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Experimental Determination and Prediction of the Fitness Effects of Random Point Mutations in the Biosynthetic Enzyme HisA
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0001-8354-2398
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0002-6831-3105
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2018 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 35, no 3, p. 704-718Article in journal (Refereed) Published
Abstract [en]

The distribution of fitness effects of mutations is a factor of fundamental importance in evolutionary biology. We determined the distribution of fitness effects of 510 mutants that each carried between 1 and 10 mutations (synonymous and nonsynonymous) in the hisA gene, encoding an essential enzyme in the L-histidine biosynthesis pathway of Salmonella enterica. For the full set of mutants, the distribution was bimodal with many apparently neutral mutations and many lethal mutations. For a subset of 81 single, nonsynonymous mutants most mutations appeared neutral at high expression levels, whereas at low expression levels only a few mutations were neutral. Furthermore, we examined how the magnitude of the observed fitness effects was correlated to several measures of biophysical properties and phylogenetic conservation.We conclude that for HisA: (i) The effect of mutations can be masked by high expression levels, such that mutations that are deleterious to the function of the protein can still be neutral with regard to organism fitness if the protein is expressed at a sufficiently high level; (ii) the shape of the fitness distribution is dependent on the extent to which the protein is rate-limiting for growth; (iii) negative epistatic interactions, on an average, amplified the combined effect of nonsynonymous mutations; and (iv) no single sequence-based predictor could confidently predict the fitness effects of mutations in HisA, but a combination of multiple predictors could predict the effect with a SD of 0.04 resulting in 80% of the mutations predicted within 12% of their observed selection coefficients.

Place, publisher, year, edition, pages
2018. Vol. 35, no 3, p. 704-718
Keywords [en]
mutation, fitness, Salmonella enterica, HisA protein
National Category
Evolutionary Biology Microbiology
Research subject
Biology with specialization in Microbiology; Biology with specialization in Molecular Evolution
Identifiers
URN: urn:nbn:se:uu:diva-339126DOI: 10.1093/molbev/msx325ISI: 000427260700017PubMedID: 29294020OAI: oai:DiVA.org:uu-339126DiVA, id: diva2:1174817
Funder
Swedish Research CouncilAvailable from: 2018-01-16 Created: 2018-01-16 Last updated: 2018-07-24Bibliographically approved

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Lundin, ErikTang, Po-ChengGuy, LionelAndersson, Dan I

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