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。作为现代人类 从非洲迁移出来，他们遇到了明显不同的致病环境，可能导致 免疫表型的群体特异性选择。与这一假设相一致的是， 在人类基因组中发现了令人信服的局部正选择的证据 参与免疫和宿主防御然而，我们对当地适应在 在人群中形成免疫应答的表型变异仍处于起步阶段。更好地 了解病原体和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--鼠疫耶尔森菌对免疫系统的选择性影响， 黑死病的代理人自1500年至6400年前在欧亚大陆出现以来，Y。瘟疫席卷了 欧亚大陆和北非及中非的两次大流行（查士丁尼，541-544年;黑死病，1347- 1351），随后通过第三次持续的大流行几乎在全世界传播。虽然Y.佩斯群岛 提出了严重扑杀欧亚人口，如何在他们的历史接触不同的群体， 鼠疫对病原体的反应尚不清楚。解决这一差距不仅对理解 人类免疫系统的最新进化，但也可能有助于揭示祖先的分子基础- 感染性疾病、慢性炎症性疾病和自身免疫性疾病易感性的相关差异 紊乱利用人类基因组学、免疫学、传染病和古代DNA方面的综合专业知识， 我们提出：（i）表征个体间和群体间对感染的免疫反应的变异性 与Y。（ii）定位与鼠疫菌中的变异相关的表达数量性状基因座（eQTL）， 对Y.鼠疫杆菌;和（iii）鉴定显示阳性选择特征的遗传基因座， Y.通过观察免疫相关基因中等位基因频率的“实时”波动， 从欧洲人群在此之前、期间和之后的骨骼遗骸中测序的免疫QTL 黑死病。这项工作有望对相关的遗传机制产生前所未有的洞察力 增加了对Y的保护。以及揭示新的遗传标记参与的易感性 预防和/或预防当代传染病

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