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

  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},
  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… 
Probing Evolutionary Repeatability: Neutral and Double Changes and the Predictability of Evolutionary Adaptation
It is found that evolution to more highly cefotaxime resistant β-lactamase proteins is still highly repeatable, and the total number of accessible pathways is dramatically affected by allowing neutral or double mutations, but the overall evolutionary repeatability is generally much less affected.
Mistranslation can enhance fitness through purging of deleterious mutations
This work evolves the antibiotic resistance protein TEM-1 towards resistance on the antibiotic cefotaxime in an Escherichia coli strain with a high mistranslation rate, and shows that this advantage is associated with a lower incidence of weakly deleterious genotype mutations.
Small changes in enzyme function can lead to surprisingly large fitness effects during adaptive evolution of antibiotic resistance
A quantitative model directly relating the in vitro physicochemical properties of the mutant enzymes to the growth rates of bacteria carrying a single chromosomal copy of the tet(X2) variants over a wide range of minocycline (MCN) concentrations was built.
Unraveling the causes of adaptive benefits of synonymous mutations in TEM-1 β-lactamase
The results suggest that synonymous mutations may have beneficial effects by increasing the expression of an enzyme with low substrate activity, which may be realized via multiple, yet unknown, post-transcriptional mechanisms.
Initial Mutations Direct Alternative Pathways of Protein Evolution
It is found that a combination of decreased enzymatic activity and lower folding cooperativity underlies negative sign epistasis in the clash between key mutations in the common and deviating lines, demonstrating that epistasis contributes to contingency in protein evolution by amplifying the selective consequences of random mutations.
Network Models of TEM β-Lactamase Mutations Coevolving under Antibiotic Selection Show Modular Structure and Anticipate Evolutionary Trajectories
The recent evolution of β-lactamase under antibiotic selection is used as a model for genetic adaptation and a network of coevolving residues is built, which has the unique ability to make predictions by placing each mutant residue position in its functional context.
Cryptic genetic variation shapes the adaptive evolutionary potential of enzymes
It is shown how cryptic molecular properties and conformational variation of active site residues in the initial genotypes cause epistasis, that could lead to distinct evolutionary outcomes, in orthologous metallo-β-lactamases.
Coevolutionary Landscape Inference and the Context-Dependence of Mutations in Beta-Lactamase TEM-1
A novel inference scheme for mutational landscapes, which is based on the statistical analysis of large alignments of homologs of the protein of interest, is developed, able to capture epistatic couplings between residues, and therefore to assess the dependence of mutational effects on the sequence context where they appear.
Mutation supply and the repeatability of selection for antibiotic resistance
It is shown experimentally that alleles carrying multiple mutations selected from large libraries confer higher resistance levels relative to alleles with only a known large-effect mutation, suggesting that the scarcity of high-resistance allelescarry multiple mutations may contribute to the decrease in repeatability at large library sizes.


Predicting Evolution by In Vitro Evolution Requires Determining Evolutionary Pathways
  • B. Hall
  • Biology
    Antimicrobial Agents and Chemotherapy
  • 2002
It is shown that no pathway exists between the wild-type TEM-1 and the supereffective cefotaxime-hydrolyzing mutant that was generated by six amino acid substitutions via DNA shuffling, but that a pathway to a fourfold more efficient enzyme resulting from four of the same substitutions does exist.
Ancestral lysozymes reconstructed, neutrality tested, and thermostability linked to hydrocarbon packing
The existence of variants that are more stable than the extant proteins suggests that selection for maximum thermostability may not have been an important factor in the evolution of this enzyme.
Missense meanderings in sequence space: a biophysical view of protein evolution
This work reviews the literature on biophysics as it relates to molecular evolution and advances a biophysical model of protein evolution that helps to understand phenomena that range from the dynamics of molecular adaptation to the clock-like rate ofprotein evolution.
The Biochemical Architecture of an Ancient Adaptive Landscape
The genotype-phenotype-fitness map shows that NAD use is a global optimum, and mediates between these two phenotypic extremes show that each amino acid contributes additively to enzyme function, with epistatic contributions confined to fitness.
Rapid evolution of a protein in vitro by DNA shuffling
It is reported here that selected mutants had a minimum inhibitory concentration of 640 μg ml-1, a 32,000-fold increase and 64-fold greater than any published TEM-1 derived enzyme.
Predicting evolutionary potential: in vitro evolution accurately reproduces natural evolution of the tem beta-lactamase.
It is predicted that a phenotype not yet observed among TEM beta-lactamases in nature-resistance to cefepime-is likely to arise in nature and the in vitro evolution technique accurately mimics natural evolution and can be used to predict the results of natural evolutionary processes.
A secondary drug resistance mutation of TEM-1 beta-lactamase that suppresses misfolding and aggregation.
The M182T substitution is an example of a naturally occurring mutation that has evolved to alter the folding pathway of a protein and confer a selective advantage during the evolution of drug resistance.
TEM beta-lactamase mutants hydrolysing third-generation cephalosporins. A kinetic and molecular modelling analysis.
The catalytic properties of six "natural" mutants of the TEM-1 beta-lactamase have been studied in detail, with special emphasis on their activity versus third-generation cephalosporins, supplying an interesting example of convergent evolution within a generally diverging family.
Antibiotics: Actions, Origins, Resistance
This new text offers a comprehensive, up to date account of those structural classes of antibiotics that have had an impact in human infectious disease. While most of the attention is on natural