Engineering a Minimal Drive System for Vector Control in Drosophila melanogaster

设计用于果蝇矢量控制的最小驱动系统

• 批准号: 1655064
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1655064
• 关键词: Engineering; Minimal; Drive; System; Vector

The significant burden exerted on global health by vector-borne transmission of human diseases such as malaria, yellow fever, dengue fever and others has dictated the need for novel and effective control methodologies. One such methodology is that of a genetic drive, facilitating population-level modification of common vectors (e.g. mosquitoes, tsetse flies, ticks, etc...). Gene drive permits researchers to repurpose naturally occurring transposable elements as a means to artificially drive the rate of inheritance of desired traits between generations of a population at a greater-than Mendelian rate. In so doing, it is possible to spread effector genes that may offer a means to inhibit disease pathogenesis. This methodology offers notable advantages over existing vector control strategies such as use of chemical pesticides, which are largely temporal and require significant logistical and economical commitment. Gene drive is a self-sustaining alternative that can be implemented to permanently address numerous challenges to human health.Synthetic gene drive systems have been described with a variety of mechanisms for the proliferation of desirable traits across a population. One such mechanism makes use of genes encoding site-specific endonucleases as a means to rapidly drive inheritance of effector genes. The gene-encoded nuclease generates a double-stranded break in a targeted genomic site, and is subsequently used as a template for homologous repair. This results in heterozygous individuals becoming homozygous for the gene - the gene is inserted into the middle of its own recognition sequence, preventing the newly repaired site from being further targeted. Such nuclease-encoding genes can be engineered to carry a cargo, and in this way frequency of the effector gene can increase and be transmitted to the host organism's progeny. Recent advances in genetic engineering have resulted in new classes of synthetic endonucleases that can be designed to specifically cleave genomic sequences. Examples of synthetic gene drive systems have since been demonstrated using Zinc-finger, TALENs and CRISPR nucleases. We now want to further optimise this synthetic gene drive in order to engineer a minimal system, offering numerous advantages over existing designs. We aim to undertake this work in Drosophila melanogaster. This model organism has significant genomic conservation to a range of target arthropods, making it a potent platform for evaluating the efficiency of this novel system, and permitting high-throughput experimentation. In this way we aim to design and engineer a novel synthetic gene drive system. Furthermore, by investigating gene drive in D. melanogaster, we will provide an avenue for implementation of this drive in a range of vectors, allowing future work to be targeted to relevant organisms in sectors outside of healthcare, such as agriculture.

疟疾、黄热病、登革热等人类疾病的病媒传播对全球健康造成了重大负担，因此需要采用新的有效控制方法。其中一种方法是遗传驱动，促进常见载体（如蚊子、采采蝇、蜱虫等）的种群水平修改。基因驱动允许研究人员重新利用自然发生的转座因子，作为一种手段，人为地推动一个群体的代际间所需性状的遗传率，使其高于孟德尔率。这样做，就有可能传播可能提供抑制疾病发病机制的手段的效应基因。与使用化学农药等现有的病媒控制战略相比，这种方法具有显著的优势，后者在很大程度上是暂时的，需要大量的后勤和经济承诺。基因驱动是一种自我维持的替代方法，可用于永久解决人类健康面临的众多挑战。合成基因驱动系统已经被描述为在种群中增殖所需性状的各种机制。其中一种机制是利用编码位点特异性内切酶的基因作为快速驱动效应基因遗传的手段。基因编码的核酸酶在目标基因组位点产生双链断裂，随后被用作同源修复的模板。这导致杂合子个体成为基因的纯合子——基因被插入其自身识别序列的中间，防止新修复的位点进一步被靶向。这种核酸酶编码基因可以被设计成携带货物，这样效应基因的频率就可以增加，并传递给宿主生物的后代。基因工程的最新进展导致了新型的合成内切酶，可以被设计成专门切割基因组序列。合成基因驱动系统的例子已经被证明使用锌指，TALENs和CRISPR核酸酶。我们现在想进一步优化这种合成基因驱动，以设计一个最小的系统，提供比现有设计更多的优势。我们的目标是在果蝇身上进行这项工作。这种模式生物对一系列目标节肢动物具有显著的基因组保守性，使其成为评估这种新系统效率的有力平台，并允许高通量实验。通过这种方式，我们的目标是设计和制造一种新的合成基因驱动系统。此外，通过研究D. melanogaster的基因驱动，我们将为在一系列载体中实施这种驱动提供途径，使未来的工作能够针对医疗保健以外的相关生物，如农业。