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、寨卡病毒和城市黄热病的主要传播媒介。 发烧病毒。登革热已成为最重要的人类节肢动物传播病毒感染 全世界。这些病原体中的每一种都可能与爆炸性流行病有关，其中高 疾病发病率和公众恐惧结合在一起，使卫生系统不堪重负。公共卫生部门 经常对以杀虫剂为基础的病媒控制措施作出紧急反应。拟除虫菊酯喷雾 杀虫剂是防治成虫的主要手段。埃及伊蚊在许多国家得到控制。而当 这种喷洒对疾病抑制的影响一直受到质疑，毫无疑问 反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的影响减弱。 超过10,000个Ae的存档样本。自2000年以来从秘鲁伊基托斯收集的埃及伊蚊正在被 保持在-80˚C并具有完整的dna。在这段时间里，伊基托斯的拟除虫菊酯喷雾效果 由于阻力，大幅下降。这些样本将被用来评估空间格局 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，就有可能检验有关拟除虫菊酯动力学的假说。 抗药性进化和关于新的基因驱动策略有效性的假设 抑制Ae.埃及伊蚊种群或降低蚊子传播病原体的能力。这些 分析配对结构的新算法将使测试成为可能。一种在空间上清晰的， Ae.的随机模型埃及伊蚊种群动态和遗传学将用 新的基因组数据，并用于预测未来的抗药性和基因驱动的动态。 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态所需的信息 由于对杀虫剂的耐药性在这种虫媒病毒中的传播。 我们在这个项目中有三个目标，这三个目标将共同产生以下更准确的预测： 目的1.使用单基因和全基因组方法来描述时间和空间遗传 Ae.埃及伊蚊种群 目标2.使用目标1中的数据来更准确地理解运动和交配 Ae.的结构埃及伊蚊 目标3.将目标2的调查结果纳入详细的AE中。Aegypti模型，并用它来测试各种 现有的和新的用于基因驱动以及监测Ae抗药性进化的策略。 埃及人使用基因驱动和杀虫剂。 好了！

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. !