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

项目摘要 病原体是人类基因组上最强的选择压力之一。随着现代人类迁移到 在非洲之外，他们遇到了明显不同的致病环境，可能导致人群特异性 免疫表型的选择。与这一假设相一致，一些最令人信服的证据表明， 在人类基因组中，免疫和宿主相关基因存在局部正选择 防御然而，我们对局部适应在形成免疫表型变异中所起作用的理解， 针对不同人群的应对措施仍处于起步阶段。为了更好地理解 病原体和宿主适应，我们建议研究选择性影响免疫系统的一个 历史上最具毁灭性的病原体-鼠疫耶尔森菌，黑死病的病原体。自1999年出现以来， 欧亚大陆1500至6400年前Y.鼠疫在两个主要地区席卷欧亚大陆、北非和中非， 流行病（查士丁尼，541-544;黑死病，开始1347-1351），随后几乎蔓延到世界各地 第三次大流行虽然Y.鼠疫被认为严重地消灭了欧亚大陆的人口， 历史上接触鼠疫的不同群体如何对病原体作出反应尚不清楚。解决 这一差距不仅对理解人类免疫系统的最新进化很重要，而且可能 有助于揭示与祖先有关的感染性疾病、慢性 炎性疾病和自身免疫性疾病。利用人类基因组学，免疫学， 传染病和古老的DNA，父母R 01建议：（i）表征个体间和个体间， 感染Y.鼠疫在人类巨噬细胞;（ii）映射 表达数量性状基因座（eQTL），这些基因座与Y.鼠疫; 和（iii）鉴定显示Y.通过“实时”观察鼠疫 免疫相关基因和免疫QTL之间等位基因频率的波动， 黑死病之前、期间和之后生活的欧洲人口的骨骼遗骸。作为其中的一部分 补充，我们建议（i）扩大工作范围，调查遗传变异对 免疫应答通过利用最近的发展， 单细胞RNAseq方法，和（ii）研究ERAP 2变体的影响，这些变体是阳性的， 在黑死病期间被选入Y.鼠疫菌MHC相关肽（MAPs），最终， 宿主对Y.鼠疫

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, the parent R01 proposes: (i) to characterize inter-individual and inter- population variability in immune responses to infection with Y. pestis in human macrophages; (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. As part of this supplement, we propose (i) to expand the scope of the work to investigate the impact of genetic variation in immune responses to Y. pestis across a larger array of immune cell types by leveraging the recent development of single cell RNAseq approaches, and (ii) to investigate the impact of ERAP2 variants that were positively selected during the Black Death to the repertoire of Y. pestis MHC-associated peptides (MAPs) and, ultimately, host protection against Y. pestis.