A Systematic Survey of an Intragenic Epistatic Landscape

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.

Correlation of fitness landscapes from three orthologous TIM barrels originates from sequence and structure constraints

“…Although there is evidence about the roughness of fitness landscapes for small deviations from the WT sequence65051, our finding of correlations between the fitness landscapes of divergent IGPS orthologues suggests that the common fold and function act together to smoothen the landscape. In fact, low throughput experiments have shown that the effects of mutations on biophysical properties such as Tm and ΔΔ G ° are largely conserved across homologues of influenza nucleoprotein52, and modern versus ancestral thioredoxins and β-lactamases53.…”

Functional Segregation of Overlapping Genes in HIV

“…Second, our analyses have made rough estimations of viral fitness and examined only single point mutations in one viral background in an artificial genomic locus, ignoring the potential for epistatic effects at multiple positions. However, positive epistasis is rare while negative epistasis is common (Bank et al, 2015), suggesting that our simplification is conservative and likely underestimates the severity of purged deleterious genotypes (Boucher et al, 2016), while missing only a few restorative double mutations. Regardless, further studies of overlaps in HIV-1 and other systems may shed more light on these aspects.…”

Genomic investigations of evolutionary dynamics and epistasis in microbial evolution experiments

“…Within the smallest modular unit, a single gene, studies of the antibiotic resistance enzyme beta lactamase [41] and comprehensive reconstructions of mutations within a 9 amino acid region in yeast Hsp90 [42, 43] have revealed widespread epistasis. This includes sign epistasis, in which a mutation shifts from beneficial to deleterious (or vice versa) depending on the genetic background it occurs in.…”