A Systematic Survey of an Intragenic Epistatic Landscape

Claudia Bank, Ryan T. Hietpas, Jeffrey Jensen, Daniel N A Bolon

Research output: Contribution to journalReview article

58 Citations (Scopus)

Abstract

Mutations are the source of evolutionary variation. The interactions of multiple mutations can have important effects on fitness and evolutionary trajectories. We have recently described the distribution of fitness effects of all single mutations for a nine-amino-acid region of yeast Hsp90 (Hsp82) implicated in substrate binding. Here, we report and discuss the distribution of intragenic epistatic effects within this region in seven Hsp90 point mutant backgrounds of neutral to slightly deleterious effect, resulting in an analysis of more than 1,000 double mutants. We find negative epistasis between substitutions to be common, and positive epistasis to be rare - resulting in a pattern that indicates a drastic change in the distribution of fitness effects one step away from the wild type. This can be well explained by a concave relationship between phenotype and genotype (i.e., a concave shape of the local fitness landscape), suggesting mutational robustness intrinsic to the local sequence space. Structural analyses indicate that, in this region, epistatic effects are most pronounced when a solvent-inaccessible position is involved in the interaction. In contrast, all 18 observations of positive epistasis involved at least one mutation at a solvent-exposed position. By combining the analysis of evolutionary and biophysical properties of an epistatic landscape, these results contribute to a more detailed understanding of the complexity of protein evolution.

Original languageEnglish (US)
Pages (from-to)229-238
Number of pages10
JournalMolecular Biology and Evolution
Volume32
Issue number1
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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epistasis
mutation
Mutation
fitness
mutants
trajectories
Yeasts
Genotype
yeasts
Phenotype
phenotype
Amino Acids
amino acids
yeast
effect
Surveys and Questionnaires
genotype
substitution
amino acid
trajectory

Keywords

  • Distribution of fitness effects
  • Epistasis
  • Experimental evolution
  • Fitness landscapes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Medicine(all)

Cite this

A Systematic Survey of an Intragenic Epistatic Landscape. / Bank, Claudia; Hietpas, Ryan T.; Jensen, Jeffrey; Bolon, Daniel N A.

In: Molecular Biology and Evolution, Vol. 32, No. 1, 01.01.2015, p. 229-238.

Research output: Contribution to journalReview article

Bank, Claudia ; Hietpas, Ryan T. ; Jensen, Jeffrey ; Bolon, Daniel N A. / A Systematic Survey of an Intragenic Epistatic Landscape. In: Molecular Biology and Evolution. 2015 ; Vol. 32, No. 1. pp. 229-238.
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