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大的选择压力之一。随着现代人的迁徙 在非洲之外，他们遇到了截然不同的致病环境，很可能导致了特定人群的 免疫表型的选择。与这一假设一致，一些最令人信服的证据表明 在人类基因组中检测到了与免疫和宿主有关的基因之间的局部正选择 防守。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 不同人群的反应仍处于初级阶段。为了更好地理解两者之间的复杂关系 病原体与宿主适应我们建议研究其中一种对免疫系统的选择性影响 历史上最具破坏性的病原体--黑死病的病原体--鼠疫耶尔森氏菌。自#年出现以来 1500到6400年前的欧亚大陆，鼠疫杆菌在欧亚大陆和北非和中非两个主要地区席卷 大流行(查士丁尼，541-544；黑死病，始于1347-1351)，随后几乎蔓延到全世界 通过正在进行的第三次大流行。尽管鼠疫杆菌被认为已经严重扑杀了欧亚大陆的人口， 历史上接触过鼠疫的不同群体对这种病原体的反应尚不清楚。寻址 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 有助于揭示与祖先相关的传染病易感性差异的分子基础 炎症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，亲本R01建议：(I)表征个体间和个体间 人巨噬细胞对鼠疫杆菌感染免疫反应的群体变异性；(Ii)定位 表达与鼠疫杆菌感染反应变异相关的数量性状基因座(EQTL)； 以及(Iii)通过查看“实时”来识别显示鼠疫杆菌正选择特征的遗传基因座 中国人免疫相关基因和免疫QTL的等位基因频率波动 生活在黑死病之前、期间和之后的欧洲人的骨骼遗骸。作为这项工作的一部分 作为补充，我们建议(I)扩大工作范围，以调查遗传变异对 利用最新发展在更多免疫细胞类型上对鼠疫杆菌的免疫反应 单细胞RNAseq方法，以及(Ii)研究ERAP2变异体对阳性的影响 在黑死病期间被选为鼠疫杆菌MHC相关多肽(MAP)的保留库，并最终， 对鼠疫耶尔森氏菌的宿主保护。

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.