A Systematic Survey of an Intragenic Epistatic Landscape
A Systematic Survey of an Intragenic Epistatic Landscape
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DOI：
10.1093/molbev/msu301
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发表时间：
2015-01-01
影响因子：
10.7
通讯作者：
Bolon, Daniel N. A.
中科院分区：
文献类型：
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作者：
Bank, Claudia;Hietpas, Ryan T.;Bolon, Daniel N. A.
突变是进化变异的根源。多个突变的相互作用可以对适应度和进化轨迹产生重要影响。我们最近描述了酵母Hsp90(Hsp82)与底物结合有关的九个氨基酸区域的所有单一突变的适合度效应的分布。在这里，我们报告和讨论了7个Hsp90点突变背景中的基因内上位效应在该区域内的分布，这些背景的中性到轻微的有害效应，导致了对1000多个双重突变的分析。我们发现替换之间的负上位性很常见，而正上位性很少见-导致了一种模式，表明适应度效应的分布发生了剧烈的变化，距离野生型一步之遥。这可以用表型和基因型之间的凹形关系(即局部适应度景观的凹形)很好地解释，这表明突变稳健性是局部序列空间固有的。结构分析表明，在这一区域，上位性效应在相互作用中涉及溶剂不可及的位置时最为明显。相比之下，所有18个阳性上位的观察结果都涉及到暴露在溶剂中的位置上的至少一个突变。通过结合上位景观的进化和生物物理属性的分析，这些结果有助于更详细地理解蛋白质进化的复杂性。
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.