Data from: Mapping the fitness landscape of gene expression uncovers the cause of antagonism and sign epistasis between adaptive mutations

How do adapting populations navigate the tensions between the costs of gene expression and the benefits of gene products to optimize the levels of many genes at once? Here we combined independently-arising beneficial mutations that altered enzyme levels in the central metabolism of Methylobacterium extorquens to uncover the fitness landscape defined by gene expression levels. We found strong antagonism and sign epistasis between these beneficial mutations. Mutations with the largest individual benefit interacted the most antagonistically with other mutations, a trend we also uncovered through analyses of datasets from other model systems. However, these beneficial mutations interacted multiplicatively (i.e., no epistasis) at the level of enzyme expression. By generating a model that predicts fitness from enzyme levels we could explain the observed sign epistasis as a result of overshooting the optimum defined by a balance between enzyme catalysis benefits and fitness costs. Knowledge of the phenotypic landscape also illuminated that, although the fitness peak was phenotypically far from the ancestral state, it was not genetically distant. Single beneficial mutations jumped straight toward the global optimum rather than being constrained to change the expression phenotypes in the correlated fashion expected by the genetic architecture. Given that adaptation in nature often results from optimizing gene expression, these conclusions can be widely applicable to other organisms and selective conditions. Poor interactions between individually beneficial alleles affecting gene expression may thus compromise the benefit of sex during adaptation and promote genetic differentiation.

处于适应过程的种群如何权衡基因表达的成本与基因产物的收益，以同时优化多基因的表达水平？本研究结合了扭脱甲基杆菌（Methylobacterium extorquens）中心代谢中调控酶水平的独立起源有益突变，以解析由基因表达水平定义的适合度景观（fitness landscape）。我们发现这类有益突变之间存在强烈的拮抗作用与符号上位性（sign epistasis）。单个突变的适合度增益最大，与其他突变的拮抗作用也最为显著，这一规律在其他模式生物的数据集分析中同样得到了验证。然而在酶表达层面，这些有益突变的效应呈相乘关系（即无上位性）。通过构建基于酶水平预测适合度的模型，我们可将观测到的符号上位性解释为：表达水平超过了由酶催化收益与适合度成本的平衡所确定的最优值，即出现了“过冲”现象。对表型景观的认知还揭示，尽管适合度峰值在表型上与祖先状态相去甚远，但在遗传上并不遥远。单个有益突变可直接指向全局最优表型，而非受限于遗传架构所预期的相关表达表型变化模式。鉴于自然界中的适应往往通过优化基因表达实现，本研究结论可广泛推广至其他生物与各类选择条件。由此可见，影响基因表达的单个有益等位基因之间的不良互作，可能会在适应过程中削弱有性生殖的优势，并推动遗传分化。