Genetic Association Mapping of Malaria Resistance in Anopheles gambiae

描述(申请人提供)：非洲冈比亚按蚊家系的遗传连锁图谱确定了基因组中的一个小的抗疟原虫岛(PRI)，它控制着蚊子对恶性疟原虫感染的大部分自然遗传变异。PRI在2L染色体上占据-15兆碱基对。系谱分析是初步发现抗病基因座的有效方法，但家系中含有的重组信息不足以从抗病岛上的1,000个基因中鉴定出真正的致病基因(S)。相比之下，遗传关联法利用自然群体中的历史性重组，将一个基因座解剖到单基因水平。在这里，我们提出了一项遗传关联研究，以确定控制冈比亚按蚊对恶性疟原虫抗性和易感性的潜在特定基因，目的如下。目的1，我们将构建一个联合小组，在杀虫剂中饲养野生捕获的冈比亚按蚊幼虫，并从自然感染的志愿者的血液中用恶性疟原虫攻击它们。目的2、以微卫星和单核苷酸多态为中性标记，开展缩小抗性控制目标区间的间接关联研究。目的3，我们将通过重新测序目标2中确定的部分或全部缩小的候选区域来进行直接关联研究，以检测自然界中控制蚊子抗性和疟疾寄生虫易感性的基因。由此得到的信息将允许对蚊子种群中遗传易感部分进行具体区分。先前的系谱连锁研究表明，有效的遗传抗性机制在媒介种群中广泛存在，并表明实际的疟疾传播是由一组离散的遗传易感蚊子进行的。我们建议，有可能开发一种新的疟疾控制形式，其基础是专门针对易感人群，以减少他们在媒介人口中的频率。 相关性：有可能制定以蚊媒为重点的疟疾控制新战略。了解影响媒介蚊子传播疟疾的遗传机制将有助于制定这种以媒介为基础的控制战略。

DESCRIPTION (provided by applicant): Genetic linkage mapping of Anopheles gambiae pedigrees in Africa identified a small Plasmodium- Resistance Island (PRI) of the genome that controls most of the natural genetic variation for mosquito resistance to Plasmodium falciparum infection. The PRI occupies -15 megabase pairs on chromosome 2L. Pedigree analysis was an efficient method for initial discovery of resistance loci, but pedigrees do not contain enough recombinational information to genetically identify the actual causative gene(s) among the 1,000 genes within the resistance island. In contrast, the method of genetic association takes advantage of historic recombination in the natural population to dissect a locus to the single-gene level. Here we propose a genetic association study to identify the underlying specific genes that control resistance and susceptibility of A. gambiae to P. falciparum in nature, with the following Aims. Aim 1, we will construct an association panel by rearing wild-caught A. gambiae larvae in the insectary, and challenging them with P. falciparum from the blood of naturally-infected volunteers. Aim 2, we will carry out an indirect association study to narrow the target interval controlling resistance, using as neutral markers microsatellites and single-nucleotide polymorphisms. Aim 3, we will carry out a direct association study by resequencing part or all of the narrowed candidate region ascertained in Aim 2, to detect the genes that underlie control of mosquito resistance and susceptibility to malaria parasites in nature. The resulting information will allow specific discrimination of the genetically susceptible fraction of the mosquito population. The previous pedigree linkage study indicated that efficient mechanisms of genetic resistance are widespread in the vector population, and suggested that actual malaria transmission is carried out by a discrete subset of genetically susceptible mosquitoes. We propose that it may be possible to develop a novel form of malaria control based on specifically targeting the susceptibles to reduce their frequency in the vector population. Relevance: It may be possible to develop new strategies for malaria control focusing on the mosquito vector. Knowledge of the genetic mechanisms that affect transmission of malaria by vector mosquitoes would aid in the development of such vector-based control strategies.