to small phenotype changes

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Wrapping up Part 1

GA- Summary

Selection:
Focus on fittest individuals Adds alternative solutions to population Makes sure that most of the search space is reached

Recombination:

Mutation:

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GA- Summary cont'd

Advantages: Basic method simple and broadly applicable No need for very detailed understandung of the problem But can be adjusted to problem if knowledge present Fast and can be scheduled in parallel Disadvantages: No guarantee to find best solution High computational demands Adapting to problems at hand can be hard, e.g. finding suitable representation/mapping and evolutionary operators Search can get caught in local optima
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More recent inputs from Biology

Populations are spatial, e.g. for speciation interaction (mating, competition) localized to maintain diversity Populations have structure, e.g. niche protection competition will be stronger if many individuals do the same to maintain diversity Diploidy with dominance / recessivity N-point crossover and other variants Morphogenesis instead of simple function mapping (allowing for modularity, making crossover less fatal)
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Part 2: Modelling GRNs

Gene Regulatory Networks (GRNs)

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Evolutionary cycle - again

(random) start population End? End? Selection Parents Parents
Recombination Mutation

Population Population
Replacement

Offspring Offspring
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Evolutionary cycle - again

(random) start population End? End? Selection Parents Parents
Recombination Mutation

Population Population
Replacement

Offspring Offspring
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Selection

Selection based on comparison of individual phenotypes with target phenotype For phenotype read: input/output system

Individual strings in population contain

parameter sets Each parameter set is used to build a different input/output system

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Decoding, Evaluating, Comparing

Decoding

info string 1

info string 2

info string 3

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Decoding

info string 1

System 1

info string 2

System 2

info string 3

System 3

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Evaluating
Input

System 1 Output 1 System 2 Output 2 System 3 Output 3

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Comparing

Output 1

Output 2

Compare wrt
Target

Output 3

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Decoding, Evaluating, Comparing

Input

info string 1

System 1 Output 1

info string 2

System 2 Output 2

Compare wrt
Target

info string 3

System 3 Output 3

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Decoding, Evaluating, Comparing

(Input) info string 1 System 1 Output 1

Decoding rules

Example F(x) = x2

Info

Rules 27

System f(x)

Input -

Output 729

Target Max

11011

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Decoding, Evaluating, Comparing

(Input) info string 1 System 1 Output 1

Decoding rules

Example F(x) = x2 GRN

Info

Rules 27 build GRN

System f(x) GRN

Input -

Output 729

Target Max

11011
Connectivity; parameter values

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(Artificial) Genetic Regulatory Networks (aGRN)

GRNs and aGRNs

Genetic Regulatory Networks (GRN)

The basic control networks that underlie the development and responses of organisms Involve interactions between genes, RNA, proteins Input output transformation systems Built using concepts taken from GRN-theory assumptions on how GRNs work As (very crude) models of the real thing Interest in computational potential

Artificial Genetic Regulatory Networks

Why aGRNs?

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GRN-theory Central Dogma

DNA

(Transcription)

RNA

(Translation)

Protein

(Reverse transcription)

Information flow

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GRN-theory Central Dogma

Control

DNA

(Transcription)

RNA

(Translation)

Protein

(Reverse transcription)

Information flow

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GRN Control

Control of gene expression

Standard notation
Promoter

DNA
Coding region Non-coding region

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Control of gene expression

Single gene
Promoter: Starting point for transcription

Upstream region: Often contains interaction points for Transcription Factors: proteins that repress or activate transcription

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Control of gene expression

TFx (activator) TFy (repressor)

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Control of gene expression

Genetic Regulatory Network
External factors (signals, maternal proteins, )

No limit to number of activators or repressors Protein that acts as an activator for one gene may act as a repressor for another

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GRN Dynamics

Dynamics: Petri-net notation

Messenger RNA dynamics

mRNA

RNA building blocks STRI, University of Hertfordshire 99

Dynamics: Petri-net notation

Messenger RNA dynamics
Factors affecting transcription rate Factors affecting breakdown rate

mRNA

transcription, modification, transport RNA building blocks STRI, University of Hertfordshire

breakdown

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Symbols: Nodes
State, Store, Place,

SBML: Species

Transition, Process,

SBML: Reaction

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Symbols: Arrows

Function of connected species:

Modifier, Inhibitor, Repressor, Activator, Enhancer,

SBML: ModifierSpecies

Function of connected species

SBML: Reactant
Input,

Funcion of connected species:

SBML: Product
Output,

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Dynamics: what happens?

mRNA production

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Dynamics: what happens?

mRNA production

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Dynamics: what happens?

mRNA production

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Dynamics: what happens?

mRNA breakdown

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Dynamics: what happens?

mRNA breakdown

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Dynamics: what happens?

mRNA breakdown

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Dynamics: what happens?

