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极其重要的话题，传染病的经济代价也是如此 超过2014年的1000亿美元。同时，免疫系统的进化也为 对进化过程的研究，因为a)关于免疫的自然选择是激烈的，因为 感染通常是生死攸关的，b)病原体有能力对宿主的适应做出反应，导致迅速 通过一场进化军备竞赛进行进化。由于昆虫缺乏适应性免疫系统，它们是优秀的 了解先天免疫的分子遗传学和进化的模型。的一个重要组成部分 先天免疫是由宿主产生和分泌的抗菌肽的补充。 细胞受到感染，并直接抑制病原体。编码这些AMP的基因的变异通常是 通过平衡选择来维持，即多个等位基因保持在同一个座位上的过程 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 举个例子。将DNA序列多样性的广泛模式与生物多样性的机制差异联系起来的能力 蛋白质功能是创新的，将为平衡选择提供一个全面的视角。此外， 通过平衡选择保持的特定氨基酸多态的识别有助于 平衡选择的机械论研究，因为假定的因果突变是先验已知的。我们的 使用果蝇作为模型系统也允许以一种更多的方式研究体内AMP的变异 比其他几种模型系统更具成本效益，同时允许在体外和 整体生物体活体研究。这些多肽是平衡选择功能研究的理想选择，因为 A)通过平衡选择、提供复制来维持几个肽的遗传变异，b)AMP C)AMP很小，很容易在体外进行研究。 目标1包括在体外测定多肽的差异，以了解单一氨基酸的变化是如何导致 不同的功能。目标2将确定AMP变异对整个生物体的影响，并调查 生活史权衡在平衡选择中的作用。该项目意义重大，因为它将提供更深层次的 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，以提高我们对人类疾病的治疗。