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

@article{Weinreich2006DarwinianEC,
  title={Darwinian Evolution Can Follow Only Very Few Mutational Paths to Fitter Proteins},
  author={Daniel M. Weinreich and Nigel F. Delaney and Mark A. DePristo and Daniel L. Hartl},
  journal={Science},
  year={2006},
  volume={312},
  pages={111 - 114}
}
Five point mutations in a particular β-lactamase allele jointly increase bacterial resistance to a clinically important antibiotic by a factor of ∼100,000. In principle, evolution to this high-resistance β-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… 
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