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

描述（由申请人提供）：我们建议测试克隆进化从根本上有缺陷的假设：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水平，种群突然灭绝。 这个过程被称为突变率灾难。我们的提议是出于对进化生物学的潜在深刻影响以及对公共卫生创新应用的潜在吸引力。如果可以利用克隆性的这种颠覆作用来消除麻烦的微生物种群，这将是一种全新的策略：虽然自然选择的适应是大多数当前抗微生物策略的最大敌人，但它将是这种新策略的朋友;事实上，这种策略将由适应驱动，种群适应得越快，它就越快地被灭绝。为了检验突变率突变假设，我们将：1）开发分析理论，2）进行大规模的计算机实验，3）用大肠杆菌进行关键的体外实验。我们的时间限制使得在体外直接观察突变率灾难的希望渺茫，但我们希望通过我们研究的三个组成部分之间的紧密相互作用来部分弥补这一不足。例如，短期的受控体外实验将提供数据，这些数据将被纳入更自由的计算机实验中。由受控体外实验提供信息的大规模计算机模拟实验中突变率灾难的自发发生应提供一个令人信服的替代品来指导体外观察。 项目叙述：我们建议测试的假设，克隆进化是从根本上有缺陷的：在克隆种群，自然选择的适应间接驱动突变率到灾难性的水平，人口突然灭绝。如果能利用这种对自然选择的颠覆来消灭麻烦的微生物种群，这将是一种全新的策略：自然选择的适应是当前大多数抗微生物策略的头号敌人，它是这种新策略的朋友;事实上，这种策略是由适应驱动的，种群适应得越快，灭绝得越快。

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.