Combining Aedes aegypti genomics and modeling to improve gene drive strategies and our understanding of resistance evolution

摘要/摘要 埃及伊蚊是登革热、基孔肯雅热、寨卡和城市黄色的主要传播媒介 发烧病毒登革热已成为人类最重要的节肢动物传播病毒感染 国际吧这些病原体中的每一种都可能与爆发性流行病有关， 疾病发病率和公众恐惧联合收割机使卫生系统不堪重负。公共卫生部门 往往采取紧急的、以杀虫剂为基础的病媒控制措施。喷洒拟除虫菊酯 杀虫剂是防治Ae.埃及人控制了许多国家。而 这种喷洒对疾病抑制的影响受到质疑，毫无疑问， 重复使用拟除虫菊酯喷雾剂导致了地理上广泛的抗药性演变 以及拟除虫菊酯对蚊子密度影响的丧失。 超过10，000份Ae的存档样本。自2000年以来，从秘鲁的伊基托斯收集的埃及 保持在-80杰C并具有完整的DNA。在这段时间内，拟除虫菊酯喷雾剂在伊基托斯的效果 由于阻力而大幅下降。这些样本将用于评估空间分布模式。 以及与拟除虫菊酯抗性相关的基因和基因组分化的时间变化。 有了这些基因组信息，就有可能检验关于拟除虫菊酯动力学的假设 抗性进化和关于新基因驱动策略功效的假设， 抑制Ae。埃及种群或降低蚊子传播病原体的能力。这些 测试将通过用于分析配合结构的新算法来实现。一个空间上明确的， Ae.随机模型埃及的人口动态和遗传学将通过 新的基因组数据，并用于预测杀虫剂抗性和基因驱动的未来动态。 这项工作的成果将为研究，监管和管理社区提供 更准确地预测各种基因驱动策略的动力学所需的信息 虫媒病毒对杀虫剂抗药性的传播。 我们在这个项目中有三个目标，它们将共同导致这些更准确的预测： AIM 1.使用单基因和全基因组方法来表征时间和空间遗传 在Ae.埃及人 AIM 2.使用目标1中的数据来更准确地理解运动和交配 的结构。aegypti AIM 3.将目标2的结果纳入详细的Ae。埃及模式，并使用它来测试各种 现有的和新的战略，基因驱动以及监测进化的抗性在Ae。 基因驱动和杀虫剂的使用。 !

Summary/Abstract The mosquito, Aedes aegypti, is a primary vector for dengue, chikungunya, Zika, and urban yellow fever viruses. Dengue has become the most important human arthropod-borne viral infection worldwide. Each of these pathogens can be associated with explosive epidemics, where high disease incidence and public fear combine to overwhelm health systems. Public health departments often react with emergency insecticide-based vector control measures. Spraying with pyrethroid insecticides is the main approach used for adult Ae. aegypti control in many countries. While the impact of this spraying on disease suppression has been questioned, there is no doubt that the repeated use of pyrethroid sprays has caused geographically widespread evolution of resistance and loss of impact of pyrethroids on mosquito densities. Over 10,000 archived samples of Ae. aegypti collected from Iquitos, Peru since 2000 are being held at -80˚C and have intact DNA. Over this period of time pyrethroid spray efficacy in Iquitos has declined substantially due to resistance. These samples will be used to assess patterns of spatial and temporal change in genes associated with pyrethroid resistance and in genomic differentiation. With this genomic information it will be possible to test hypotheses about the dynamics of pyrethroid resistance evolution and hypotheses about the efficacy of new gene drive strategies that could suppress Ae. aegypti populations or lower the ability of the mosquito to transmit pathogens. These tests will be enabled by new algorithms for analysis of mating structure. A spatially explicit, stochastic model of Ae. aegypti population dynamics and genetics will be parameterized with the new genomic data and used to predict future dynamics of insecticide resistance and gene drives. Outcomes of this work will provide research, regulatory, and management communities with information needed to more accurately predict dynamics of a variety of gene drive strategies as well as the spread of resistance to insecticides in this arbovirus vector. We have three Aims in this project that will together result in these more accurate predictions: AIM 1. Use single gene and genome-wide methods to characterize temporal and spatial genetic differentiation in Ae. aegypti populations AIM 2. Use the data from Aim 1 to develop a more accurate understanding of the movement and mating structure of Ae. aegypti AIM 3. Incorporate findings from Aim 2 into a detailed Ae. aegypti model, and use it to test a variety of existing and new strategies for gene drives as well as for monitoring evolution of resistance in Ae. aegypti to use of gene drives and insecticides. !