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Darwinian Evolution Can Follow Only Very Few Mutational Paths to Fitter Proteins
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Darwinian Evolution Can Follow Only Very Few Mutational Paths to Fitter Proteins
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Journal Article
Darwinian Evolution Can Follow Only Very Few Mutational Paths to Fitter Proteins
2006
Overview
Five point mutations in a particular {szligbeta}-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 {szligbeta}-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 {szligbeta}-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.
Publisher
American Association for the Advancement of Science,The American Association for the Advancement of Science
Subject
/ Anti-Bacterial Agents - pharmacology
/ beta-Lactamases - metabolism
/ Biological and medical sciences
/ Enzymes
/ Escherichia coli - drug effects
/ Escherichia coli - enzymology
/ Fundamental and applied biological sciences. Psychology
/ Genetics of eukaryotes. Biological and molecular evolution
/ Mutation
/ Proteins
