Evolvability as a function of purifying selection in TEM-1 β-lactamase.
Evolvability—the capacity to generate beneficial heritable variation—is a central property of biological systems. However, its origins and modulation by environmental factors have not been examined systematically. Here, we analyze the fitness effects of all single mutations in TEM-1 β-lactamase (4,997 variants) under selection for the wild-type function (ampicillin resistance) and for a new function (cefotaxime resistance). Tolerance to mutation in this enzyme is bimodal and dependent on the strength of purifying selection in vivo, a result that derives from a steep non-linear ampicillin-dependent relationship between biochemical activity and fitness. Interestingly, cefotaxime resistance emerges from mutations that are neutral at low levels of ampicillin but deleterious at high levels; thus the capacity to evolve new function also depends on the strength of selection. The key property controlling evolvability is an excess of enzymatic activity relative to the strength of selection, suggesting that fluctuating environments might select for high-activity enzymes.
Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA.
Michael A
MA
Stiffler
Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA.
Doeke R
DR
Hekstra
Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA. Electronic address: rama.ranganathan@utsouthwestern.edu.
Rama
R
Ranganathan
D000667:Ampicillin / Q000494:pharmacology; D000668:Ampicillin Resistance; D002439:Cefotaxime / Q000494:pharmacology*; D019020:Directed Molecular Evolution; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D056084:Genetic Fitness; D009154:Mutation; D018440:beta-Lactam Resistance; D001618:beta-Lactamases / Q000737:chemistry / Q000235:genetics*
D000667:Ampicillin; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1; D002439:Cefotaxime