title: Variation in Mutational Robustness between Different Proteins and the Predictability of Fitness Effects.
abstract: Random mutations in genes from disparate protein classes may have different distributions of fitness effects (DFEs) depending on different structural, functional, and evolutionary constraints. We measured the fitness effects of 156 single mutations in the genes encoding AraC (transcription factor), AraD (enzyme), and AraE (transporter) used for bacterial growth on l-arabinose. Despite their different molecular functions these genes all had bimodal DFEs with most mutations either being neutral or strongly deleterious, providing a general expectation for the DFE. This contrasts with the unimodal DFEs previously obtained for ribosomal protein genes where most mutations were slightly deleterious. Based on theoretical considerations, we suggest that the 33-fold higher average mutational robustness of ribosomal proteins is due to stronger selection for reduced costs of translational and transcriptional errors. Whereas the large majority of synonymous mutations were deleterious for ribosomal proteins genes, no fitness effects could be detected for the AraCDE genes. Four mutations in AraC and AraE increased fitness, suggesting that slightly advantageous mutations make up a significant fraction of the DFE, but that they often escape detection due to the limited sensitivity of commonly used fitness assays. We show that the fitness effects of amino acid substitutions can be predicted based on evolutionary conservation, but those weakly deleterious mutations are less reliably detected. This suggests that large-effect mutations and the fraction of highly deleterious mutations can be computationally predicted, but that experiments are required to characterize the DFE close to neutrality, where many mutations ultimately fixed in a population will occur.
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.|Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Lind
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Arvidsson
authors.affiliation: Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Otto G
authors.initials: OG
authors.lastname: Berg
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Dan I
authors.initials: DI
authors.lastname: Andersson
mesh_terms: D051777:AraC Transcription Factor / Q000235:genetics; D001089:Arabinose / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics*; D005075:Biological Evolution; D015964:Gene Expression Regulation, Bacterial; D056084:Genetic Fitness; D014644:Genetic Variation; D008957:Models, Genetic; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009154:Mutation; D012269:Ribosomal Proteins / Q000235:genetics; D012486:Salmonella typhimurium / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D051777:AraC Transcription Factor; C109577:AraE protein, bacteria; D001426:Bacterial Proteins; D009004:Monosaccharide Transport Proteins; D012269:Ribosomal Proteins; D014157:Transcription Factors; D001089:Arabinose
keywords: arabinose operon; bacteria; fitness; mutation; protein; robustness