Role of spatial structure in shaping viral population diversity and evolution

总结 病毒进化使新的病毒病原体在人群中出现。的演变 甲型流感病毒对于在宿主免疫的情况下维持季节性谱系也是至关重要的。 进化可以是选择的结果，导致适应性的增加，也可以是随机过程的结果， 健身因此，选择力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。基于进化理论，我们假设随机效应的大小 在病毒进化中，病毒在宿主中传播的空间结构对其有很大的影响。在 换句话说，病毒种群在太空中的扩张可能会引起随机的宿主内瓶颈， 创始人效应削弱了自然选择的效率。塑造病毒传播的因素-包括病毒 表型、宿主反应和宿主环境的物理特征-因此预测， 影响病毒遗传多样性和进化。我们的总体假设是，调节 病毒空间结构也调节病毒多样性和进化。我们将用流感来检验这一假设 一种病毒，使用模拟建模和实验方法的良好集成组合。目标1： 将使用计算机、细胞培养和雪貂模型来研究空间结构传播的后果 病毒种群的遗传多样性在我们的实验中，我们将使用携带选择性中性 条形码以允许病毒多样性的稳健定量。这样，随机效应 将在一系列条件下检查主要病毒动力学。在目标2中，我们将评估 空间结构扩散的结果，为净化和积极的选择。的计算方法 将被用来发展长距离病毒传播如何影响从头有益的能力的假设， 和有害的突变来达到统治地位。这些模型预测将通过实验进行测试。 在常见和罕见的长距离扩散条件下的进化。通过这种方式，我们将测试理论 与空间结构相关的随机效应阻碍了自然选择作用于 扩大人口。综合起来，这两个目标中提出的研究将揭示 空间结构到病毒种群生物学和进化，加深我们对力量的基本理解 塑造自然界中病毒的进化。

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.