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: 10403998
• 负责人: Luis Bruno Barreiro
• 金额: $ 45.09万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403998
• 关键词: Address; Africa; African American population; 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; SNP genotyping; Sampling; Shapes; Techniques; Technology; Testing; Time; Variant; Work; Yersinia; Yersinia infections; Yersinia pestis; cytokine; fighting; functional genomics; genetic variant; genome-wide; genome-wide analysis; genomic locus; 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

项目摘要 病原体是人类基因组上最强的选择压力之一。作为现代人类 从非洲迁移到非洲，他们遇到了明显不同的致病环境，可能导致 特定于人群的免疫表型选择。与这个假设一致，其中一些 在基因之间检测到了人类基因组中局部阳性选择的令人信服的证据 参与免疫力和宿主防御。然而，我们对当地适应在中的作用的理解 跨种群免疫复杂的表型变化仍处于起步阶段。更好 了解病原体与宿主适应之间的复杂关系，我们建议研究 对历史上最具破坏性病原体之一的免疫系统的选择性影响 - 黑人死亡的代理人。自从它出现在1500年至6400年前的欧亚大陆以来 欧亚大陆，北非和中非在两个主要的大流行中（贾斯汀尼安，541-544；黑色死亡，从1347年开始 1351年），随后通过第三次正在进行的大流行而在全球范围内传播。虽然柴油是 提议严重淘汰欧亚人口，在历史暴露中有所不同 瘟疫对病原体的反应尚不清楚。解决这一差距不仅对于理解 人类免疫系统的最新演变，但也可能有助于揭示祖先的分子基础 对传染病，慢性炎症性疾病和自身免疫的易感性相关差异 疾病。使用人类基因组学，免疫学，传染病和古代DNA的联合专业知识， 我们提出：（i）表征免疫调查中的个体间和人口间的变异性 与Y. Pestis一起； （ii）绘制与变化有关 对Y. Pestis感染的反应； （iii）通过 Y. Pestis通过查看与免疫相关基因中等位基因频率的“实时”波动和 免疫学QTL从居住之前，之中和之后的欧洲人群的骨骼遗体测序 黑色死亡。预计这项工作将对相关的遗传机制产生前所未有的见解 随着对Pestis的保护增加，并揭示了易感性涉及的新型遗传标记 对和/或保护当代传染病