PMID:16601193

Citation	Weinreich, DM, Delaney, NF, Depristo, MA and Hartl, DL (2006) Darwinian evolution can follow only very few mutational paths to fitter proteins. Science 312:111-4
Abstract	Five point mutations in a particular beta-lactamase allele jointly increase bacterial resistance to a clinically important antibiotic by a factor of approximately 100,000. In principle, evolution to this high-resistance beta-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 beta-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.
Links	PubMed Online version:10.1126/science.1123539
Keywords	Alleles; Anti-Bacterial Agents/pharmacology; Cefotaxime/metabolism; Cefotaxime/pharmacology; Drug Resistance, Bacterial; Enzyme Stability; Epistasis, Genetic; Escherichia coli/drug effects; Escherichia coli/enzymology; Escherichia coli/genetics; Evolution, Molecular; Models, Genetic; Mutation; Mutation, Missense; Point Mutation; Probability; Selection, Genetic; beta-Lactamases/genetics; beta-Lactamases/metabolism
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