title: A comprehensive, high-resolution map of a gene's fitness landscape.
abstract: Mutations are central to evolution, providing the genetic variation upon which selection acts. A mutation's effect on the suitability of a gene to perform a particular function (gene fitness) can be positive, negative, or neutral. Knowledge of the distribution of fitness effects (DFE) of mutations is fundamental for understanding evolutionary dynamics, molecular-level genetic variation, complex genetic disease, the accumulation of deleterious mutations, and the molecular clock. We present comprehensive DFEs for point and codon mutants of the Escherichia coli TEM-1 β-lactamase gene and missense mutations in the TEM-1 protein. These DFEs provide insight into the inherent benefits of the genetic code's architecture, support for the hypothesis that mRNA stability dictates codon usage at the beginning of genes, an extensive framework for understanding protein mutational tolerance, and evidence that mutational effects on protein thermodynamic stability shape the DFE. Contrary to prevailing expectations, we find that deleterious effects of mutation primarily arise from a decrease in specific protein activity and not cellular protein levels.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University.
authors.forename: Elad
authors.initials: E
authors.lastname: Firnberg
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Labonte
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Gray
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University oster@jhu.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Ostermeier
mesh_terms: D018389:Codon, Nonsense; D004795:Enzyme Stability; D004926:Escherichia coli / Q000235:genetics*; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D005815:Genetic Code; D056084:Genetic Fitness; D014644:Genetic Variation; D008958:Models, Molecular; D059645:Mutation Rate; D020125:Mutation, Missense; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D058615:Synthetic Biology; D001618:beta-Lactamases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D029968:Escherichia coli Proteins; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1
keywords: beta-lactamase; fitness landscape; protein evolution