The causes of balancing selection on immunity genes: from populations to molecular interactions.

免疫基因平衡选择的原因：从群体到分子相互作用。

• 批准号: 9918867
• 负责人: Robert L Unckless
• 金额: $ 36.53万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-17 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918867
• 关键词: Adaptive Immune System; Address; Alleles; Amino Acids; Animals; Antibiotic Resistance; Antimicrobial Effect; Autoimmune Process; Binding; Biological Assay; Biological Models; Cells; Cessation of life; Communicable Diseases; Complement; DNA Sequence; Data; Dissection; Drosophila genus; Environment; Equilibrium; Evolution; Exhibits; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Growth; Health; Host Defense; Human; Immune; Immune system; Immunity; In Vitro; Individual; Infection; Innate Immune System; Insecta; Invertebrates; Lead; Life; Light; Link; Maintenance; Measures; Membrane; Microbe; Minimum Inhibitory Concentration measurement; Modeling; Molecular; Molecular Genetics; Molecular Profiling; Mutation; Natural Immunity; Natural Selections; Organism; Outcome; Partner in relationship; Pathway interactions; Pattern; Peptides; Plants; Play; Population; Predatory Behavior; Process; Publishing; Race; Reporting; Resistance; Role; Secure; Specificity; Testing; Therapeutic; Time; Variant; Whole Organism; Work; antimicrobial; antimicrobial peptide; arm; causal variant; cost; cost effective; economic cost; experimental study; fitness; flexibility; genetic evolution; genome editing; gut microbiota; human disease; human pathogen; in vivo; innovation; insight; laboratory experiment; life history; male; microbiota; mutant; pathogen; peptide drug; peptide structure; pressure; protein function; success; trait

Project Summary Immunity is an enormously important topic for human health with economic costs of infectious disease eclipsing $100 billion in 2014. At the same time, the evolution of the immune system is fertile ground for the study of evolutionary processes because a) natural selection on immunity is intense since the outcome of infection is often life or death and b) pathogens have the ability to respond to host adaptation leading to rapid evolution through an evolutionary arms race. Since insects lack an adaptive immune system, they are excellent models to understand the molecular genetics and evolution of innate immunity. An important component of innate immunity is the complement of antimicrobial peptides (AMPs) that are produced and secreted by host cells upon infection and directly inhibit pathogens. Variation in the genes encoding these AMPs is often maintained by balancing selection, the process by which multiple alleles are maintained at the same locus through various mechanisms. While instances of balancing selection are being reported more and more frequently, we lack a comprehensive understanding of the mechanistic basis of balancing selection in most examples. The ability to connect broad scale patterns of DNA sequence diversity to mechanistic differences in protein function is innovative and would provide a comprehensive view of balancing selection. Furthermore, the identification of particular amino acid polymorphisms that are maintained by balancing selection facilitates the mechanistic study of balancing selection because the presumptive causative mutations are known a priori. Our use of Drosophila as a model system also allows for study of AMP variation in vivo in a way that is much more cost effective than several other model systems, while allowing the flexibility to move between in vitro and whole organism in vivo study. These peptides are ideal for the functional study of balancing selection because a) genetic variation in several peptides is maintained by balancing selection, providing replication, b) AMPs are effectors and thus interact directly with pathogens and c) AMPs are small and can be easily studied in vitro. Aim 1 involves determining peptide differences in vitro to understand how single amino acid changes lead to different function. Aim 2 will determine the effect of AMP variation on the entire organism and investigate the role of life history tradeoffs in balancing selection. The project is significant because it will provide a deeper understanding of evolutionary processes by uncovering molecular mechanisms and may provide a better understanding of innate immunity to enhance our treatment of human disease.

项目摘要 免疫是人类健康的一个非常重要的主题，具有传染病的经济成本 2014年剥夺了1000亿美元。与此同时，免疫系统的演变是肥沃的。 研究进化过程是因为a）自然选择免疫是强烈的，因为 感染通常是生命或死亡，b）病原体具有对宿主适应的反应能力，导致快速 通过进化的军备竞赛进化。由于昆虫缺乏适应性免疫系统，它们非常出色 了解先天免疫的分子遗传学和进化的模型。一个重要组成部分 先天免疫是由宿主产生和分泌的抗菌肽（AMP）的补充 感染后细胞并直接抑制病原体。编码这些放大器的基因的变化通常是 通过平衡选择维护，多个等位基因保持在相同基因座的过程 通过各种机制。越来越多 通常，我们缺乏对大多数人平衡选择机械基础的全面理解 例子。将DNA序列多样性的大规模模式连接到机械差异的能力 蛋白质功能具有创新性，将提供平衡选择的全面视图。此外， 通过平衡选择维持的特定氨基酸多态性的鉴定有助于促进 平衡选择的机械研究是因为假定的致病突变是先验的。我们的 果蝇作为模型系统的使用还可以以更多的方式研究体内的AMP变化 具有比其他几个模型系统的成本效益，同时允许在体外和 整个生物体研究。这些肽是平衡选择功能研究的理想选择 a）通过平衡选择来维持几种肽的遗传变异，提供复制，b）AMPS是 效应子，因此直接与病原体相互作用，c）AMP很小，可以在体外容易研究。 AIM 1涉及确定体外肽差异以了解单个氨基酸的变化如何导致 不同的功能。 AIM 2将确定AMP变异对整个生物体的影响，并研究 生活历史折衷在平衡选择中的作用。该项目很重要，因为它将提供更深的 通过发现分子机制来了解进化过程，并可能提供更好的 了解先天免疫以增强我们对人类疾病的治疗。