Reciprocal Sign Epistasis between Frequently Experimentally Evolved Adaptive Mutations Causes a Rugged Fitness Landscape
Reciprocal Sign Epistasis between Frequently Experimentally Evolved Adaptive Mutations Causes a Rugged Fitness Landscape
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DOI：
10.1371/journal.pgen.1002056
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发表时间：
2011-04-01
期刊：
影响因子：
4.5
通讯作者：
Sherlock, Gavin
中科院分区：
文献类型：
--
作者：
Kvitek, Daniel J.;Sherlock, Gavin
适应度图景捕捉了基因和进化适应度之间的关系，是一个普遍使用的比喻，用于描述可能的适应进化轨迹。然而，人们对适应环境的实际形态知之甚少，包括低适应度山谷是否会产生局部适应最优状态，从而成为适应变化的障碍。在这里，我们提供了在酿酒酵母无性种群的进化实验中出现的崎岖的分子适应性图景的证据。我们使用全基因组测序来识别在进化过程中出现的突变，并使用竞争适应度分析来描述单独导致适应的突变。此外，我们还发现MTH1和HXT6/HXT7基因的两个适应性突变之间的适应度谷是由符号上位互换引起的，其中双突变体的适应度成本阻止了这两个突变在相同的遗传背景下被选择。由互换符号上位施加的约束导致突变在实验期间保持互斥，即使这两个基因在实验期间在独立的谱系中发生了几次适应性突变。我们的结果表明，上位性在适应过程中起着关键作用，基因间的相互作用可以作为适应性解决方案之间的障碍。这些结果还对经典的Dobzansky-Muller生殖隔离模型提供了新的解释，并显示了一些令人惊讶的与肿瘤相关基因突变的相似之处。
The fitness landscape captures the relationship between genotype and evolutionary fitness and is a pervasive metaphor used to describe the possible evolutionary trajectories of adaptation. However, little is known about the actual shape of fitness landscapes, including whether valleys of low fitness create local fitness optima, acting as barriers to adaptive change. Here we provide evidence of a rugged molecular fitness landscape arising during an evolution experiment in an asexual population of Saccharomyces cerevisiae. We identify the mutations that arose during the evolution using whole-genome sequencing and use competitive fitness assays to describe the mutations individually responsible for adaptation. In addition, we find that a fitness valley between two adaptive mutations in the genes MTH1 and HXT6/HXT7 is caused by reciprocal sign epistasis, where the fitness cost of the double mutant prohibits the two mutations from being selected in the same genetic background. The constraint enforced by reciprocal sign epistasis causes the mutations to remain mutually exclusive during the experiment, even though adaptive mutations in these two genes occur several times in independent lineages during the experiment. Our results show that epistasis plays a key role during adaptation and that inter-genic interactions can act as barriers between adaptive solutions. These results also provide a new interpretation on the classic Dobzhansky-Muller model of reproductive isolation and display some surprising parallels with mutations in genes often associated with tumors.