Department of Biochemistry and Molecular Pharmacology
Amino Acids, Peptides, and Proteins | Biophysics | Ecology and Evolutionary Biology | Fungi | Genetic Phenomena | Genetics and Genomics | Molecular Biology | Structural Biology
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 1000 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.
evolutionary biology, mutations, evolution, yeast Hsp90, intragenic epistatic effects, double-mutants
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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
DOI of Published Version
bioRxiv 010645; doi: https://doi.org/10.1101/010645. Link to preprint on bioRxiv service.
Now published in Molecular Biology and Evolution doi: 10.1093/molbev/msu301.
Bank C, Hietpas RT, Jensen JD, Bolon DN. (2014). A systematic survey of an intragenic epistatic landscape. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/010645. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1563
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