A systematic survey of an intragenic epistatic landscape [preprint]
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
PreprintPublication Date
2014-10-23Keywords
evolutionary biologymutations
evolution
yeast Hsp90
intragenic epistatic effects
double-mutants
Amino Acids, Peptides, and Proteins
Biophysics
Ecology and Evolutionary Biology
Fungi
Genetic Phenomena
Genetics and Genomics
Molecular Biology
Structural Biology
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Show full item recordAbstract
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.Source
bioRxiv 010645; doi: https://doi.org/10.1101/010645. Link to preprint on bioRxiv service.
DOI
10.1101/010645Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29337Related Resources
Now published in Molecular Biology and Evolution doi: 10.1093/molbev/msu301.
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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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.Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1101/010645
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Except where otherwise noted, this item's license is described as 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.