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。作为现代人 从非洲迁徙出来，他们遇到了截然不同的致病环境，很可能导致 免疫表型的群体特异性选择。与这一假设相一致的是，一些最 人类基因组中存在局部正选择的令人信服的证据已在基因间检测到 参与了豁免权和宿主防御。然而，我们对本地适应在其中所起作用的理解 塑造人群间免疫反应的表型变异仍处于初级阶段。为了更好地 了解病原体和寄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，鼠疫杆菌席卷了 欧亚大陆和北非和中非的两大流行病(查士丁尼，541-544；黑死病，从1347年开始- 1351)，随后通过第三次持续的大流行几乎在全世界范围内传播。尽管鼠疫杆菌是 被认为已经严重扑杀了欧亚人口，不同的群体在他们历史上接触到的 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- 感染疾病、慢性炎症性疾病和自身免疫易感性的相关差异 精神错乱。利用人类基因组学、免疫学、传染病和古代DNA的综合专业知识， 我们建议：(I)表征感染免疫反应的个体间和种群间的变异性 (Ii)定位与鼠疫菌变异相关的表达数量性状基因座(EQTL)。 对感染鼠疫杆菌的反应；及。(Iii)找出显示阳性选择特征的遗传基因座。 鼠疫杆菌通过观察免疫相关基因和 生活在前、中、后的欧洲人骨骼遗骸中的免疫QTL测序 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 增强了对鼠疫杆菌的保护作用，并揭示了与易感性有关的新的遗传标记 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