title: Darwinian evolution can follow only very few mutational paths to fitter proteins.
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.
authors.affiliation: Department of Organismic and Evolutionary Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA. dmw@post.harvard.edu
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Weinreich
authors.forename: Nigel F
authors.initials: NF
authors.lastname: Delaney
authors.forename: Mark A
authors.initials: MA
authors.lastname: Depristo
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Hartl
mesh_terms: D000483:Alleles; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002439:Cefotaxime / Q000378:metabolism / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004795:Enzyme Stability; D004843:Epistasis, Genetic; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D019143:Evolution, Molecular; D008957:Models, Genetic; D009154:Mutation; D020125:Mutation, Missense; D017354:Point Mutation; D011336:Probability; D012641:Selection, Genetic; D001618:beta-Lactamases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; C445691:TEM-52 beta-lactamase; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1; D002439:Cefotaxime