Peter Schuster- Evolutionary Dynamics

8/3/2019 Peter Schuster- Evolutionary Dynamics

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Evolutionary Dynamics

A physicists view bridging from Darwin to molecular biology

Peter Schuster

Institut fr Theoretische Chemie, Universitt Wien, Austriaand

The Santa Fe Institute, Santa Fe, New Mexico, USA

BioScience Day

University of Maryland, College Park, 12.11.2008


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Web-Page for further information:

http://www.tbi.univie.ac.at/~pks


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1. Charles Darwins pathbreaking thoughts

2. Evolution without cellular life

3. Chemical kinetics of molecular evolution

4. Consequences of neutrality

5. Modeling optimization of molecules


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Populations adapt to their environmentsthrough multiplication, variation, andselection Darwins natural selection .

All forms of (terrestrial) life descendfrom one common ancestor phylogeny

and the tree of life .


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Three necessary conditions for Darwinian evolution are:

1. Multiplication,

2. Variation , and

3. Selection .

Biologists distinguish the genotype the genetic information andthe phenotype the organisms and all its properties. The genotype isunfolded in development and yields the phenotype .

Variation operates on the genotype through mutation andrecombination whereas the phenotype is the target of selection .

One important property of the Darwinian mechanism is that variationsin the form of mutation or recombination events occur uncorrelated totheir effects on the selection of the phenotype.


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t i m e

Charles Darwin,The Origin of Species , 6th edition.Everymans Library, Vol.811, Dent London, pp.121-122.


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Modern phylogenetic tree: Lynn Margulis, Karlene V. Schwartz.Five Kingdoms . An Illustrated Guide to the Phyla of Life on Earth . W.H. Freeman, San Francisco, 1982.


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The molecular clock of evolution

Motoo Kimura.The Neutral Theory of

Molecular Evolution . CambridgeUniversity Press. Cambridge, UK, 1983.


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RNA sample

Stock solution: Q RNA-replicase, ATP, CTP, GTP and UTP, buffer

Time

0 1 2 3 4 5 6 69 70

D.R.Mills, R.L.Peterson, S.Spiegelman, An extracellular Darwinian experiment with a self-duplicating nucleic acid molecule . Proc.Natl.Acad.Sci.USA58 (1967), 217-224

Application of serial transfer to RNA evolution in the test tube


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Reproduction of the original figure of theserial transfer experiment with Q RNA

D.R.Mills, R,L,Peterson, S.Spiegelman,

. Proc.Natl.Acad.Sci.USA(1967), 217-224

An extracellular Darwinian experiment with a self-duplicating nucleic acid molecule58


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Replication fork in DNA replication

The mechanism of DNA replication is semi-conservative


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Complementary replication isthe simplest copying mechanismof RNA.Complementarity is determinedby Watson-Crick base pairs:

G C and A=U


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Kinetics of RNA replicationC.K. Biebricher, M. Eigen, W.C. Gardiner, Jr.

Biochemistry 22 :2544-2559, 1983


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A point mutation is caused byan incorrect incorporation ofa nucleobase into the growingchain during replication:

plus strand U C

minus strand A G

Replication and mutation areparallel chemical reactions.


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Stock solution:

activated monomers, ATP, CTP, GTP,UTP (TTP);

a replicase, an enzyme that performscomplemantary replication;buffer solution

G.Strunk, T.Ederhof, Machines for automated evolution experiments in vitro based on the serial transfer concept .Biophysical Chemistry66 (1997), 193-202

F.hlenschlager, M.Eigen, 30 years later A new approach to Sol Spiegelmans and

Leslie Orgels in vitro evolutionary studies . Orig.Life Evol.Biosph.27 (1997),437-457


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Evolutionary design of RNA molecules

A.D. Ellington, J.W. Szostak,In vitro selection of RNA molecules that bind specific ligands .Nature346 (1990), 818-822

C. Tuerk, L. Gold,SELEX - Systematic evolution of ligands by exponential enrichment: RNAligands to bacteriophage T4 DNA polymerase . Science249 (1990), 505-510

D.P. Bartel, J.W. Szostak, Isolation of new ribozymes from a large pool of random sequences .

