Mutation rate catastrophe: testing a novel theory for the extinction of clonal or

描述(申请人提供)：我们建议测试克隆进化是有根本缺陷的假设：在没有遗传交换的情况下，自然选择的适应间接地将突变率推向灾难性的水平，种群突然灭绝这一过程被称为突变率灾难。我们的提议的动机是进化生物学中潜在的深刻影响，以及对公共卫生创新应用的兴趣。如果克隆的这种颠覆效应能够被利用来消灭令人烦恼的微生物种群，这将是一种全新的战略：尽管自然选择适应是当前大多数抗微生物战略的头号敌人，但它将是这一新战略的朋友；事实上，这一战略将由适应驱动，一个种群适应得越快，它就越快被灭绝。为了验证突变率突变假说，我们将：1)发展分析理论，2)进行大规模的电子实验，3)对大肠杆菌进行关键的体外实验。我们的时间有限，对突变率灾难的直接体外观察几乎没有希望，但我们希望通过我们调查的三个组成部分之间的紧密互动来部分弥补这一不足。例如，短期的体外受控实验将提供数据，这些数据将被纳入更自由的硅胶实验。由体外对照实验得知的大规模电子实验中的突变率突变的自发发生，应该为指导体外观察提供一个令人信服的替代物。 项目描述：我们建议测试克隆进化是有根本缺陷的假设：在克隆种群中，自然选择的适应间接地将突变率推向灾难性的水平，种群突然灭绝。如果能够利用这种对自然选择的颠覆来消灭令人烦恼的微生物种群，这将是一种全新的战略：尽管自然选择适应是当前大多数抗微生物战略的头号敌人，但它是这一新战略的朋友；事实上，这一战略是由适应驱动的，一个种群适应得越快，它就越快被灭绝。

DESCRIPTION (provided by applicant): We propose to test the hypothesis that clonal evolution is fundamentally flawed: in the absence of genetic exchange, adaptation by natural selection indirectly drives mutation rates to catastrophic levels, and the population abruptly goes extinct a process that has been dubbed the mutation-rate catastrophe. Our proposal is motivated by the potential for deep implications in evolutionary biology and by intriguing potential for innovative applications to public health. If this subverting effect of clonality could be harnessed to eliminate troublesome microbial populations, it would be an altogether new kind of strategy: whereas adaptation by natural selection is the foremost enemy of most current anti-microbial strategies, it would be a friend to this new strategy; indeed, this strategy would be driven by adaptation, and the faster a population adapts, the more quickly it would be driven extinct. To test the mutation-rate catastrophe hypothesis, we will: 1) develop analytical theory, 2) perform large-scale in silico experiments, and 3) perform key in vitro experiments with Escherichia coli. Our time limitations leave little hope for direct in vitro observation of the mutation-rate catastrophe, but we hope to partially compensate for this short-coming through tight interaction among the three components of our investigation. Short-term, controlled in vitro experiments, for example, will provide data that will be incorporated into the more laisser-faire in silico experiments. Spontaneous occurrence of the mutation-rate catastrophe in large-scale in silico experiments that are informed by controlled in vitro experiments, should provide a compelling surrogate to direct in vitro observation. PROJECT NARRATIVE: We propose to test the hypothesis that clonal evolution is fundamentally flawed: in clonal populations, adaptation by natural selection indirectly drives mutation rates to catastrophic levels, and the population abruptly goes extinct. If such a subversion of natural selection could be harnessed to eliminate troublesome microbial populations, it would be an altogether new kind of strategy: whereas adaptation by natural selection is the foremost enemy of most current anti-microbial strategies, it is a friend to this new strategy; indeed, this strategy is driven by adaptation, and the faster a population adapts, the more quickly it is driven extinct.