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.

项目概要 免疫是人类健康的一个极其重要的话题，传染病会带来经济损失 2014 年这一数字超过了 1000 亿美元。与此同时，免疫系统的进化为 进化过程的研究，因为 a) 免疫的自然选择是激烈的，因为 感染通常是生死攸关的问题，b) 病原体有能力对宿主适应做出反应，从而导致快速 通过进化军备竞赛进行进化。由于昆虫缺乏适应性免疫系统，因此它们非常出色 了解先天免疫的分子遗传学和进化的模型。的重要组成部分 先天免疫是宿主产生和分泌的抗菌肽 (AMP) 的补充 细胞感染后直接抑制病原体。编码这些 AMP 的基因的变异通常是 通过平衡选择来维持，即多个等位基因维持在同一基因座的过程 通过各种机制。虽然平衡选择的实例越来越多地被报道 通常，我们对大多数情况下平衡选择的机制基础缺乏全面的了解 例子。将DNA序列多样性的广泛模式与DNA序列多样性的机制差异联系起来的能力 蛋白质功能具有创新性，将为平衡选择提供全面的视角。此外， 通过平衡选择维持的特定氨基酸多态性的鉴定有利于 平衡选择的机制研究，因为假定的致病突变是先验已知的。我们的 使用果蝇作为模型系统还可以以一种更有效的方式研究体内 AMP 变异 比其他几个模型系统更具成本效益，同时允许在体外和体外之间灵活移动 整个生物体的体内研究。这些肽非常适合平衡选择的功能研究，因为 a) 通过平衡选择、提供复制来维持多种肽的遗传变异，b) AMP c) AMP 很小，易于在体外研究。 目标 1 涉及在体外确定肽差异，以了解单个氨基酸变化如何导致 不同的功能。目标 2 将确定 AMP 变异对整个生物体的影响并研究 生活史权衡在平衡选择中的作用。该项目意义重大，因为它将提供更深入的 通过揭示分子机制来理解进化过程，并可能提供更好的 了解先天免疫可以增强我们对人类疾病的治疗。