Science261 (1993), 1411-1418R.D. Jenison, S.C. Gill, A. Pardi, B. Poliski, High-resolution molecular discrimination by RNA .Science263 (1994), 1425-1429

Y. Wang, R.R. Rando,Specific binding of aminoglycoside antibiotics to RNA . Chemistry &Biology2 (1995), 281-290

L. Jiang, A. K. Suri, R. Fiala, D. J. Patel,Saccharide-RNA recognition in an aminoglycoside antibiotic-RNA aptamer complex . Chemistry & Biology4 (1997), 35-50


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An example of artificial selectionwith RNA molecules or breeding of biomolecules


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The SELEX technique for the preparation of aptamers through applied evolution


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tobramycin

RNA aptamer,n = 27

Formation of secondary structure of the tobramycin binding RNA aptamer withK D = 9 nM

L. Jiang, A. K. Suri, R. Fiala, D. J. Patel,Saccharide-RNA recognition in an aminoglycoside antibiotic- RNA aptamer complex. Chemistry & Biology4:35-50 (1997)


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The three-dimensional structure of thetobramycin aptamer complex

L. Jiang, A. K. Suri, R. Fiala, D. J. Patel,Chemistry & Biology4:35-50 (1997)


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A ribozyme switch

E.A.Schultes, D.B.Bartel, Science289 (2000), 448-452


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Two ribozymes of chain lengths n = 88 nucleotides: An artificial ligase (A) and a natural cleavageribozyme of hepatitis--virus (B)


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The sequence at theintersection :

An RNA molecules which is 88nucleotides long and can form bothstructures


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Two neutral walks through sequence space with conservation of structure and catalytic activity


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Application of molecular evolution to problems in biotechnology


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Artificial evolution in biotechnology and pharmacology

G.F. Joyce. 2004. Directed evolution of nucleic acid enzymes. Annu.Rev.Biochem . 73 :791-836.

C. Jckel, P. Kast, and D. Hilvert. 2008. Protein design bydirected evolution. Annu.Rev.Biophys . 37 :153-173.

S.J. Wrenn and P.B. Harbury. 2007. Chemical evolution as atool for molecular discovery. Annu.Rev.Biochem . 76 :331-349.


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Results from evolution experiments :

Replication of RNA molecules in vitro gives rise to exponentialgrowth under suitable conditions.

Evolutionary optimization does not require cells and occurs aswell in cell-free molecular systems.

In vitro evolution allows for production of molecules for

predefined purposes and gave rise to a branch of biotechnology.


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19771988

1971

Chemical kinetics of molecular evolution


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Chemical kinetics of replication and mutation as parallel reactions


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Formation of a quasispeciesin sequence space


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Uniform distribution insequence space


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Fitness landscapes showing error thresholds


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Error threshold: Individual sequences

n = 10, = 2 and d = 0, 1.0, 1.85,s = 491


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Molecular evolution of viruses


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Results from kinetic theory of molecular evolution :

Replicating ensembles of molecules form stationary populationscalled quasispecies , which represent the genetic reservoir ofasexually reproducing species.

For stable inheritance of genetic information mutation ratesmust not exceed a precisely defined and computable error-threshold.

The error-threshold can be exploited for the development ofnovel antiviral strategies.


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What is neutrality ?

Selective neutrality == several genotypes having the same fitness .

Structural neutrality == several genotypes forming molecules withthe same structure .

OCH 2O

N 1

5' - end


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OHO

PO

O

OO

CH 2

OHO

PO

O

O

N 2

OCH 2

OHO

PO

O

O

N3

OCH 2

OHO

PO

O

O

N 4

N A U G Ck = , , ,

3' - end

Na

Na

Na

Na

5'-end 3-endGCGGAU AUUCGCUUA AGUUGGGA G CUGAAGA AGGUC UUCGAUC A ACCAGCUC GAGC CCAGA UCUGG CUGUG CACAG

Definition of RNA structure

N = 4 n


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NS < 3 n

Criterion: Minimum free energy (mfe)

Rules: _ ( _ ) _ {AU,CG ,GC ,GU ,UA,UG}

A symbolic notation of RNA secondary structure that is equivalent to the conventional graphs


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many genotypes one phenotype


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A fitness landscape including neutrality


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Motoo Kimuras population genetics ofneutral evolution.

Evolutionary rate at the molecular level. Nature 217 : 624-626, 1955.

The Neutral Theory of Molecular Evolution .Cambridge University Press. Cambridge,UK, 1983.


