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

项目概要 病原体是对人类基因组最强的选择压力之一。作为现代人类 迁出非洲后，他们遇到了明显不同的致病环境，可能导致 免疫表型的人群特异性选择。与这一假设相一致的是，一些最 在基因中检测到人类基因组局部正选择的令人信服的证据 参与免疫和宿主防御。然而，我们对当地适应所发挥的作用的理解 塑造不同人群免疫反应的表型变异仍处于起步阶段。为了更好 了解病原体与宿主适应之间的复杂关系，我们建议研究 历史上最具破坏性的病原体之一——鼠疫耶尔森氏菌对免疫系统的选择性影响， 黑死病的代理人。自从 1500 至 6400 年前在欧亚大陆出现以来，鼠疫耶尔森氏菌已经席卷全球 欧亚大陆以及北非和中非发生了两次重大流行病（查士丁尼，541-544 年；黑死病，始于 1347- 1351），随后通过第三次持续大流行几乎在全世界范围内传播。尽管鼠疫耶尔森氏菌 提议严厉剔除欧亚裔人口，历史上接触不同的群体如何 鼠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进化，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性疾病易感性的相关差异 失调。综合利用人类基因组学、免疫学、传染病和古代 DNA 方面的专业知识， 我们建议：（i）描述个体间和群体间对感染的免疫反应的变异性 鼠疫耶尔森氏菌； (ii) 绘制与变异相关的表达数量性状位点 (eQTL) 对鼠疫耶尔森氏菌感染的反应； (iii) 识别显示正选择特征的遗传位点 鼠疫耶尔森氏菌通过观察免疫相关基因等位基因频率的“实时”波动， 从生活在之前、期间和之后的欧洲人群的骨骼遗骸中测序出的免疫学 QTL 黑死病。这项工作有望对相关遗传机制产生前所未有的见解 增强对鼠疫耶尔森氏菌的保护，并揭示与易感性相关的新遗传标记 和/或预防当代传染病