Evolutionary Genomics of Anti-Malaria Genes in Mosquito

描述(申请人提供)：疟疾是一种毁灭性的全球杀手，人与人之间的疾病传播必须通过少数合格的媒介蚊子物种进行。蚊子对感染的血粉中存在的疟疾寄生虫建立了强有力的免疫防御。这通常会导致寄生虫死亡率很高，但不完全。野生蚊子种群的隔离是因为在抑制寄生虫发展的能力方面存在相当大的遗传差异，因此一些个体完全不能传播，而另一些个体则高度敏感。由于感染疟疾，蚊子遭受了可衡量的适应成本，这表明在有效的免疫防御方面具有潜在的选择性优势。根据这项建议，我们将探索冈比亚按蚊对疟疾天然抗药性的遗传基础，冈比亚按蚊是人类疟疾最常见和最具破坏性的媒介。这将通过一项基因型-表型关联研究来完成，该研究测试60个疟疾反应候选基因的多态与寄生虫抑制的表型措施之间的统计相关性。其中20个候选基因将在多个按蚊物种中进行深入的种群遗传分析。焦点按蚊物种将被选为不同的媒介/非媒介对，其中非媒介在系统发育上嵌套在媒介中。收集的数据将产生该物种的基本种群遗传特征，其中任何一个都没有从种群遗传角度进行充分描述，并将允许对自然选择驱动的适应进行测试。被研究物种的系统发育结构将使专门与人类疟疾相关的自然选择的强大分子进化测试成为可能。将这项提案的三个目标结合起来，将产生对按蚊物种和疟疾寄生虫之间共同进化的全面看法，并将突出宿主和寄生虫之间共同进化的“紧张”点，在这些点上，有针对性的人类干预可以打破平衡，扰乱疾病传播。 将探索野生蚊子对疟疾抗药性的遗传基础。蚊子防御基因的进化模式将被用来识别与疟疾寄生虫共同进化的蛋白质。这项工作可能会提出可以被操纵以限制疟疾传播的遗传目标。

DESCRIPTION (provided by applicant): Malaria is a devastating global killer, with human-to-human disease transmission necessarily proceeding through a handful of competent vector mosquito species. Mosquitoes mount a vigorous immune defense against malaria parasites present in an infected bloodmeal. This typically results in high, but incomplete, parasite mortality. Wild mosquito populations segregate for considerable genetic variation in the ability to suppress parasite development, such that some individuals are completely refractory to transmission while others are highly susceptible. Mosquitoes suffer measurable fitness costs as a result of malaria infection, suggesting a potential selective advantage to efficacious immune defense. Under this proposal, we will explore the genetic basis for natural resistance to malaria in Anopheles gambiae, the most common and destructive vector of human malaria. This will be done with a genotype-phenotype association study, testing statistical correlation between polymorphism in 60 malaria responsive candidate genes and phenotypic measures of parasite suppression. Twenty of the candidate genes will be further examined with in-depth population genetic analyses in multiple Anopheles species. The focal Anopheles species will be chosen as distinct vector/non-vector pairs, where the non-vectors are phylogenetically nested within the vectors. The data collected will result in a basic population genetic characterization of the species, none of which have been adequately described from a population genetic perspective, and will allow tests for adaptation driven by natural selection. The phylogenetic structure of the species examined will allow powerful molecular evolutionary tests for natural selection specifically associated with exposure to human malaria. Integration of the three aims of this proposal will yield a comprehensive view of coevolution between Anopheles species and malaria parasites, and will highlight points of coevolutionary "tension" between host and parasite where targeted human intervention could tip the balance to disrupt disease transmission. The genetic basis of resistance to malaria in wild mosquitoes will be explored. Evolutionary patterns in mosquito defense genes will be used to identify proteins that coevolve with malaria parasites. This work may suggest genetic targets that could be manipulated to limit malaria transmission.