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The average time of replacement of a dominant genotype in a populationis the reciprocal mutation rate, 1/ , and therefore independent ofpopulation size.

Is the Kimura scenario correct for virus populations?

Fixation of mutants in neutral evolution (Motoo Kimura, 1955)


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d H = 1

5.0)()(lim 210 == p x p x p

d H = 2

a p x

a p x

p

p=

=

1)(lim)(lim

20

10

d H 3random fixation in the sense of

Motoo KimuraPairs of genotypes in neutral replication networks


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Neutral network: Individual sequences

n = 10, = 1.1, d = 1.0


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Consensus sequence of a quasispecies of two strongly coupled sequences of Hamming distance dH(Xi,,X j) = 1.


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Neutral network: Individual sequences

n = 10, = 1.1, d = 1.0


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Consensus sequence of a quasispecies of two strongly coupled sequences of Hamming distance dH(Xi,,X j) = 2.


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N = 7

Neutral networks with increasing : = 0.10, s = 229


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Evolution in silico

W. Fontana, P. Schuster,Science 280 (1998), 1451-1455


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Phenylalanyl-tRNA astarget structure

Structure of randomly choseninitial sequence

Replication rate constant

(Fi )


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(Fitness) :

f k = / [ + dS (k)]dS (k) = dH(Sk,S )

Selection pressure :

The population size,

N = # RNA moleucles,

is determined by the flux:

Mutation rate :

p = 0.001/ Nucleotide Replication

N N t N )(

The flow reactor as a device forstudying the evolution of molecules

in vitro and in silico .


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In silico optimization in the flow reactor: Evolutionary Trajectory

28 neutral point mutations during a


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28 neutral point mutations during along quasi-stationary epoch

Transition inducing point mutationschange the molecular structure

Neutral point mutations leave themolecular structure unchanged

Neutral genotype evolution during phenotypic stasis


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Evolutionary trajectory

Spreading of the populationon neutral networks

Drift of the population centerin sequence space


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A sketch of optimization on neutral networks


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Charles Darwin.The Origin of Species . Sixth edition. John Murray. London: 1872


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Neutrality in molecular structures and its role inevolution :

Neutrality is an essential feature in biopolymer structures at theresolution that is relevant for function.

Neutrality manifests itself in the search for minimum free energystructures.

Diversity in function despite neutrality in structures results fromdifferences in suboptimal conformations and folding kinetics.

Neutrality is indispensible for optimization and adaptation.

Acknowledgement of support

F d F d g d i h ftli h F h g (FWF)


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Fonds zur Frderung der wissenschaftlichen Forschung (FWF)Projects No. 09942, 10578, 11065, 13093

13887, and 14898

Wiener Wissenschafts-, Forschungs- und Technologiefonds (WWTF)Project No. Mat05

Jubilumsfonds der sterreichischen NationalbankProject No. Nat-7813

European Commission: Contracts No. 98-0189, 12835 (NEST)

Austrian Genome Research Program GEN-AU: BioinformaticsNetwork (BIN)

sterreichische Akademie der Wissenschaften

Siemens AG, Austria

Universitt Wien and the Santa Fe Institute

Universitt Wien

Coworkers

Peter Stadler , Brbel M. Stadler , Universitt Leipzig, GE


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Paul E. Phillipson , University of Colorado at Boulder, CO

Heinz Engl, Philipp Kgler , James Lu , Stefan Mller , RICAM Linz, AT

Jord Nagel , Kees Pleij , Universiteit Leiden, NL

Walter Fontana , Harvard Medical School, MA

Christian Reidys , Christian Forst , Los Alamos National Laboratory, NM

Ulrike Gbel, Walter Grner , Stefan Kopp , Jaqueline Weber, Institut frMolekulare Biotechnologie, Jena, GE

Ivo L.Hofacker , Christoph Flamm , Andreas Svr ek-Seiler , Universitt Wien, AT

Kurt Grnberger, Michael Kospach , Andreas Wernitznig , Stefanie Widder,Stefan Wuchty , Universitt Wien, AT

Jan Cupal , Stefan Bernhart , Lukas Endler, Ulrike Langhammer , Rainer Machne,

Ulrike Mckstein , Hakim Tafer, Thomas Taylor, Universitt Wien, AT

Universitt Wien


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Web-Page for further information:

http://www.tbi.univie.ac.at/~pks


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Peter Schuster- Evolutionary Dynamics