No activator, no production

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Dynamics: what happens?

No activator, no production

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Worth remembering (1)

Reactant - Consumed during reaction

Reactant stoichiometry > 0 Product stoichiometry > 0

Product - Produced during reaction

Modifier - Neither: only affects reaction rate

Stoichiometry = 0 Dependence defined in the reactions rate equation

(SBML: KineticLaw; transfer function, ) Shape of rate equation depends on process (and how much we know about it)

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Dynamics
Messenger RNA and protein product dynamics

mRNA

protei n

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Dynamics
Messenger RNA and protein product dynamics

protein

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Worth remembering (2)

Constant production without breakdown:

Amount will increase linearly over time

exceptions)

Production plus breakdown:

Amount will reach plateau (usually; there are In general: breakdown processes determine

Time to reach plateau determined by breakdown rate, not production rate

how rapidly a system can respond (adapt) to new external conditions

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Combining control and dynamics

Creating a dynamic GRN model Questions (1)

Aim:

Model as realistic as possible? Computational tool? Control network? Genes (if so: what do they represent)? Transcription factors? Other regulators (e.g. regulatory RNA)? Intermediates (e.g. mRNA)? Signals? Transcription? Translation? Breakdown? Signalling?

GRN constituents

Processes to incorporate Multicellularity

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Creating a dynamic GRN model Questions (2)

Equations that describe process dynamics

Mass-action type rate equations? Saturable? Additive? Logical? Continuous? Discrete multivalued? Boolean (if so: what do 0 and 1 represent)? Continuous? Discrete? Numerical integration of rate equations (if so: stochastic or deterministic)? Finite state automaton? Boolean switching?

Rules for (combined) effects of regulatory interactions

Numerical representation of component values

Representation of time
Evaluation method

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Basic GRN model

Control

Dynamics
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Possible dynamic representation

Rate equations
Product production rate:

v k f ( modifiers ) p p
Product breakdown rate:

v [P ] b k b
Plateau value (steady state):

k p [ P ] f ( modifiers ) k b
kp, kb: production and breakdown rate constants [x]: concentration or amount of species x P: gene product

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Rules for activation and repression

Saturable activation:
p m [ M ] p 1 m [ M ] S ,A

Saturable repression:
1 S , R p 1 m [ M ]

Linear activation:
L ,A m [ M ]p

Linear repression:
L ,R p m [ M ]

m: multiplier p: exponent

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Rules for combinatorial modifier effects

Logical disjunction (or) (saturable):
S S S f ( modifiers ) ( 1 ) 1 2 1 S S f ( modifiers ) 1 2

Logical conjunction (and) (saturable):

S S f ( modifiers ) 1 2 S S f ( modifiers ) 1 2

Addition, multiplication (linear):

L L f ( modifiers ) 1 2 L L f ( modifiers ) 1 2

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Note on GRN representation

No single proper representation method Chosen method depends on aim of study and personal preference However, be aware of:

the way your representation relates to the real thing the type of simplifications that have been made

Tips:

usually, amounts or concentrations do not have negative values simple negative feedback systems are often oscillatory, but the oscillations may well disappear when using smaller time steps, or a less crude representation

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Part 3: Evolving biological clocks

with artificial genetic regulatory networks (aGRNS)

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Introduction

Biological clocks abound in all organisms, even the simplest single celled ones like Gonyaulax' (red tide organism): characteristic example of responsiveness of life on earth
Evolvability of Genetic Regulatory Networks (GRNs) as a paradigm for novel computation

developmental mapping parallelism

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Schematic drawing

Note: no proper genotype/phenotype distinction is made in this drawing!

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Schematic drawing - Phenotype

A gene is a gene-node in a regulatory network here This is the phenotype!!!

