Error thresholds on realistic fitness landscapes

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2 Error thresholds on realistic fitness landscapes Peter Schuster Institut für Theoretische Chemie, Universität Wien, Austria and The Santa Fe Institute, Santa Fe, New Mexico, USA Evolutionary Dynamics: Mutation, Selection, and the Origin of Information University of Utrecht,

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4 Prologue The work on a molecular theory of evolution started 42 years ago Chemical kinetics of molecular evolution

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7 1. Open system and constant population size 2. Chemical kinetics of replication and mutation 3. Complexity of fitness landscapes 4. Quasispecies on realistic landscapes 5. Neutrality and replication 6. Lethal variants and mutagenesis

8 1. Open system and constant population size 2. Chemical kinetics of replication and mutation 3. Complexity of fitness landscapes 4. Quasispecies on realistic landscapes 5. Neutrality and replication 6. Lethal variants and mutagenesis

9 Stock solution: [A] = a = a 0 Flow rate: r = R -1 The population size N, the number of polynucleotide molecules, is controlled by the flow r N ( t) N ± N The flowreactor is a device for studying evolution in vitro and in silico

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11 Replication and mutation in the flowreactor

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14 Derivation of the replication-mutation equation from the flowreactor

15 1. Open system and constant population size 2. Chemical kinetics of replication and mutation 3. Complexity of fitness landscapes 4. Quasispecies on realistic landscapes 5. Neutrality and replication 6. Lethal variants and mutagenesis

16 Manfred Eigen = = = = = = n i i n i i i j i n i ji j x x f Φ n j Φ x x W x 1 1 1, 1,2, ; dt d K Mutation and (correct) replication as parallel chemical reactions M. Eigen Naturwissenschaften 58:465, M. Eigen & P. Schuster Naturwissenschaften 64:541, 65:7 und 65:341

17 Taq = thermus aquaticus Accuracy of replication: Q = q 1 q 2 q 3 q n The logics of DNA replication

18 RNA replication by Q -replicase C. Weissmann, The making of a phage. FEBS Letters 40 (1974), S10-S18

19 dx dt dx dt 1 2 = f2 x2 and = f1 x1 x, f = f f 1 = f2 ξ1 x2 = f1 ξ2, ζ = ξ1 + ξ2, η = ξ1 ξ2, 1 2 η( t) = η(0) e ft ζ ( t) = ζ (0) e ft Complementary replication as the simplest molecular mechanism of reproduction

20 Christof K. Biebricher, Kinetics of RNA replication C.K. Biebricher, M. Eigen, W.C. Gardiner, Jr. Biochemistry 22: , 1983

21 = = = = = = = = n i i n i i i j i i n i ji j i n i ji j x x f Φ n j Φ x x f Q Φ x x W x , 1,2, ; dt d K Factorization of the value matrix W separates mutation and fitness effects.

22 Mutation-selection equation: [I i ] = x i 0, f i 0, Q ij 0 dx i n n n = Q f x x i n x f x j ij j j i φ, = 1,2, L, ; i i = 1; φ = j j j dt = = 1 = 1 = 1 f solutions are obtained after integrating factor transformation by means of an eigenvalue problem x i () t = n 1 k n j= 1 ( 0) exp( λkt) c ( 0) exp( λ t) l = 0 ik ck ; i = 1,2, L, n; c (0) = n 1 k l k= 0 jk k k n i= 1 h ki x i (0) W 1 { f Q ; i, j= 1,2, L, n} ; L = { l ; i, j= 1,2, L, n} ; L = H = { h ; i, j= 1,2, L, n} i ij ij ij { λ ; k = 0,1,, n 1} 1 L W L = Λ = k L

23 Perron-Frobenius theorem applied to the value matrix W W is primitive: (i) is real and strictly positive (ii) λ 0 λ0 > λ k for all k 0 λ 0 (iii) is associated with strictly positive eigenvectors λ 0 (iv) is a simple root of the characteristic equation of W (v-vi) etc. W is irreducible: (i), (iii), (iv), etc. as above (ii) λ0 λ k for all k 0

24 constant level sets of Selection of quasispecies with f 1 = 1.9, f 2 = 2.0, f 3 = 2.1, and p = 0.01, parametric plot on S 3

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26 Chain length and error threshold n p n p n p p n p Q n σ σ σ σ σ ln : constant ln : constant ln ) ln(1 1 ) (1 max max = K K sequence master superiority of length chain rate error accuracy replication ) (1 K K K K = = m j j m n f f σ n p p Q

27 Quasispecies Uniform distribution Stationary population or quasispecies as a function of the mutation or error rate p Error rate p = 1-q

28 Eigenvalues of the matrix W as a function of the error rate p

29 Quasispecies Driving virus populations through threshold The error threshold in replication: No mutational backflow approximation

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31 Molecular evolution of viruses

32 1. Open system and constant population size 2. Chemical kinetics of replication and mutation 3. Complexity of fitness landscapes 4. Quasispecies on realistic landscapes 5. Neutrality and replication 6. Lethal variants and mutagenesis

33 0, 0 largest eigenvalue and eigenvector diagonalization of matrix W complicated but not complex W = G F mutation matrix fitness landscape ( complex ) complex sequence structure complex mutation selection Complexity in molecular evolution

34 Sewall Wright Evolution in Mendelian populations. Genetics 16: The roles of mutation, inbreeding, crossbreeding, and selection in evolution. In: D.F.Jones, ed. Proceedings of the Sixth International Congress on Genetics, Vol.I. Brooklyn Botanical Garden. Ithaca, NY, pp Surfaces of selective value revisited. The American Naturalist 131:

