Dynamics of Gene Drives in Natural Populations

自然种群中基因驱动的动态

• 批准号: 9898258
• 负责人: JACKSON CHAMPER
• 金额: $ 6.93万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898258
• 关键词: Address; Adult; Affect; Alleles; Animal Model; Anopheles Genus; Arthropods; Automobile Driving; CRISPR/Cas technology; Chromosomes; Cleaved cell; Containment; Culicidae; Data; Demography; Dengue; Development; Disadvantaged; Disease; Drosophila genus; Drosophila melanogaster; Engineering; Environment; Extinction (Psychology); Female; Frequencies; Future; Gene Frequency; Generations; Genes; Genetic; Genetic Engineering; Genetic Variation; Geography; Goals; Heterozygote; Homing; Homozygote; Individual; Insecta; Invaded; Laboratories; Larva; Link; Malaria; Maps; Measures; Modeling; Monitor; Mosquito-borne infectious disease; Movement; Nonhomologous DNA End Joining; Performance; Phenotype; Play; Population; Population Genetics; Population Heterogeneity; Protocols documentation; Resistance; Role; Safety; Savings; Sister; Site; Structure; System; Target Populations; Techniques; Testing; Variant; Vector-transmitted infectious disease; Work; ZIKA; alpha Toxin; antitoxin; base; cost; design; egg; experimental study; fitness; fly; gene drive allele; gene drive system; genetic variant; genomic locus; homing gene drive; medea gene drive; migration; next generation; pathogen; prevent; repaired; resistance allele; sample fixation; simulation; transgenic insect; vector

Project Summary/Abstract Mosquito-transmitted diseases, including malaria, dengue and Zika, continue to take a devastating toll. Gene drive systems could provide a new strategy for controlling these diseases by spreading genetically engineered alleles into vector populations, such as allelic variants that make the insects resistant to a pathogen or deleterious alleles than directly suppress their populations. The recently developed CRISPR/Cas9 homing gene drive system promises to be a highly adaptable mechanism that works by converting heterozygotes for the driver construct into homozygotes. However, it remains unclear whether this mechanism will work in wild populations given the expected high rate of generation of resistance alleles, which are created by the drive mechanism itself when cleavage is repaired by nonhomologous end joining. Another proposed gene drive system, Medea, likely suffers less from the generation of resistance alleles, but it spreads more slowly and is highly sensitive to fitness costs. The goal of our project is to identify and quantify parameters that are critical to determining whether these systems can in fact spread in diverse, natural populations. In our first aim, we will employ laboratory examples of homing drivers and Medea drivers to quantify the drive efficiency and origination rate of resistance alleles in genetically diverse but well characterized lines of the model organism Drosophila melanogaster. We will then use these results to map the genetic loci associated with differences in drive efficiency and resistance levels. Our second aim will determine the ability of each gene drive system to invade genetically diverse populations. For this purpose, a small number of gene drive flies will be introduced into population cages with a mix of Global Diversity Line flies. Phenotype frequencies will be tracked over several generations to determine the ability of the gene drive to successfully invade the population. This work will be done in a state-of-the-art arthropod containment lab to prevent escape of transgenic insects. In our third aim, we will compare the ability of homing drivers and Medea drivers to spread in geographically structured populations using sophisticated population genetic simulations. We will identify the parameters that will allow a gene drive system to establish, spread, and either fix or persist sufficiently long in a large natural population under realistic assumptions of demography and population structure. Overall our experiments and modeling will provide crucial data for predicting the dynamics of gene drive systems in natural target populations. The conclusions from our studies will play an important role in designing and implementing the next generation of gene drive systems for optimal performance in realistic populations.

项目摘要/摘要 包括疟疾，登革热和Zika在内的蚊子传播疾病继续造成毁灭性损失。基因 驱动系统可以通过传播基因工程来提供一种新的策略来控制这些疾病 等位基因到矢量种群中，例如使昆虫抗病机构或 有害等位基因比直接抑制其人群。 最近开发的CRISPR/CAS9归巢基因驱动系统有望成为高度适应的 通过将驱动器构造的杂合子转换为纯合子来起作用的机制。但是，它 尚不清楚这种机制是否在野生种群中有效，鉴于预期的高率 产生电阻等位基因，这是由驱动机构本身创造的 非同源结局加入。另一个提出的基因驱动系统MEDEA可能少于 产生的阻力等位基因，但扩散得更慢，并且对健身成本高度敏感。目标 我们的项目是识别和量化参数，这些参数对于确定这些系统是否可以在 事实传播到多样化的自然人群中。 在我们的第一个目标中，我们将采用实验室示例的归宿司机和美狄亚司机来量化驱动器 遗传多样性但特征良好的线条的效率和抗性等位基因的起源速率 模型有机体果蝇Melanogaster。然后，我们将使用这些结果来映射遗传基因座相关 驱动效率和电阻水平的差异。 我们的第二个目标将决定每个基因驱动系统入侵遗传多样的人群的能力。 为此，将少量的基因驱动蝇引入人口笼中 全球多样性线苍蝇。表型频率将在几代人中进行跟踪以确定 基因驱动成功入侵人群的能力。这项工作将在最先进的 节肢动物遏制实验室，以防止转基因昆虫逃脱。 在我们的第三个目标中，我们将比较归宿司机和美狄亚司机在地理上传播的能力 使用复杂的种群基因模拟的结构化种群。我们将确定参数 将允许基因驱动系统建立，传播并固定或持续到足够长的大天然 人口统计学和人口结构的现实假设下的人口。 总体而言，我们的实验和建模将提供至关重要的数据来预测基因驱动的动力学 自然目标人群中的系统。我们研究的结论将在设计中发挥重要作用 并实施下一代基因驱动系统，以在现实种群中进行最佳性能。