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What does a gene-node consist of?

module binding site binding site activatory/inhibitory Protein produced activation type

... + / - ...

gene-node

binding sites: protein input from other genes module: grouping of inputs any number of binding sites, any number of modules one protein output type and one activation type
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Encoding of gene-nodes and genome

Genome consists of a number of genes plus a compartment coding parameters global to the cell '0'/'1' code, '2' module boundary, '3' gene boundary; used for compartmentalization
encodes one gene-node

0210013

010111021101020011113
gene delimiter

0110011

module boundary

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Encoding of gene-nodes and genome contd

Two modules:
1) inhibitory (starting with 0) binding a combination of proteins 5 (101) and 6 (110) 2) activatory cis-module (starting with 1) to which protein 5 (101) will bind.

gene activation type modules 1) and 2) output binding sites b. site protein

010111021101020011113
regulator type junk (ignored bits)

Last three zeros of 11010200 are ignored junk. Will produce protein 7 (111) and is off by default (last bit is 1).

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Activation

binding sites: AND(

modules: OR( gene (activiation function):
activation increases one protein level
+ + -

protein levels: (global, 8 here)

7
131

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Activation contd

As protein values are not boolean, AND is actually minimum and OR is a sum, but effect very similar

every gene is either of constituitive (default on, dotted line) or induced (default off, continuous line) type
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Gene-node activation example

protein 5: 20 per site and type 6: 1 per site bind

binding sites: modules:

5:20

6:1
-

[=1] [-1]

5:20

[=20]

+ [+20]

gene: (activation function f)

[f(-1+20)=~125]
activation increases

protein level:

7:+125
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Environmental in-/output

simple protein in-/output periodic functions used:

input 1)-4), 400 time steps wavelength 20 time steps

variations with perturbations: +/- noise with std. dev. 0.1 +/- 2x blackout of 20 steps desired behaviors 1) or 3) closeness of match = fitness
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Selection and Variation

Tournament selection:

15 individuals randomly picked from population,

best two of them chosen as parents weak elitism (only the best individual copied over)

Mutation:

1% chance for every bit to flip 0->1, 1->0

Recombination:

unequal crossing over, always two parents for two

children Length of genes might change, number of genes is held constant in these experiments
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Recombination

Unequal crossing-over allows for genomes of varying length, important for varying number of binding sites and modules Unequal crossover point is shifted by an offset Note that offset always stays within the compartment, so all crossover point genes but one are kept intact 0210013

010111021101020011113 1100110 110111021101020011113 0110011 +

parents
1102103

offset of 3

offspring

0210013

010111021 020011113 0110011

1102103 110111021 021101020011113 1100110

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Population development example

Can easily evolve to show cyclic behavior Genome length and junk length increase on average (average over 10 runs)

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Individual dynamics analysis

internalization of (quasi-) periodic behaviour in many cases the more unreliable the input the more this was found
two evolved GRNs getting out of synchrony when stimuli are missing

two evolved GRNs with extremely different internalized wavelengths

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Evolvability - Heterochronicity
slightly mutated variants

evolved wild type

all variants are one or two bit flips away from each other can allow heterochronic control: changes in timing are possible while preserving general dynamics remember: small genotype changes usually should cause small phenotype changes for smooth adaptation
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Differentiation schematic

Individual has two cells with same genome and almost same input, but different behavior required

Note: Again no clear seperation of genotype and phenotype in this drawing!

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Differentiation: two pathways

Same ultimate goal functions (periodic and inverse) but different fitness evaluations over initial generations

Immediate setting:

fitness is final objective from beginning: one cell reproduces phase of input while the other has to produce inverse

gradual setting:

fitness is initially the same phase reproduction from beginning, but target phase shifts for one of the cells over generations changing fitness landscape!
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Typical example runs for the two settings

1) immediate

2) gradual evaluation

Best results similar, but average much better for 2), robustly finds good results
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Part 4: Netbuilder'

a tool for construction, simulation and evolution of GRNS

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NetBuilder (Project Apostrophe)

A tool for construction modelling simulation (stochastic, deterministic, hybrid) evolution future: Analysis of GRNs Uses the Petri-net formalism
Download:

http://strc.herts.ac.uk/bio/maria/Apostrophe/
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NetBuilder NetBuilder

