Reports

Darwinian Evolution Can Follow Only Very Few Mutational Paths to Fitter Proteins

Daniel M. Weinreich,^* Nigel F. Delaney, Mark A. DePristo, Daniel L. Hartl

Five point mutations in a particular ß-lactamase allele jointly increase bacterial resistance to a clinically important antibiotic by a factor of 100,000. In principle, evolution to this high-resistance ß-lactamase might follow any of the 120 mutational trajectories linking these alleles. However, we demonstrate that 102 trajectories are inaccessible to Darwinian selection and that many of the remaining trajectories have negligible probabilities of realization, because four of these five mutations fail to increase drug resistance in some combinations. Pervasive biophysical pleiotropy within the ß-lactamase seems to be responsible, and because such pleiotropy appears to be a general property of missense mutations, we conclude that much protein evolution will be similarly constrained. This implies that the protein tape of life may be largely reproducible and even predictable.

Department of Organismic and Evolutionary Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA.

Present address: Integrative Oceanography Division, Scripps Institute of Oceanography, 9500 Gilman Drive, La Jolla, CA 92037, USA.

^* To whom correspondence should be addressed. E-mail: dmw{at}post.harvard.edu

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Mutational paths towards increased fluoroquinolone resistance in Legionella pneumophila.

I. Almahmoud, E. Kay, D. Schneider, and M. Maurin (2009)
J. Antimicrob. Chemother. 64, 284-293
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In the Light of Evolution III: Two Centuries of Darwin Sackler Colloquium: In the light of directed evolution: Pathways of adaptive protein evolution.

J. D. Bloom and F. H. Arnold (2009)
PNAS 106, 9995-10000
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Markov models for accumulating mutations.

N. Beerenwinkel and S. Sullivant (2009)
Biometrika
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Experimental evolution of a microbial predator's ability to find prey.

K. L Hillesland, G. J Velicer, and R. E Lenski (2009)
Proc R Soc B 276, 459-467
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Evolution of C4 Phosphoenolpyruvate Carboxykinase in Grasses, from Genotype to Phenotype.

P.-A. Christin, B. Petitpierre, N. Salamin, L. Buchi, and G. Besnard (2009)
Mol. Biol. Evol. 26, 357-365
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Adaptive protein evolution grants organismal fitness by improving catalysis and flexibility.

P. E. Tomatis, S. M. Fabiane, F. Simona, P. Carloni, B. J. Sutton, and A. J. Vila (2008)
PNAS 105, 20605-20610
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Ohno's Model Revisited: Measuring the Frequency of Potentially Adaptive Mutations under Various Mutational Drifts.

S. Bershtein and D. S. Tawfik (2008)
Mol. Biol. Evol. 25, 2311-2318
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Evolutionary Switch and Genetic Convergence on rbcL following the Evolution of C4 Photosynthesis.

P.-A. Christin, N. Salamin, A. M. Muasya, E. H. Roalson, F. Russier, and G. Besnard (2008)
Mol. Biol. Evol. 25, 2361-2368
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Accelerated evolution of resistance in multidrug environments.

M. Hegreness, N. Shoresh, D. Damian, D. Hartl, and R. Kishony (2008)
PNAS 105, 13977-13981
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Energy-dependent fitness: A quantitative model for the evolution of yeast transcription factor binding sites.

V. Mustonen, J. Kinney, C. G. Callan Jr, and M. Lassig (2008)
PNAS 105, 12376-12381
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Inaugural Article: Historical contingency and the evolution of a key innovation in an experimental population of Escherichia coli.

Z. D. Blount, C. Z. Borland, and R. E. Lenski (2008)
PNAS 105, 7899-7906
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The Frequency of Fitness Peak Shifts Is Increased at Expanding Range Margins Due to Mutation Surfing.

O. J. Burton and J. M. J. Travis (2008)
Genetics 179, 941-950
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The genetic basis of parallel and divergent phenotypic responses in evolving populations of Escherichia coli.

E. A Ostrowski, R. J Woods, and R. E Lenski (2008)
Proc R Soc B 275, 277-284
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A burst of protein sequence evolution and a prolonged period of asymmetric evolution follow gene duplication in yeast.

D. R. Scannell and K. H. Wolfe (2008)
Genome Res. 18, 137-147
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Crystal Structure of an Ancient Protein: Evolution by Conformational Epistasis.

E. A. Ortlund, J. T. Bridgham, M. R. Redinbo, and J. W. Thornton (2007)
Science 317, 1544-1548
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Mutational Reversions During Adaptive Protein Evolution.

M. A. DePristo, D. L. Hartl, and D. M. Weinreich (2007)
Mol. Biol. Evol. 24, 1608-1610
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Profile of Daniel L. Hartl.

H. D. Tinsley (2007)
PNAS 104, 9111-9113
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Evolvability of physiological and biochemical traits: evolutionary mechanisms including and beyond single-nucleotide mutation.

M. E. Feder (2007)
J. Exp. Biol. 210, 1653-1660
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Adaptive Divergence in Experimental Populations of Pseudomonas fluorescens. III. Mutational Origins of Wrinkly Spreader Diversity.

E. Bantinaki, R. Kassen, C. G. Knight, Z. Robinson, A. J. Spiers, and P. B. Rainey (2007)
Genetics 176, 441-453
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Fitness Landscape of Human Immunodeficiency Virus Type 1 Protease Quasispecies.

G. Fernandez, B. Clotet, and M. A. Martinez (2007)
J. Virol. 81, 2485-2496
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Deterministic and Stochastic Regimes of Asexual Evolution on Rugged Fitness Landscapes.

K. Jain and J. Krug (2007)
Genetics 175, 1275-1288
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Adaptations to fluctuating selection in Drosophila.

V. Mustonen and M. Lassig (2007)
PNAS 104, 2277-2282
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