Manipulating the genetics of wild populations

分子遗传学的最新惊人进展，加上基因组测序计划的新数据，给了我们前所未有的能力来操纵动植物的基因类型和表型。这反过来又表明，一些古老的人类祸害，即人类、农作物和牲畜的害虫和疾病，可能会通过对致病生物、它们的媒介或野生水库的基因操作来控制。在某种程度上，转基因作物已经开始实现这一点，例如杀虫的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，例如农作物和牲畜，但我们没有能力将基因引入野生种群。多个研究小组正试图在实验室中识别基因和结构，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，许多这样的系统将会出现。这项研究目前侧重于蚊媒疾病，但同样适用于各种植物和牲畜疾病。然而，到目前为止，还没有将这些基因引入野生种群的方法，换句话说，就是利用它们。这被一些人认为是整个“难对付昆虫”策略的致命缺陷。问题如下。任何这样的基因构建，例如降低病原体传播媒介物种能力的构建，很可能都会有与之相关的适应成本。这意味着，与打算取代的野生型相比，转基因载体将处于选择性劣势。因此，如果将耐药菌株简单地释放到田间，相对于野生型，它将被选择，这样所需的性状就不会传播。虽然这种特性本身可能会带来选择性优势，例如，通过允许工程载体避免与携带病原体相关的适应成本，但这不太可能。因此，工程化的耐火结构不太可能在没有辅助的情况下在野生种群中传播。相反，一个有效的系统将构建物引入野生媒介种群，才能将“难治虫”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，尤其是监管方面的原因，基因驱动系统最好不是太具侵入性，换句话说，它将停留在您放置的位置，在某些可定义的参数内。在少数几个被描述为具有这一性质的系统中，至少在理论上，Davis等人(2001)基于“欠优势”的系统之一[例如，与Chen等人(2007)更具侵入性的Medea类系统形成对比]。学生将开发必要的关键工具，以产生基于欠显性的基因驱动系统。具体地说，这需要设计和构建相互抑制的显性致死遗传元件对。Oxitec在控制农业和公共卫生有害生物的可抑制致死系统方面的工作将为此奠定基础。这项工作将首先在蚊子埃及伊蚊中进行，我们在那里有初步数据和数学模型来支持这种方法的发展。这个物种之所以被选中，是因为它对基因驱动系统的兴趣/需求，基因组序列的可用性，以便于识别必要的分子工具，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等人(2007)一种合成的母体效应自私遗传元素驱动了果蝇的种群更替。《科学》316：597 Davis，S.等人(2001)。设计的劣势允许有效和经济地将性状导入害虫种群。J Theor Biol 212：83

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