NetBuilder':

completely overhauled version different model visualisation more simulation and analysis methods
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NetBuilder - Petri net

bipartite graph place e.g. proteins (circle) transition e.g. reaction, gene (rectangle) arc - connection between a place and a transition (what is
consumed to produce what)

transition

place

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NetBuilder - GUI

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NetBuilder - GUI

Drawing area

arcs layers places transitions text objects

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NetBuilder - GUI

Table of attributes of an selected object

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NetBuilder - GUI

Model hierarchy

overview about which place/transition belongs

to which layer

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NetBuilder - GUI

Tool bar
open

new layer
save

print zoom

copy paste

new layer place

arc text

select rectangular delete region

transition

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Evolution in NetBuilder'

Based on Johannes' GA Differences:

Genotype: list of arcs, places, transitions,

parameters Phenotype: Petri net Mapping: Petri net construction Fitness: likeness to target function (sum square error)
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Genotype - Phenotype

Gene:

These arcs or nodes in a gene are fixed and cannot be removed by evolutionary operators but attributes can be adjusted

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Genotype Phenotype (2)

Network:

Activation and inhibition of protein production between genes Changeable

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Furthermore

Remember:

No limit to number of activators or repressors Protein that acts as an activator for one gene may act as a repressor for another

Mathematical description:

Automatically created by NetBuilder' or users add their own function to each transition

Environmental input:

Each place can have any input function (e.g. sine or step functions like in Johannes' GA)
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Selection

Tournament:

Select randomly 15 networks (default) The two best networks of these 15 are
recombined

Elitism:

By default the best network is kept in the next

generation (fitness never decreases)
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Recombination

Two networks recombined A gene and its arcs go into the child Probability: 90% (default)

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Mutations

Add or remove arcs

Increase or decrease arc attributes (e.g. arc weight = stochiometry)

Duplicate or remove genes (inluding arcs)

Increase or decrease transition rate Probability: 1% (default)

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Fitness
Fitness: Likeness between target function and current results protein

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Parameters

as adjustable as possible
General parameters:

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Parameters

as adjustable as possible
General parameters:

Probabilities:

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Parameters

as adjustable as possible
Probabilities:
General parameters:

Setting parameters to 0 turns operators off

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Summary NetBuilder'

Easy-to-use GUI
Free and open-source Create network, simulate (and evolve) it

Evolution adjustable to user's needs

Evolutionary algorithm in test phase now and will be available in NetBuilder soon !!
https://lists.sourceforge.net/lists/listinfo/apostrophe-users

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ICSB 2007 - Posters

For further discussions meet us at our posters (Tuesday and Wednesday):

Johannes: In Silico Evolution Of Biological Clocks With Genetic Regulatory Networks, F5 Katja: Netbuilder' - A Tool For The Modeling And Simulation Of Genetic Regulatory Networks, G8

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Acknowledgement

Chrystopher L. Nehaniv
Ralph Gauges Mark Robinson Slides:
http://strc.herts.ac.uk/bio/maria/Apostrophe/

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Resources

Evolutionary Algorithms
http://www.talkorigins.org/faqs/faq-intro-to-biology.html Evonet flying circus http://evonet.lri.fr/CIRCUS2/node.php The on-line tutorial on evolutionary computation http://www.lcc.uma.es/~ccottap/semEC/ Bck, T, Fogel, D B and Michalewicz, Z, ed.: Evolutionary Computation 1 & 2. Taylor & Francis 2000 Goldberg, D. E. Genetic Algorithms in Search, Optimization, and Machine Learning. Addison-Wesley 1989 Langdon, W.B. and Poli, R. Foundations of Genetic Programming. Springer 2002

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References

Evolving biological clocks with aGRNs

Knabe, J. F., Nehaniv, C. L. and Schilstra, M. J. Genetic Regulatory Network models of Biological Clocks: Evolutionary history matters. In Artificial Life, 2007 (in press). http://panmental.de/GRNclocks/ Knabe, J. F., Nehaniv, C. L. and Schilstra, M. J. Evolutionary Robustness of Differentiation in Genetic Regulatory Networks. In Proceedings of the 7th German Workshop on Artificial Life 2006 (GWAL7), pages 75-84, Akademische Verlagsgesellschaft Aka, Berlin, 2006. http://panmental.de/GWALdiff/ Knabe, J. F., Nehaniv, C. L. and Schilstra, M. J. The Essential Motif that wasn't there: Topological and Lesioning Analysis of Evolved Genetic Regulatory Networks. In IEEE Symposium on Artificial Life (CI-ALife'07), pages 69-76, Omnipress, 2007. http://panmental.de/GRNmotifs/ and references therein

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