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 在我们对宿主-寄生虫相互作用如何维持遗传变异的理解上存在着根本性的空白 包括人类在内的物种。人类和长寿真核寄生虫之间的相互作用可能是 人类基因组中自然选择的最重要因素，并可能负责 维持人类全基因组功能变异（平衡选择）。然而，将 平衡选择与它们的基因组靶的药剂仍然是一个主要的挑战。持续存在， 差距是一个重要的问题，因为直到它被填补，有一个有限的了解机制 负责物种内遗传变异的潜在维持。研究者的长期目标 实验室的目的是了解宿主-寄生虫适应的遗传基础。未来五年的目标 是为了确定从宿主-寄生虫相互作用中产生的选择的代理和目标。核心假设是， 宿主-寄生虫相互作用维持物种内的遗传变异。理论基础是， 在遗传模型植物拟南芥中已经发生了果蝇谱系的遗传模型， 允许深入研究。在强有力的初步数据的指导下，这一假设将通过追求这两个 主要研究问题：1）。确定支持向寄生虫过渡的分子遗传变化 2）确定宿主-寄生虫相互作用是否导致果蝇中全基因组变异的维持， 植物在第一个问题下，进化过渡到寄生的基因组结构将 在果蝇科中被识别出来。下一代测序和比较基因组学研究将确定 从自由生活的果蝇进化寄生所必需的基因。初步研究表明， 该方法对于发现“寄生物基因”具有很大的希望，并且该方法在申请人的研究中是可行的。 手在第二个问题下，寄生蝇的种群将进化为单一或混合宿主 基因型在抗性性状上的差异。一种进化和重新测序的方法将测试基因组范围的变异是否 是通过平衡果蝇的选择来维持的在植物中，全基因组关联（GWAS）研究方法 将用于鉴定与抗蝇性相关的基因座。申请人已经表明，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 方法将被用来连接进化模式与功能表型。拟议的研究是 重要的是，这将是一个连续的研究，预计将导致一个综合的研究， 理解宿主-寄生虫相互作用在塑造基因组进化模式中的作用。有 承诺将发现与宿主-寄生虫相互作用在宿主-寄生虫相互作用中所起作用有关的一般原则。 保持遗传变异。所提出的研究是创新的，因为它代表了一种背离 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。