Co-evolutionary Genetics of Host-Parasite Interactions

宿主-寄生虫相互作用的共同进化遗传学

• 批准号: 9142912
• 负责人: NOAH K WHITEMAN
• 金额: $ 35.49万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-11 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9142912
• 关键词: Address; Architecture; Autoimmune Diseases; Crohn' s disease; DNA Resequencing; Data; Disease; Drosophila genus; Drosophilidae; Equilibrium; Evolution; Genes; Genetic; Genetic Models; Genetic Variation; Genome; Genomics; Genotype; Goals; Hand; Human; Human Genome; Immune System Diseases; In Vitro; Knowledge; Laboratories; Lead; Life; Link; Lupus; Maintenance; Microbe; Mission; Molecular Genetics; Mouse-ear Cress; Multiple Sclerosis; Mutation; Natural Selections; Parasites; Pattern; Phenotype; Plants; Play; Population; Public Health; Research; Research Personnel; Resistance; Rheumatoid Arthritis; Role; Shapes; System; Testing; Time; Variant; base; comparative genomics; fly; genetic variant; genome wide association study; genome-wide; in vivo; innovation; next generation sequencing; parasitism; targeted agent; trait

ABSTRACT There is a fundamental gap in our understanding of how host-parasite interactions maintain genetic variation within species, including humans. Interactions between humans and long-lived eukaryotic parasites may be the most important agents of natural selection across the human genome and may be responsible for the maintenance of genome-wide functional variation within humans (balancing selection). However, linking the agents of balancing selection with their genomic targets remains a major challenge. Continued existence of this gap is an important problem because until it is filled there is a limited understanding of the mechanisms responsible for potential maintenance of genetic variation within species. The long-term goal of the investigator's laboratory is to understand the genetic basis of host-parasite adaptations. The objective over the next five years is to identify agents and targets of selection arising from host-parasite interactions. The central hypothesis is that host-parasite interactions maintain genetic variation within species. The rationale is that transitions to parasitism on the genetic model plant Arabidopsis thaliana has occurred within the genetic model Drosophila lineage, allowing in-depth study. Guided by strong preliminary data, this hypothesis will be tested by pursuing these two overarching research questions: 1). Identify molecular genetic changes that underpin the transition to parasitism in a fly, 2) Determine if host-parasite interactions lead to the maintenance of genome-wide variation in flies and plants. Under the first question, the genomic architecture underlying the evolutionary transition to parasitism will be identified in the Drosophilidae. Next-generation sequencing and comparative genomics studies will identify genes necessary for the evolution parasitism from free living fruit flies. Preliminary studies show that this approach holds great promise for finding “parasite-genes” and that the approach is feasible in the applicants' hands. Under the second question, populations of parasitic flies will be evolved with single or mixed host genotypes that vary in resistance traits. An evolve-and-resequence approach will test if genome-wide variation is maintained by balancing selection in flies. In the plants, a genome-wide association (GWAS) study approach will be used to identify loci associated with resistance to flies. The applicants have shown that these approaches will identify targets of balancing selection. Under both aims, functional studies using in vitro and in vivo approaches will be used to link evolutionary patterns with functional phenotypes. The proposed research is significant because it will be the first study in a continuum of research expected to lead to an integrative understanding of the role that host-parasite interactions play in shaping patterns of genome evolution. There is promise that general principles will be discovered relating to the role host-parasite interactions play in the maintenance of genetic variation. The research proposed is innovative because it represents a departure from current approaches to studies on the evolution of host-parasite interactions, which are restricted to microbes or non-model systems.

抽象的 我们对宿主 - 寄生虫相互作用如何保持遗传变异的理解有根本的差距 在物种中，包括人类。人与长寿的真核寄生虫之间的相互作用可能是 在人类基因组中最重要的自然选择药物，可能是负责的 维持人体内基因组功能变化（平衡选择）。但是，链接 平衡选择及其基因组靶标的代理仍然是一个重大挑战。继续存在 差距是一个重要的问题，因为直到填补它之前，对机制的理解有限 负责潜在的物种内遗传变异。调查员的长期目标 实验室将了解宿主 - 寄生虫适应的遗传基础。未来五年的目标 是确定由宿主 - 寄生虫相互作用引起的选择的药物和靶标。中心假设是 宿主 - 寄生虫相互作用保持物种内的遗传变异。理由是向寄生虫过渡 关于遗传模型植物拟南芥发生在遗传模型果蝇谱系中， 允许深入研究。在强大的初步数据的指导下，将通过追求这两个来检验该假设 总体研究问题：1）。确定基于过渡到寄生虫的分子遗传变化 在苍蝇中，2）确定宿主 - 寄生虫相互作用是否导致苍蝇全基因组变异的维持 植物。在第一个问题下，进化过渡向寄生虫的基因组建筑将将 下一代测序和比较基因组学研究将确定 自由果蝇的进化寄生虫所必需的基因。初步研究表明这一点 方法对寻找“寄生虫生成”有很大的希望，并且该方法在申请人中是可行的 手。在第二个问题下，寄生虫种群将与单个或混合宿主一起进化 抗性性状各不相同的基因型。进化和质量方法将测试全基因组的变化是否变化 通过平衡苍蝇的选择来维护。在植物中，全基因组关联（GWAS）研究方法 将用于识别与果蝇抗性相关的局部情况。申请人表明这些方法 将确定平衡选择的目标。在这两个目标下，使用体外和体内的功能研究 方法将用于将进化模式与功能表型联系起来。拟议的研究是 意义重大，因为它将是一项预计会导致综合研究的研究中的第一项研究 了解宿主 - 寄生虫相互作用在基因组进化模式中起着作用。有 承诺将发现与宿主 - 寄生虫互动有关的一般原则 维持遗传变异。提出的研究具有创新性，因为它代表了偏离 当前有关宿主 - 寄生虫相互作用演变的研究方法，这些方法仅限于微生物或 非模型系统。