Characterizing variation and adaptation in the immune response to plague (Y. pestis) through single-cell sequencing and ancient genomics

通过单细胞测序和古代基因组学表征鼠疫（鼠疫耶尔森氏菌）免疫反应的变异和适应

• 批准号: 10559526
• 负责人: Tauras P Vilgalys
• 金额: $ 7.18万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10559526
• 关键词: Address; Affect; Africa; Africa South of the Sahara; African ancestry; Area; Autoimmune Diseases; Automobile Driving; Bacteria; Basic Science; Blood Cells; Bubonic Plague; Cell Culture Techniques; Cells; Chronic; Communicable Diseases; DNA; Data; Disease; Disease susceptibility; Environment; Europe; European; European ancestry; Event; Evolution; Exposure to; Frequencies; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Grain; Health; Host Defense; Human; Human Genome; Immune; Immune response; Immune system; Immunity; Immunologics; Individual; Infection; Inflammation; Inflammatory; Influentials; Invaded; Link; Macrophage; Mediating; Mentors; Modernization; Molecular; Natural Selections; Overlapping Genes; Pasteurella pseudotuberculosis; Pathogenicity; Pathway interactions; Peripheral Blood Mononuclear Cell; Plague; Population; Population Genetics; Positioning Attribute; Predisposition; Quantitative Trait Loci; Recording of previous events; Research Design; Resistance; Sampling; Shapes; Testing; Time; Training; Variant; Work; Yersinia; Yersinia pestis; cell type; disorder risk; emerging pathogen; experience; functional genomics; genetic approach; genetic variant; genome sequencing; genomic data; genomic locus; genomic signature; health disparity; host-pathogen coevolution; human pathogen; immune function; in vitro Assay; in vivo; insight; interest; migration; mortality; new technology; novel; pathogen; pressure; protective allele; response; single cell sequencing; single-cell RNA sequencing

PROJECT SUMMARY Pathogens have been one of the strongest selective pressures in human evolution. Migrating out of Africa, modern humans encountered novel pathogens along with new environments. These populations likely adapted to these pathogens, leading to population-specific adaptations. Consistent with this hypothesis, some of the most compelling signatures of local adaptation in the human genome overlap genes involved in immunity and host defense. Importantly, these regions also overlap genetic loci which are associated with infectious, autoimmune, and inflammatory disease risk in modern humans. Thus, understanding adaptation to pathogens throughout history is important for understanding modern human health. The Black Plague was likely one of the strongest selective events in recent human history. Exposure to Yersinia pestis (the causative agent of plague) therefore likely drove adaptations in the human immune system which continue to shape modern immune variation. Importantly, because the plague ravaged Eurasia while leaving sub-Saharan Africa relatively untouched, adaptation to plague likely occurred in European but not African populations. However, it is not known whether human populations differ in their immune response to plague as a consequence of prior evolutionary history. 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 disease, chronic inflammation, and autoimmune disorders. The basic research questions driving this proposal are: What was the impact of Y. pestis to the functional differentiation of immune responses between African- and European-ancestry individuals? To which extent natural selection has favored the increase in frequency of protective alleles in Europeans, a population with increased exposure to Y. pestis? What cell types and immunological pathways show the most divergence in response to Y. pestis between populations? To answer this questions, I will experimentally infected peripheral blood cells in culture to characterize the immune response to plague. Using single-cell RNA sequencing I will be able to analyze variation in the immune response across cell types, but also characterize differences in the proportion of cells responding to infection and the strength of that response. Using this data, I will identify genes and pathways which are regulated differently in individuals of European and African ancestry, and identify genetic variants which contribute to these differences. I will then use a combination of ancient and modern genomics to test whether loci underlying variation in the immune response to Y. pestis also experienced position selection during the Black Plague. Thus, this project is a novel integration of functional and population genetic approaches to study adaptation to a deadly human pathogen. At its conclusion, this study will reveal how Europeans adapted to Y. pestis exposure during the plague, and identify highly-promising genetic candidates which may contribute to disease susceptibility in modern human populations.

项目摘要 病原体是人类进化过程中最强大的选择压力之一。从非洲迁移出来， 现代人在新的环境中遇到了新的病原体沿着。这些种群很可能适应了 这些病原体，导致人口特定的适应。与这一假设相一致的是， 人类基因组中局部适应的引人注目的特征与参与免疫和宿主的基因重叠 防御重要的是，这些区域还与与感染性、自身免疫性 和炎症性疾病的风险。因此，了解整个过程中对病原体的适应 历史对于理解现代人类健康很重要。 黑死病可能是人类近代史上最强的选择性事件之一。暴露于 因此，鼠疫耶尔森氏菌（鼠疫的病原体）很可能驱动了人类免疫系统的适应 这些基因继续塑造现代免疫变异。重要的是，因为瘟疫肆虐欧亚大陆， 撒哈拉以南非洲相对未受影响，欧洲可能发生了对鼠疫的适应，而非洲则没有 人口。然而，目前尚不清楚人类群体对鼠疫的免疫反应是否存在差异， 是先前进化历史的结果解决这一差距不仅对理解 人类免疫系统的最新进化，但也可能有助于揭示祖先相关的分子基础 感染性疾病、慢性炎症和自身免疫性疾病易感性的差异。 推动这一提议的基本研究问题是：Y.鼠疫的功能 非洲和欧洲血统个体之间的免疫反应差异？在多大程度上 自然选择有利于欧洲人保护等位基因频率的增加， 增加对Y的暴露。鼠疫？什么样的细胞类型和免疫途径显示出最大的分歧， 回答Y。人口之间的瘟疫为了回答这个问题，我将实验性地感染外周 血细胞培养来表征对鼠疫的免疫反应。使用单细胞RNA测序， 能够分析不同细胞类型的免疫反应的变化，但也表征了不同细胞类型的免疫反应的差异。 对感染作出反应的细胞的比例以及这种反应的强度。利用这些数据，我将找出 以及在欧洲和非洲血统的个体中受到不同调节的途径， 识别导致这些差异的遗传变异。然后我将使用古代和 现代基因组学来测试是否基因座潜在的变化，在免疫反应的Y。鼠疫也经历了 黑死病期间的职位选择因此，该项目是一个新颖的功能和人口的整合 研究人类对致命病原体的适应性的遗传学方法。在其结论中，这项研究将揭示如何 欧洲人适应了Y.鼠疫期间的鼠疫暴露，并确定非常有前途的遗传候选人 这可能导致现代人群的疾病易感性。