Characterizing the impact of Yersinia Pestis to the phenotypic evolution of the human immune system

表征鼠疫耶尔森菌对人类免疫系统表型进化的影响

• 批准号: 9803109
• 负责人: Luis Bruno Barreiro
• 金额: $ 47.67万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9803109
• 关键词: Address; Africa; African American; American; Autoimmune Diseases; Bacteria; Biological Assay; Bubonic Plague; Cells; Central Africa; Chronic; Collection; Communicable Diseases; Complex; DNA; Data; Disease; Environment; European; Evolution; Exposure to; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Determinism; Genetic Markers; Genetic Transcription; Genetic Variation; Genetic study; Genotype; Growth; Host Defense; Hour; Human; Human Genome; Immune; Immune response; Immune system; Immunity; Immunologics; Immunology; Individual; Infection; Inflammatory; Maps; Measures; Mediating; Modernization; Molecular; Natural Selections; Northern Africa; Pasteurella pseudotuberculosis; Pathogenicity; Phenotype; Plague; Play; Population; Population Genetics; Population Group; Predisposition; Proxy; Quantitative Trait Loci; Recording of previous events; Resistance; Resolution; Role; Sampling; Shapes; Single Nucleotide Polymorphism; Techniques; Technology; Testing; Time; Variant; Work; Yersinia; Yersinia infections; Yersinia pestis; cytokine; fighting; functional genomics; genetic variant; genome-wide; genome-wide analysis; host-pathogen coevolution; human genomics; in vitro Assay; induced pluripotent stem cell; infancy; insight; macrophage; novel; pandemic disease; pathogen; pressure; response; skeletal; tool; trait; transcriptome sequencing

Project Summary Pathogens are one of the strongest selective pressures on the human genome. As modern humans migrated out of Africa, they encountered markedly different pathogenic environments, likely resulting in population-specific selection of immune phenotypes. Consistent with this hypothesis, some of the most compelling evidence for local positive selection in the human genome has been detected among genes involved in immunity and host defense. Yet, our understanding of the role that local adaptation plays in shaping phenotypic variation in immune responses across populations is still in its infancy. To better understand the complex relationship between pathogens and host adaptation we propose to study the selective impact on the immune system of one of the most devastating pathogens in history – Yersinia pestis, the agent of the Black Death. Since its emergence in Eurasia 1500 to 6400 years ago Y. pestis has swept Eurasia and North and Central Africa in two major pandemics (Justinian, 541-544; Black Death, starting 1347- 1351) and has subsequently spread nearly worldwide via a third ongoing pandemic. Although Y. pestis is proposed to have severely culled the Eurasian population, how groups that differ in their historical exposure to plague respond to the pathogen is not known. Addressing this gap is not only important for understanding the recent evolution of the human immune system, but may also help reveal the molecular basis of ancestry- related differences in susceptibility to infectious diseases, chronic inflammatory disorders, and autoimmune disorders. Using combined expertise in human genomics, immunology, infectious diseases and ancient DNA, we propose: (i) to characterize inter-individual and inter-population variability in immune responses to infection with Y. pestis; (ii) to map expression quantitative trait loci (eQTLs) that are associated with variation in response to infection with Y. pestis; and (iii) to identify genetic loci showing signatures of positive selection by Y. pestis by looking at “real-time” fluctuations in allele frequencies among immune-related genes and immunological QTLs sequenced from skeletal remains of European populations living before, during, and after the Black Death. This work is expected to yield unprecedented insight into the genetic mechanisms associated with increased protection against Y. pestis as well as reveal novel genetic markers involved in the susceptibility to and/or protection against contemporary infectious diseases

项目总结