Population genetics of transgenes in mosquito vectors

描述（由申请人提供）：昆虫品系已经过基因工程改造，以降低繁殖能力和不能传播致病病原体。具有这些性状的昆虫不会通过自然选择的直接作用取代本地昆虫的基因型，因此有必要开发遗传驱动机制，迫使这些转基因进入本地昆虫种群。讨论了利用特定驱动机制的一些潜在策略，并建立了初步的群体遗传模型来评估某些策略的可行性。这些评估存在许多差距。拟议的研究将开发一个全面的建模框架，可用于确定最有可能成功抑制特定地区特定虫媒疾病的转基因方法。一个主要的焦点将是建立一个空间明确的随机模型的矢量种群动态和遗传学。该模型将与疾病流行病学模型相结合。第一个模型将被设计成适合埃及伊蚊和登革热病毒（DV）的生物学特性。许多相关生物学参数的估计可以从以前和正在进行的研究中获得。其他参数将从拟议的实验中估计，这些实验将测量与转基因插入相关的适应度成本，以及负载转座子的基因组内运动模式。将研究的具体转基因操作有：1)条件致死性等位基因的插入，2)雌性特异性致死性等位基因的插入，3)工程劣势的插入，4)负载自主转座子的插入，5)转基因沃尔巴克氏菌菌株的感染。使用新型转基因操作的可能性将用更一般的模型进行检验。建模工作的结果将根据当前的生物学数据预测在特定环境条件下哪种DV抑制策略有望成功。结果还将表明未来的实证研究工作应该集中在哪里，以获得对伊蚊关键生物学参数的更精确和准确的估计。蚊。将举行多学科讲习班，以确保制定的最终模型框架足够灵活，可供研究疟疾和其他虫媒疾病的研究人员使用。将编制一套方便使用者使用的模型，以及一份易于查阅的手册，并放在互联网上。

DESCRIPTION (provided by the applicant): Insect strains have been genetically engineered for decreased capacity to reproduce and for inability to transmit disease-causing pathogens. Insects with such traits are not expected to replace native insect genotypes through the direct action of natural selection so there is a need to develop genetic drive mechanisms that will force these transgenes into native insect populations. A number of potential strategies for using specific drive mechanisms have been discussed, and preliminary population genetic models have been developed to assess the feasibility of certain strategies. There are numerous gaps in these assessments. The proposed research will develop a comprehensive modeling framework that can be used in determining the transgenic approaches that are most likely to successfully suppress specific insect-borne diseases in specific regions. A major focus will be the building of a spatially explicit stochastic model of vector population dynamics and genetics. This model will be coupled to models of disease epidemiology. The first model will be designed to fit the biology of Aedes aegypti and dengue virus (DV). Estimates of many relevant biological parameters are available from previous and ongoing research. Other parameters will be estimated from proposed experiments that will measure the fitness costs expected to be associated with insertion of transgenes, and the pattern of intra-genomic movement of loaded transposons. Specific transgenic manipulations that will be examined are: 1) insertion of conditional lethal alleles, 2) insertion of female-specific lethality alleles 3) engineered underdominance, 4) insertion of loaded autonomous transposons, 5) infection with transgenic Wolbachia strains. The potential for using novel transgenic manipulations will be examined with more general models. Results of the modeling work will predict, based on current biological data, which DV suppression strategies are expected to succeed under specific environmental conditions. The results will also indicate where future empirical research efforts should be focused to gain more precise and accurate estimates of critical biological parameters for Ae. aegypti. Interdisciplinary workshops will be held to ensure that the final model framework developed is flexible enough to be used by researchers working with malaria and other insect-borne diseases. A user-friendly form of the models as well as an accessible manual will be developed and placed on the internet.