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

项目摘要 免疫是人类健康的一个极其重要的主题，传染病的经济成本 在2014年超过1000亿美元。与此同时，免疫系统的进化也是免疫系统的肥沃土壤。 进化过程的研究，因为a）免疫的自然选择是激烈的，因为结果 感染通常是生死攸关的，并且B）病原体具有响应宿主适应的能力，导致快速的 通过进化军备竞赛来进化。由于昆虫缺乏适应性免疫系统， 模型来理解先天免疫的分子遗传学和进化。的重要组成部分 天然免疫是由宿主产生和分泌的抗菌肽（AMP）的补充 细胞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，通过平衡选择，多个等位基因被保持在同一基因座上的过程 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，我们缺乏对大多数情况下平衡选择的机制基础的全面理解。 例子.将DNA序列多样性的大规模模式与基因组中的机制差异联系起来的能力， 蛋白质功能是创新的，并将提供一个全面的观点平衡选择。而且 通过平衡选择维持的特定氨基酸多态性的鉴定有助于 平衡选择的机制研究，因为推定的致病突变是先验已知的。我们 使用果蝇作为模型系统也允许以一种更复杂的方式研究体内AMP的变化。 比其他几种模型系统更具成本效益，同时允许在体外和 全生物体体内研究。这些肽是平衡选择功能研究的理想选择， a）通过平衡选择维持几种肽的遗传变异，提供复制，B）AMP是 c）AMP是小的并且可以容易地在体外研究。 目的1涉及在体外确定肽的差异，以了解单个氨基酸的变化如何导致 不同的功能。目的2将确定AMP变异对整个生物体的影响，并研究AMP变异对整个生物体的影响。 生活史权衡在平衡选择中的作用。该项目意义重大，因为它将提供一个更深层次的 通过揭示分子机制来理解进化过程，并可能提供更好的 对先天免疫的理解，以提高我们对人类疾病的治疗。

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.