The Evolution of Evolvability in Microbial Populations

演化动力学模型通常将演化参数视为固定参数。然而，这些参数本身可以通过突变进行修改，然后通过自然选择进行作用，这种现象被称为可进化性的进化。例如，增加或减少突变率的增变基因或反增变基因等位基因通常在微生物种群中传播，而打开或关闭未来适应性轨迹的突变可以改变“适应性”。尽管做了大量的工作，我们对微生物种群进化性的理解仍然非常有限。基本的问题是，在许多微生物和病毒所特有的大规模无性种群中，进化往往以挑战传统模型的方式进行，因为同时发生的事情太多了。许多突变通常同时存在，由于重组是有限的，选择不能单独作用于每个突变。相反，突变是在物理染色体上连接在一起的各种组合中不断发生的，选择只能对这些组合作为一个整体起作用。这些被称为干扰选择的效应对微生物进化产生了巨大的限制，并且使得分析自然选择如何作用于改变进化参数的突变变得困难。PI将通过使用数学模型和芽殖酵母中的实验进化的组合来解决这个问题，以分析这些干扰选择效应普遍存在的微生物种群中的可进化性的进化。该项目将产生大量的数据，描述固定突变，序列多样性，并在有性和无性酵母菌群的健身变化，沿着相应的菌株库，这将作为社区的资源。在这个过程中，这项工作将提供广泛的跨学科培训，从进化生物学，分子遗传学，群体遗传学的方法，并在PI的实验室为博士后和研究生和本科生应用数学。为了帮助培养这些不同领域的潜在定量生物学家的更广泛的社区，PI将开展外联工作，以传播他为本科生物学入门开发的新课程，该课程提供了对生物学，物理学，化学，计算机科学和数学的综合介绍。最后，PI将开发一本新的教科书，介绍进化和群体遗传学，针对数学家和物理学家。这本教科书将提供一个数学上复杂的介绍该领域，没有任何生物学的先决条件，根据材料的PI开发的本科课程在这个问题上，并在夏季课程由PI组织。在这个建议中描述的行波框架是这个主题的一个关键的理论基础，并将在书中发挥重要作用。高通量实验技术和测序技术的进步说明了干扰选择在整个微生物进化过程中的普遍重要性。受此启发，最近的许多工作都分析了大型无性种群的干扰。然而，这项工作仅限于简单的情况下，进化参数是固定的，因此不能解释进化的进化。在这个项目中，PI将通过将统计物理学启发的新理论方法与直接观察芽殖酵母实验种群的进化相结合来解决这个问题。PI将专注于分析改变突变率、适应性和鲁棒性的等位基因。中心目标是预测（1）干扰选择如何影响这些修饰基因等位基因的进化动态和命运，从而影响微生物种群可进化性的长期进化，（2）可进化性修饰基因如何影响种群内序列多样性的动态，以及（3）该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准。

Models of evolutionary dynamics often treat the evolutionary parameters as fixed. Yet these parameters can themselves be modified by mutations, which are then acted on by natural selection, a phenomenon known as the evolution of evolvability. For example, mutator or antimutator alleles that increase or decrease mutation rates often spread through microbial populations, and mutations that open up or close off future adaptive trajectories can alter "adaptability". Despite extensive work, our understanding of the evolution of evolvability in microbial populations remains very limited. The basic problem is that in the large and mostly asexual populations characteristic of many microbes and viruses, evolution often acts in ways that challenge traditional models, because there is too much going on at once. Many mutations are often present simultaneously, and because recombination is limited, selection cannot act on each separately. Rather, mutations are constantly occurring in a variety of combinations linked together on physical chromosomes, and selection can only act on these combinations as a whole. These effects, known as interference selection, place enormous constraints on microbial evolution, and have made it difficult to analyze how natural selection acts on mutations that modify evolutionary parameters. The PI will address this question by using a combination of mathematical models and experimental evolution in budding yeast to analyze the evolution of evolvability in microbial populations where these interference selection effects are widespread. This project will produce extensive data describing fixed mutations, sequence diversity, and changes in fitness in sexual and asexual yeast populations, along with a corresponding library of strains, which will serve as a resource for the community. In the process, this work will provide broad interdisciplinary training in methods from evolutionary biology, molecular genetics, population genetics, and applied math for a postdoc and graduate and undergraduate students in the PI's lab. To help train the broader community of potential quantitative biologists in these diverse fields, the PI will develop outreach efforts to disseminate a new curriculum he has developed for introductory undergraduate biology, which provides an integrated introduction to biology, physics, chemistry, computer science, and mathematics. Finally, the PI will develop a new textbook providing an introduction to evolution and population genetics, aimed at mathematicians and physical scientists. This textbook will provide a mathematically sophisticated introduction to the field, without any biological prerequisites, based on materials the PI developed for an undergraduate course on this subject and on a summer course organized by the PI. The traveling wave framework described in this proposal is a key theoretical underpinning of much of this subject, and will play an important role in the book. High-throughput experimental techniques and advances in sequencing technology now illustrate the pervasive importance of interference selection throughout microbial evolution. Motivated by this, much recent work has analyzed interference in large asexual populations. However, this work is limited to simple situations where the evolutionary parameters are fixed, and hence cannot explain the evolution of evolvability. In this project, the PI will address this question by combining novel theoretical methods inspired by statistical physics with direct observation of evolution in experimental populations of budding yeast. The PI will focus on analyzing alleles that modify mutation rates, adaptability, and robustness. The central goals are to predict (1) how interference selection affects the evolutionary dynamics and fates of these modifier alleles and hence the long-term evolution of evolvability in microbial populations, (2) how the modifiers of evolvability affect the dynamics of sequence diversity within the population, and (3) how recombination affects the evolution of evolvability.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.