Role of spatial structure in shaping viral population diversity and evolution

空间结构在塑造病毒种群多样性和进化中的作用

• 批准号: 10458087
• 负责人: Katharina V Koelle
• 金额: $ 55.96万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-17 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458087
• 关键词: Bar Codes; Cell Culture System; Cell Culture Techniques; Cells; Characteristics; Collection; Complement; Coupled; Cysteine; Data; Disease; Distant; Effectiveness; Environment; Epidemic; Epidemiology; Event; Evolution; Experimental Models; Ferrets; Founder Effect; Frequencies; Genetic Drift; Genetic Polymorphism; Genetic Recombination; Genetic Variation; Genome; Heterogeneity; Human; Immune response; Immunity; Influenza A Virus, H3N2 Subtype; Influenza A virus; Lead; Maintenance; Mathematics; Measures; Modeling; Molecular; Molecular Virology; Mutation; NP protein; Natural Selections; Nature; Nucleotides; Panama; Pattern; Phenotype; Population; Population Biology; Population Dynamics; Population Heterogeneity; Property; Public Health; RNA Viruses; Research; Research Support; Role; Seeds; Shapes; Site; Stochastic Processes; Structure; System; Testing; Variant; Viral; Virion; Virus; Virus Diseases; Work; base; design; driving force; experimental study; fitness; genetic evolution; genetic selection; influenzavirus; insight; models and simulation; next generation sequencing; novel; pandemic influenza; pathogenic virus; permissiveness; predictive modeling; systems research; theories; tool; virus genetics; zoonotic spillover

Summary Viral evolution enables the emergence of novel viral pathogens in the human population. The evolution of influenza A virus is also critical for the maintenance of seasonal lineages in the context of host immunity. Evolution can result from selection, leading to increased fitness, or stochastic processes that typically decrease fitness. The relative potency of selective and stochastic forces is therefore a critical determinant of the adaptive potential of a population. Based on evolutionary theory, we hypothesize that the magnitude of stochastic effects in viral evolution is strongly impacted by the spatial structure that characterizes viral spread within a host. In other words, the expansion of a virus population in space may give rise to random, within-host bottlenecks and founder effects that weaken the efficiency of natural selection. Factors that shape viral spread - including viral phenotypes, host responses and physical characteristics of the host environment - are therefore predicted to impact viral genetic diversity and evolution. Our overarching hypothesis is that viral features that modulate viral spatial structure also modulate viral diversity and evolution. We will test this hypothesis for influenza A virus using a well-integrated combination of simulation modeling and experimental approaches. In Aim 1, we will use computational, cell culture and ferret models to examine the consequences of spatially structured spread for genetic diversity of viral populations. For our experiments, we will use viruses carrying a selectively neutral barcode to allow robust quantification of viral diversity. In this way, the degree to which stochastic effects dominate viral dynamics will be examined under a range of conditions. In Aim 2, we will evaluate the consequences of spatially structured spread for both purifying and positive selection. Computational approaches will be used to develop hypotheses of how long distance virus dispersal impacts the ability of de novo beneficial and deleterious mutations to reach dominance. These model predictions will then be tested using experimental evolution under conditions of common vs. rare long distance dispersal. In this way, we will test the theoretical concept that stochastic effects associated with spatial structure impede the ability of natural selection to act on expanding populations. Taken together, the research proposed in these two aims will uncover the importance of spatial structure to viral population biology and evolution, deepening our fundamental understanding of the forces shaping viral evolution in nature.

概括 病毒进化使人种群中新型病毒病原体的出现。演变 流感病毒对于在宿主免疫的背景下维持季节性谱系也至关重要。 进化可能是由于选择而导致的，导致健身或通常会降低的随机过程 健康。因此，选择性和随机力的相对效力是适应性的关键决定因素 人口的潜力。基于进化论，我们假设随机效应的幅度 在病毒演化中，在宿主内病毒传播的空间结构受到强烈影响。在 换句话说，空间中病毒种群的扩展可能会引起随机的，内部的瓶颈，并且 创始人效应削弱了自然选择效率。塑造病毒传播的因素 - 包括病毒 因此，预测表型，宿主反应和宿主环境的身体特征 - 影响病毒遗传多样性和进化。我们的总体假设是调节病毒特征 病毒空间结构还调节病毒多样性和进化。我们将检验流感的假设 使用模拟建模和实验方法的完善组合的病毒。在AIM 1中，我们 将使用计算，细胞培养和雪貂模型来检查空间结构扩散的后果 用于病毒种群的遗传多样性。对于我们的实验，我们将使用携带有选择性中性的病毒 条形码以允许对病毒多样性的强大定量。这样，随机效应的程度 在一系列条件下，将检查主导病毒动力学。在AIM 2中，我们将评估 空间结构扩散的后果既可以纯化和阳性选择。计算方法 将用于制定假设的假设，即距离病毒分散多长时间影响从头有益的能力 和有害突变以达到主导地位。然后将使用实验测试这些模型预测 在常见条件与稀有长距离分散条件下的进化。这样，我们将测试理论 与空间结构相关的随机效应的概念阻碍了自然选择作用的能力 人口不断扩大。综上所述，这两个目标中提出的研究将揭示 病毒种群生物学和进化的空间结构，加深了我们对力量的基本理解 在自然界中塑造病毒进化。