Department of Genetics, Stanford University, Stanford, California, United States of America.
PLoS Genet. 2011 Apr;7(4):e1002056. doi: 10.1371/journal.pgen.1002056. Epub 2011 Apr 28.
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.
适应度景观捕捉了基因型和进化适应度之间的关系，是一个普遍用于描述适应进化可能轨迹的隐喻。然而，关于适应度景观的实际形状，包括低适应度的山谷是否会形成局部适应度最优值，从而成为适应变化的障碍，我们知之甚少。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粗糙分子适应度景观的证据。我们使用全基因组测序来识别进化过程中出现的突变，并使用竞争适应度测定来描述单个突变对适应的贡献。此外，我们发现，在基因 MTH1 和 HXT6/HXT7 中的两个适应性突变之间存在一个适应度低谷，这是由于相互符号上位性造成的，即双突变体的适应度代价阻止了这两个突变在相同的遗传背景中被选择。相互符号上位性所施加的约束导致在实验过程中这些突变保持相互排斥，尽管在实验过程中这两个基因中的适应性突变在独立的谱系中发生了几次。我们的研究结果表明，上位性在适应过程中起着关键作用，并且基因间相互作用可以作为适应性解决方案之间的障碍。这些结果还为经典的 Dobzhansky-Muller 生殖隔离模型提供了新的解释，并与经常与肿瘤相关的基因中的突变显示出一些令人惊讶的相似之处。
