Population genetics of transgenes in mosquito vectors

描述(由申请人提供)：对昆虫品系进行了基因改造，使其繁殖能力降低，不能传播致病病原体。具有这种特征的昆虫不会通过自然选择的直接作用来取代本地昆虫的基因型，因此需要开发遗传驱动机制，迫使这些转基因进入本地昆虫种群。已经讨论了一些使用特定驱动机制的潜在策略，并开发了初步的种群遗传模型来评估某些策略的可行性。这些评估中有许多空白。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在特定地区成功抑制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上明确的媒介种群动力学和遗传学的随机模型。这一模型将与疾病流行病学模型相结合。第一个模型将设计成适合埃及伊蚊和登革病毒(DV)的生物学。许多相关生物参数的估计可从先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，这些实验将测量预期与转基因插入相关的适应成本，以及加载的转座子在基因组内运动的模式。将考察的具体转基因操作包括：1)插入条件致死等位基因，2)插入雌性特有的致死等位基因，3)转基因低显性，4)插入加载的自主转座子，5)感染转基因沃尔巴克氏菌株。使用新的转基因操作的潜力将通过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，在特定的环境条件下，哪些DV抑制策略有望成功。这些结果还将表明，未来的实证研究工作应该集中在哪里，以获得对Ae的关键生物学参数的更准确和准确的估计。埃及伊蚊。将举办跨学科讲习班，以确保制定的最后模型框架足够灵活，可供研究疟疾和其他昆虫传播疾病的研究人员使用。将开发一种方便用户使用的模型形式以及一份可访问的手册，并将其放在互联网上。

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.