35 Build-up principle of binary sequence spaces

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37 Build-up principle of four letter (AUGC) sequence spaces

38 linear and multiplicative hyperbolic Smooth fitness landscapes

39 The linear fitness landscape shows no error threshold

40 Error threshold on the hyperbolic landscape

41 single peak landscape step linear landscape Rugged fitness landscapes

42 Error threshold on the single peak landscape

43 Error threshold on a single peak fitness landscape with n = 50 and = 10

44 Error threshold on the step linear landscape

45 The error threshold can be separated into three phenomena: 1. Decrease in the concentration of the master sequence to very small values. 2. Sharp change in the stationary concentration of the quasispecies distribuiton. 3. Transition to the uniform distribution at small mutation rates. All three phenomena coincide for the quasispecies on the single peak fitness lanscape.

46 The error threshold can be separated into three phenomena: 1. Decrease in the concentration of the master sequence to very small values. 2. Sharp change in the stationary concentration of the quasispecies distribuiton. 3. Transition to the uniform distribution at small mutation rates. All three phenomena coincide for the quasispecies on the single peak fitness lanscape.

47 1. Open system and constant population size 2. Chemical kinetics of replication and mutation 3. Complexity of fitness landscapes 4. Quasispecies on realistic landscapes 5. Neutrality and replication 6. Lethal variants and mutagenesis

48 single peak landscape realistic landscape Rugged fitness landscapes over individual binary sequences with n = 10

49 Error threshold: Individual sequences n = 10, = 2, s = 491 and d = 0, 1.0, 1.875

50 Shift of the error threshold with increasing ruggedness of the fitness landscape

51 d = d = Case I: Strong Quasispecies n = 10, f 0 = 1.1, f n = 1.0, s = 919

52 d = d = Case II: Dominant single transition n = 10, f 0 = 1.1, f n = 1.0, s = 541

53 d = d = Case II: Dominant single transition n = 10, f 0 = 1.1, f n = 1.0, s = 541

54 d = d = Case II: Dominant single transition n = 10, f 0 = 1.1, f n = 1.0, s = 541

55 d = d = Case III: Multiple transitions n = 10, f 0 = 1.1, f n = 1.0, s = 637

56 d = d = Case III: Multiple transitions n = 10, f 0 = 1.1, f n = 1.0, s = 637

57 1. Open system and constant population size 2. Chemical kinetics of replication and mutation 3. Complexity of fitness landscapes 4. Quasispecies on realistic landscapes 5. Neutrality and replication 6. Lethal variants and mutagenesis

58 Motoo Kimuras population genetics of neutral evolution. Evolutionary rate at the molecular level. Nature 217: , The Neutral Theory of Molecular Evolution. Cambridge University Press. Cambridge, UK, 1983.

59 Motoo Kimura Is the Kimura scenario correct for frequent mutations?

60 0.5 ) ( ) ( lim = = p x p x p d H = 1 a p x a p x p p = = 1 ) ( lim ) ( lim d H = 2 d H 3 1 ) ( 0,lim ) ( lim or 0 ) ( 1,lim ) ( lim = = = = p x p x p x p x p p p p Random fixation in the sense of Motoo Kimura Pairs of neutral sequences in replication networks P. Schuster, J. Swetina Bull. Math. Biol. 50:

61 A fitness landscape including neutrality

62 Neutral network: Individual sequences n = 10, = 1.1, d = 1.0

63 Consensus sequence of a quasispecies of two strongly coupled sequences of Hamming distance d H (X i,,x j ) = 1.

64 Neutral network: Individual sequences n = 10, = 1.1, d = 1.0

65 Consensus sequence of a quasispecies of two strongly coupled sequences of Hamming distance d H (X i,,x j ) = 2.

66 N = 7 Adjacency matrix Neutral networks with increasing : = 0.10, s = 229

67 1. Open system and constant population size 2. Chemical kinetics of replication and mutation 3. Complexity of fitness landscapes 4. Quasispecies on realistic landscapes 5. Neutrality and replication 6. Lethal variants and mutagenesis

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73 Coworkers Peter Stadler, Bärbel M. Stadler, Universität Leipzig, GE Walter Fontana, Harvard Medical School, MA Universität Wien Martin Nowak, Harvard University, MA Christian Reidys, Nankai University, Tien Tsin, China Thomas Wiehe, Ulrike Göbel, Walter Grüner, Stefan Kopp, Jaqueline Weber, Institut für Molekulare Biotechnologie, Jena, GE Ivo L.Hofacker, Christoph Flamm, Universität Wien, AT Kurt Grünberger, Michael Kospach, Andreas Wernitznig, Stefanie Widder, Stefan Wuchty, Jan Cupal, Stefan Bernhart, Lukas Endler, Ulrike Langhammer, Rainer Machne, Ulrike Mückstein, Erich Bornberg-Bauer, Universität Wien, AT

74 Acknowledgement of support Fonds zur Förderung der wissenschaftlichen Forschung (FWF) Projects No , 10578, 11065, , and Universität Wien Wiener Wissenschafts-, Forschungs- und Technologiefonds (WWTF) Project No. Mat05 Jubiläumsfonds der Österreichischen Nationalbank Project No. Nat-7813 European Commission: Contracts No , (NEST) Austrian Genome Research Program GEN-AU: Bioinformatics Network (BIN) Österreichische Akademie der Wissenschaften Siemens AG, Austria Universität Wien and the Santa Fe Institute

75 Thank you for your attention!

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