MECHANISMS AND CONSEQUENCES OF DELETERIOUS EVOLUTION IN BACTERIA

描述(由申请人提供)：分离选择和随机遗传漂移对自然遗传变异的影响是进化生物学中的一个中心挑战。许多理论和实证研究都集中在适合度方面“略有有害”的突变。这些突变的动态受到针对它们的弱自然选择的影响。然而，特别是在小种群中，漂移的随机过程可能会让这些轻微有害的突变持续存在，并最终成为固定的。最近对自然细菌种群的调查显示，有害突变比之前怀疑的更普遍；然而，控制这些突变动态的力量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，这标志着我们对形成自然遗传变异的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，并将在种群、蛋白质和整个基因组水平上探索这些变化的后果。我们将检验种群遗传学理论中的一个关键假设：种群规模的减少会加速轻微有害变化的积累。我们在不同细菌生活方式的背景下测试了这一预测。具体目标包括(1)对比塑造依赖宿主的细菌和它们的自由生活近亲中蛋白质进化的力量，(2)检查有害突变如何塑造宿主与微生物的联系，包括种群水平的变异和基因内容的变化，以及(3)测试基于序列的有害替代推断是否对应于实验室分析中蛋白质活性的降低。这些研究将区分细菌选择和遗传漂移之间的平衡，特别关注种群大小对有害变化动态的影响。意义：该项目的结果将阐明宿主相关细菌之间的进化模式，包括病原体和仅生活在真核宿主细胞内的互助体。对它们的分子多样性和进化动力学的拟议研究将阐明这些物种适应现有寄主和产生新寄主联系的能力。通过破译影响细菌基因组进化的基本机制，这项研究将有助于建立一个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.