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.

摘要 我们对寄主-寄生虫相互作用如何维持遗传变异的理解存在着根本的差距 在物种内部，包括人类。人类与长寿的真核寄生虫之间的相互作用可能是 人类基因组中最重要的自然选择因素，并可能对 维持人类全基因组功能变异(平衡选择)。但是，将 平衡选择和他们的基因组目标的代理人仍然是一个主要的挑战。这一点继续存在 缺口是一个重要的问题，因为在它被填补之前，人们对其机制的了解是有限的 负责维持物种内潜在的遗传变异。调查员的长期目标是 实验室是为了了解宿主-寄生虫适应的遗传基础。未来五年的目标是 是确定宿主-寄生虫相互作用产生的选择因子和目标。中心假设是 寄主-寄生虫的相互作用维持了物种内的遗传变异。其基本原理是向寄生的过渡 在遗传模式植物拟南芥中，已经出现了遗传模式果蝇的血统， 允许深入研究。在强劲的初步数据的指导下，这一假说将通过追求这两项来检验 主要研究问题：1)。确定支持向寄生的转变的分子遗传变化 在果蝇中，2)确定宿主-寄生虫的相互作用是否导致果蝇全基因组变异的维持以及 植物。在第一个问题下，向寄生进化过渡的基因组结构将 在果蝇科中被鉴定。下一代测序和比较基因组学研究将确定 自由生活果蝇寄生进化所必需的基因。初步研究表明，这 这种方法在寻找“寄生虫基因”方面有很大的希望，而且这种方法在申请者的 举起手来。在第二个问题中，寄生苍蝇种群将由单一或混合宿主进化而来。 抗性性状不同的基因类型。一种进化和重新测序的方法将测试全基因组范围的变异 是通过平衡果蝇的选择来维持的。在植物中，基因组范围关联(GWAS)研究方法 将被用于识别与苍蝇抗药性相关的基因座。申请者已经证明，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 将使用方法将进化模式与功能表型联系起来。拟议的研究是 意义重大，因为这将是一系列研究中的第一项研究，预计将导致 了解寄主-寄生虫相互作用在塑造基因组进化模式中所起的作用。的确有 承诺将发现与宿主-寄生虫相互作用在 保持遗传变异。提出的这项研究具有创新性，因为它代表了与 目前研究宿主-寄生虫相互作用进化的方法仅限于微生物或 非模型系统。