Nonlinear fitness landscape of a molecular pathway.
Nonlinear fitness landscape of a molecular pathway.
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DOI：
10.1371/journal.pgen.1002160
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发表时间：
2011-07
期刊：
影响因子：
4.5
通讯作者：
Lässig M
中科院分区：
文献类型：
--
作者：
Perfeito L;Ghozzi S;Berg J;Schnetz K;Lässig M
基因受到调控，因为它们的表达涉及生物体的适应性成本。通过转录和翻译产生蛋白质是众所周知的成本因素，但所产生的蛋白质的酶活性也会降低适应性，这取决于细胞的内部状态和环境。在这里，我们映射的健身成本的一个关键的代谢网络，乳糖利用途径在大肠杆菌。我们测量了几种调节乳糖操纵子突变体在不同环境中诱导乳糖基因表达的生长。我们发现一个惊人的非线性健身景观，这取决于生产率和活性率的紫胶蛋白。一个简单的健身模型的乳糖途径，基本的生物物理过程的基础上，预测所有观察到的菌株的生长速度。适应性的非线性可以用反馈回路来解释：紫胶蛋白的产生和活性会降低生长，但生长也会影响这些分子的密度。这种非线性对分子的功能和进化有着重要的影响。它在适合度景观中产生了一个悬崖，超过这个悬崖，人口就无法保持增长。在有活力的群体中，存在lac基因的表达屏障，其在任何静止生长过程中都不能被超过。此外，非线性决定了操纵子突变体的适应性如何取决于诱导物环境。我们认为，健身非线性，表达障碍，基因与环境的相互作用是代谢途径的健身景观的一般特征，我们讨论了它们的影响，监管的演变。生物体产生的蛋白质水平可能会改变其适应性，从而可能推动遗传调控的进化。重要的是，蛋白质表达产生成本以及收益。在这里，我们使用一个模型遗传系统，乳糖操纵子的大肠杆菌，调查不同来源的健身成本。我们发现，健身不仅取决于蛋白质的生产率，但也对他们的酶活性。一个简单的定量模型，这是基于蛋白质的生产和活动的生物物理学，准确地再现了实验结果，并提供可测试的预测。该模型描述了分子途径和细胞生长速率之间的反馈循环：途径活性阻碍生长，但生长本身影响途径。这种反馈可以产生戏剧性的效果，如基因表达障碍，健身悬崖和人口排斥，这可以由小的环境或遗传变化引发。我们的研究结果解开了蛋白质生产和活动的复杂相互作用，并展示了这些过程如何塑造简单生物体的进化。
Genes are regulated because their expression involves a fitness cost to the organism. The production of proteins by transcription and translation is a well-known cost factor, but the enzymatic activity of the proteins produced can also reduce fitness, depending on the internal state and the environment of the cell. Here, we map the fitness costs of a key metabolic network, the lactose utilization pathway in Escherichia coli. We measure the growth of several regulatory lac operon mutants in different environments inducing expression of the lac genes. We find a strikingly nonlinear fitness landscape, which depends on the production rate and on the activity rate of the lac proteins. A simple fitness model of the lac pathway, based on elementary biophysical processes, predicts the growth rate of all observed strains. The nonlinearity of fitness is explained by a feedback loop: production and activity of the lac proteins reduce growth, but growth also affects the density of these molecules. This nonlinearity has important consequences for molecular function and evolution. It generates a cliff in the fitness landscape, beyond which populations cannot maintain growth. In viable populations, there is an expression barrier of the lac genes, which cannot be exceeded in any stationary growth process. Furthermore, the nonlinearity determines how the fitness of operon mutants depends on the inducer environment. We argue that fitness nonlinearities, expression barriers, and gene–environment interactions are generic features of fitness landscapes for metabolic pathways, and we discuss their implications for the evolution of regulation. The levels of protein produced by an organism are likely to change its fitness, potentially driving the evolution of genetic regulation. Importantly, protein expression generates costs as well as benefits. Here, we use a model genetic system, the lac operon of Escherichia coli, to investigate different sources of fitness costs. We find that fitness depends not only on the production rate of proteins but also on their enzymatic activity. A simple quantitative model, which is based on the biophysics of protein production and activity, accurately reproduces the experimental results and provides testable predictions. The model describes a feedback cycle between a molecular pathway and the growth rate of cells: pathway activity impedes growth, but growth itself affects the pathway. This feedback can generate dramatic effects, such as gene expression barriers, fitness cliffs, and population extinctions, which can be triggered by small environmental or genetic changes. Our results disentangle the complex interplay of protein production and activity, and they show how these processes shape the evolution of simple organisms.
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影响因子：
64.8
作者：
Dekel, E;Alon, U
通讯作者：
Alon, U
DOI：
10.1073/pnas.43.7.553
发表时间：
1957-01-01
影响因子：
11.1
作者：
NOVICK, A;WEINER, M
通讯作者：
WEINER, M
影响因子：
2.9
作者：
LENSKI, RE;ROSE, MR;TADLER, SC
通讯作者：
TADLER, SC
影响因子：
2
作者：
Noel, Jason T.;Pilyugin, Sergei S.;Narang, Atul
通讯作者：
Narang, Atul
影响因子：
3.8
作者：
Cheng, B;Fournier, RL;Schisler, J
通讯作者：
Schisler, J