Manipulating the genetics of wild populations

操纵野生种群的遗传学

• 批准号: BB/H015647/1
• 负责人: Steven Sinkins
• 金额: $ 9.59万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Training Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH015647%2F1
• 关键词: Manipulating; genetics; wild; populations

The astonishing recent advances of molecular genetics, together with the new data from genomic sequencing programs, give us an unprecedented ability to manipulate the genotypes and phenotypes of plants and animals. This in turn holds out the prospect that some of the ancient scourges of mankind, the pests and diseases of humans, crops and livestock, might be controlled by genetic manipulation of the causative organisms, their vectors or wild reservoirs. To an extent, this has begun to be realised in the case of GM crops, for example the insecticidal Bt crops. However, while we can disseminate new genes in populations where we have complete control of their reproduction and location, for example crops and livestock, we have no capacity to introgress genes into wild populations. Multiple research groups are attempting to identify in the laboratory genes and constructs which, if present in a wild population of a disease vector, would reduce disease transmission. The pace of current research suggests that within a decade, and probably much sooner, many such systems will be available. This research is focused at present on mosquito-borne diseases, but is equally applicable to various diseases of plants and livestock. However, there is as yet no method to introgress these genes into wild populations, in other words to use them. This has been identified by some as a fatal flaw in the entire 'refractory insect' strategy. The problem is as follows. It is likely that any such genetic construct, e.g. one which reduces the capacity of vector species to transmit pathogens, will have a fitness cost associated with it. This means the genetically altered vector will be at a selective disadvantage relative to the wild type that it is intended to replace. Thus, if the refractory strain were simply released into the field it would be selected against, relative to the wild type, so the desired trait would not spread. While it is possible that the trait itself may confer a selective advantage, for example by allowing the engineered vectors to avoid fitness costs associated with carrying pathogens, this is unlikely. Thus, an engineered refractory construct is unlikely to spread through a wild population unaided. Rather, an effective system for driving the construct into wild vector populations is essential in order to bring the 'refractory insect' strategy to practical utility. Such systems are generically termed 'gene drive' systems, or 'gene drivers'. For many reasons, not least regulatory, it is desirable that the gene drive system is not too invasive, in other words will stay where you put it, within some definable parameters. One of the few systems to have been described with this property, at least in theory, is the 'underdominance'-based system of Davis et al (2001) [in contrast to the more invasive Medea-like system of Chen et al (2007) for example]. The student will develop key tools necessary to produce an underdominance-based gene drive system. Specifically, this requires the design and construction of pairs of mutually suppressing dominant lethal genetic elements. Oxitec's work on repressible lethal systems for control of agricultural and public health pests will form the foundation for this. The work will initially be conducted in the mosquito Aedes aegypti, where we have preliminary data and mathematical models to support the development of this approach. This species was selected for its combination of interest in / need for gene drive systems, availability of the genome sequence to facilitate the identification of the necessary molecular tools, and Oxitec's previous investment in developing genetic tools and methods for this species. Chen et al (2007) A synthetic maternal-effect selfish genetic element drives population replacement in Drosophila. Science 316:597 Davis, S., et al (2001). Engineered underdominance allows efficient and economic introgression of traits into pest populations. J theor Biol 212: 83

分子遗传学最近的惊人进展，加上基因组测序项目的新数据，使我们有了前所未有的能力来操纵植物和动物的基因型和表型。这反过来又提出了这样一种前景，即人类的一些古老祸害，即人类、作物和牲畜的病虫害，可以通过对致病生物体、其载体或野生宿主进行遗传操纵来加以控制。在某种程度上，这一点已经开始在转基因作物中实现，例如杀虫Bt作物。然而，虽然我们可以在我们完全控制其繁殖和位置的种群中传播新基因，例如作物和牲畜，但我们没有能力将基因渗入野生种群。多个研究小组正试图在实验室中确定哪些基因和结构如果存在于疾病媒介的野生种群中，将减少疾病传播。目前的研究速度表明，在10年内，甚至可能更短的时间内，许多这样的系统将可用。本研究目前主要针对蚊媒疾病，但同样适用于植物和牲畜的各种疾病。然而，目前还没有办法将这些基因渗入到野生种群中，换句话说，没有办法利用它们。一些人认为这是整个“难治性昆虫”策略的致命缺陷。问题如下。任何这样的遗传结构，例如，降低病媒物种传播病原体能力的遗传结构，都可能有与其相关的适应度成本。这意味着基因改变的载体相对于它想要取代的野生型将处于选择性劣势。因此，如果简单地将难处理菌株释放到野外，相对于野生型，它将被选中，因此所需的性状不会传播。虽然这种特性本身可能具有选择优势，例如，通过允许工程载体避免与携带病原体相关的适应性成本，但这是不太可能的。因此，一个工程的耐火结构不可能在没有帮助的情况下在野生种群中传播。相反，一个有效的系统来驱动构建到野生媒介种群是必不可少的，以便将“难治昆虫”策略付诸实践。这种系统通常被称为“基因驱动”系统或“基因驱动”。出于许多原因，不仅仅是监管方面的原因，基因驱动系统不具有太大的侵入性是可取的，换句话说，它将停留在你放置它的地方，在一些可定义的参数内。至少在理论上，被描述具有这种特性的为数不多的系统之一是Davis等人（2001）基于“劣势”的系统[与Chen等人（2007）更具侵入性的Medea-like系统形成对比]。学生将开发必要的关键工具，以产生基于劣势的基因驱动系统。具体来说，这需要设计和构建一对相互抑制的显性致死遗传元件。Oxitec在控制农业和公共卫生害虫的可抑制致命系统方面的工作将为这一目标奠定基础。这项工作将首先在埃及伊蚊中进行，我们有初步的数据和数学模型来支持这种方法的发展。该物种被选中的原因是其对基因驱动系统的兴趣/需求，基因组序列的可用性，以促进必要的分子工具的鉴定，以及Oxitec之前在开发该物种的遗传工具和方法方面的投资。Chen et al .（2007）一种合成的母系效应自私遗传因素驱动果蝇种群更替。李春华，李春华等（2001）。改造过的劣势可以有效和经济地将性状渗入害虫种群。生物学理论[J] . 212: 83