Evolvability as a Function of Purifying Selection in TEM-1 β-Lactamase

Michael A. Stiffler, Doeke R. Hekstra, Rama Ranganathan

Research output: Contribution to journalArticlepeer-review

148 Scopus citations


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. PaperClip

Original languageEnglish (US)
Pages (from-to)882-892
Number of pages11
Issue number5
StatePublished - Feb 26 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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