MECHANISMS AND CONSEQUENCES OF DELETERIOUS EVOLUTION IN BACTERIA

描述（由申请人提供）：解开自然遗传变异的选择和随机遗传漂变的影响代表了进化生物学的核心挑战。许多理论和实证研究都集中在对适应性“轻微有害”的突变上。这些突变的动态受到针对它们的弱自然选择的影响。然而，特别是在小群体中，漂移的随机过程可能会使这些轻度有害的突变持续存在并最终变得固定。最近对天然细菌种群的调查显示，有害突变比以前怀疑的更普遍;然而，控制这些突变动态的力量之间的相互作用在很大程度上仍未被探索。由于细菌构成了地球生物多样性的很大一部分，这表明我们对自然遗传变异过程的理解存在巨大差距。目的：拟议的项目将阐明影响细菌有害突变动态的进化力量，并将探索这些变化在种群、蛋白质和整个基因组水平上的后果。我们将检验种群遗传理论的一个关键假设：种群规模的减少加速了轻度有害变化的积累。我们在不同细菌生活方式的背景下测试了这一预测。具体目的包括：（1）对比宿主依赖性细菌与其自由生活的亲属中形成蛋白质进化的力量，（2）检查有害突变如何形成宿主-微生物关联，包括种群水平的变异和基因内容的改变，以及（3）测试有害取代的基于序列的推断是否对应于基于实验室的测定中蛋白质活性的降低。这些调查将区分选择和细菌遗传漂变之间的平衡，特别关注种群大小对有害变化动态的影响。重要性：这个项目的结果将阐明宿主相关细菌之间的进化模式，包括病原体和只生活在真核宿主细胞内的互利主义者。拟对其分子多样性和进化动力学进行的研究将阐明这些物种适应当前宿主和产生新的宿主关系的能力。通过破译影响细菌基因组进化的基本机制，这项研究将有助于了解微生物如何进化的预测框架。

DESCRIPTION (provided by applicant): Disentangling the effects of selection and random genetic drift on natural genetic variation represents a central challenge in evolutionary biology. Many theoretical and empirical studies have focused on mutations that are 'slightly deleterious' with respect to fitness. The dynamics of these mutations are influenced by weak natural selection against them. However, particularly in small populations, the stochastic process of drift may allow these mildly harmful mutations to persist and eventually become fixed. Recent surveys of natural bacterial populations reveal that deleterious mutations are more prevalent than previously suspected; yet the interplay of forces governing the dynamics of these mutations remains largely unexplored. Since bacteria comprise a substantial fraction of Earth's biodiversity, this signals an enormous gap in our understanding of the processes that shape natural genetic variation. OBJECTIVES: The proposed project will clarify the evolutionary forces that influence the dynamics of deleterious mutations in bacteria, and will explore the consequences of these changes at the levels of populations, proteins, and whole genomes. We will test a key hypothesis from population genetic theory: a reduction in population size accelerates the accumulation of mildly harmful changes. We test this prediction in the context of different bacterial lifestyles. Specific Aims include (1) contrasting forces that shape protein evolution in host-dependent bacteria versus their free-living relatives, (2) examining how deleterious mutations shape host-microbe associations, including population-level variation and alterations in gene content, and (3) testing whether sequence-based inferences of deleterious substitutions correspond to reduced protein activities in lab-based assays. These investigations will distinguish the balance between selection and genetic drift in bacteria, with a particular focus on the influence of population size on the dynamics of deleterious changes. SIGNIFICANCE: Results of this project will elucidate modes of evolution among host-associated bacteria, including both pathogens and mutualists that live exclusively within eukaryotic host cells. The proposed studies of their molecular diversity and evolutionary dynamics will clarify the ability of these species to adapt to current hosts and to originate new host associations. By deciphering fundamental mechanisms that influence bacterial genome evolution, this study will contribute to a predictive framework for understanding how microbes evolve.