Evolutionary dynamics of CRISPR gene drives in natural populations

项目摘要 CRISPR基因驱动可以有效地将具有一个驱动等位基因副本的杂合子细胞转化为 纯合子，从而使超孟德尔遗传成为可能。这样的机制可以用于 例如，通过疾病媒介种群快速传播基因有效载荷，从而减少 病原体传播或直接抑制病媒，有望成为控制该病的新策略 病媒传播的疾病。然而，我们目前对这种方法将如何在 自然人口充其量也就是最基本的。CRISPR基因驱动是一个复杂的进化过程 取决于各种因素，如抵抗演变为对驱动力的可能性，空间 目标种群的结构和迁徙模式，以及个体之间的遗传变异。这个 这一建议的首要目标是更好地理解生物进化的动力学 CRISPR基因驱动策略在目标人群的现实模型中考虑了这些复杂性 帐号。在具体目标1中，我们将开发一个全面的CRISPR基因建模框架 我们最近在驱动机制、抗性等位基因等方面的实验发现将为我们提供信息 在遗传多样性的种群中，耐药性的形成和变异。这一框架将允许 美国将探索旨在降低阻力潜力的不同驱动策略的表现，例如 多个gRNA的使用和单倍体不足基因的靶向。在具体目标2中，我们将利用 我们实验室开发的尖端模拟方法，用于研究CRISPR基因驱动如何运行 在空间上明确的人口模型中，个体在连续的地貌中移动，并且可以 体验彼此之间以及与当地环境之间的复杂互动。我们假设这些 空间模型将产生泛泛种群模型中不存在的新现象，如 作为一种已经蔓延到很大一部分人口中的驱动力的消除 由于这场运动的健身成本，当地的人口数量急剧减少。在具体目标3中，我们将使用建模 前两项中开发的框架旨在研究最近提出的安全措施是否可以 在驱动器被释放到目标人群之后，可靠地限制和控制驱动器，专注于 驱动遗传学、抗性进化和迁移动力学之间的复杂相互作用 个人胜过现实的风景。我们的框架将使我们能够调查和预测人口 CRISPR基因驱动方法在特定经验条件下的动力学，这将是 任何关于这种方法的可行性、稳健性和风险的知情讨论。

Project Summary CRISPR gene drives can efficiently convert heterozygous cells with one copy of the drive allele into homozygotes, thereby enabling super-Mendelian inheritance. Such a mechanism could be used, for example, to rapidly disseminate a genetic payload through a disease-vector population that reduces pathogen transmission or directly suppresses the vector, promising novel strategies for the control of vector-borne diseases. However, our current understanding of how such an approach would perform in a natural population is at best rudimentary. CRISPR gene drive is a complex evolutionary process that depends on various factors such as the likelihood that resistance evolves against the drive, the spatial structure and migration patterns of the target population, and genetic variation among individuals. The overarching goal of this proposal is to gain a better understanding of the evolutionary dynamics of CRISPR gene drive strategies in realistic models of target populations that take these complexities into account. In Specific Aim 1 we will develop a comprehensive modeling framework for CRISPR gene drives that will be informed by our recent experimental findings on drive mechanisms, resistance allele formation, and variation in resistance rates in genetically diverse populations. This framework will allow us to explore the performance of different drive strategies aimed at reducing resistance potential, such as the use of multiple gRNAs and the targeting of haploinsufficient genes. In Specific Aim 2 we will utilize cutting-edge simulation approaches developed in our lab to study how CRISPR gene drives will perform in spatially explicit population models, in which individuals move across a continuous landscape and can experience complex interactions with each other and their local environment. We hypothesize that these spatial models will give rise to new phenomena that are not present in panmictic population models, such as the elimination of a drive that has already spread into a large fraction of the population when populations collapse locally due to the fitness cost of the drive. In Specific Aim 3 we will use the modeling framework developed in the first two aims to study whether recently proposed safety measures can reliably confine and control a drive after it has been released into a target population, focusing on the complex interplay between drive genetics, the evolution of resistance, and the migration dynamics of individuals over realistic landscapes. Our framework will allow us to probe and predict the population dynamics of CRISPR gene drive approaches under specific empirical conditions, which will be integral to any informed discussion about the feasibility, robustness, and risks of such approaches.