Manipulating the genetics of wild populations

分子遗传学的惊人进展，以及基因组测序程序的新数据，使我们拥有了前所未有的能力来操纵植物和动物的基因型和表型。这反过来又提供了一种前景，即人类的一些古老疾病，人类、作物和牲畜的害虫和疾病，可能通过对致病生物、其载体或野生宿主进行基因操纵而得到控制。在某种程度上，转基因作物已经开始实现这一点，例如Bt杀虫作物。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鉴定基因和结构，如果这些基因和结构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，在十年内，甚至可能更快，许多这样的系统将可用。这项研究目前主要集中在蚊子传播的疾病上，但同样适用于植物和牲畜的各种疾病。然而，目前还没有将这些基因渗入野生种群的方法，换句话说，还没有利用这些基因的方法。这被一些人认为是整个“难治性昆虫”策略的致命缺陷。问题如下。任何这种基因结构，例如降低病媒物种传播病原体的能力的基因结构，都可能有与之相关的适应性成本，这意味着基因改变的病媒相对于它打算取代的野生型将处于选择性劣势。因此，如果简单地将难治菌株释放到田间，相对于野生型，它将被选择，因此所需的性状不会传播。虽然性状本身可能赋予选择性优势，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，但这不太可能。因此，工程化的难治性构建体不太可能在没有帮助的情况下通过野生群体传播。相反，一个有效的系统驱动的构建体进入野生载体种群是必不可少的，以使“难治性昆虫”的策略，以实际用途。这样的系统一般称为“基因驱动”系统或“基因驱动程序”。出于许多原因，尤其是监管方面的原因，希望基因驱动系统不会太具侵入性，换句话说，它会在一些可定义的参数内停留在你放置它的地方。至少在理论上，已经描述了具有这种性质的少数系统之一是Davis等人（2001）的基于“不足”的系统[例如，与Chen等人（2007）的更具侵入性的Medea样系统形成对比]。学生将开发必要的关键工具，以产生一个基于显性不足的基因驱动系统。具体而言，这需要设计和构建成对的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死系统方面的工作将为此奠定基础。这项工作最初将在埃及伊蚊中进行，我们有初步的数据和数学模型来支持这种方法的发展。选择该物种是因为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识别，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）A synthetic maternal-effect selfish genetic element drives population replacement in Drosophila.科学316：597戴维斯，S.，等（2001）。工程化的弱显性允许性状有效和经济地渗入害虫种群。第212章：你是谁？

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