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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。

基本信息

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
项目类别：
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

项目摘要

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.

项目总结