The role of natural selection in SLE risk among African-Americans

 描述(申请人提供)：系统性红斑狼疮(SLE)是一种严重的自身免疫性疾病，对非裔美国人(AA)的影响不成比例。尽管在阐明其遗传病因方面取得了巨大进展，但研究主要局限于高加索人，在识别特定的致病功能变异方面进展甚微。由于种群的基因组结构受到环境压力的影响，免疫反应对环境特别敏感，在整个进化过程中，种群特有的正向自然选择可能导致等位基因频率增加，这些等位基因也容易患上SLE等自身免疫性疾病。该项目的目标是发现系统性红斑狼疮的功能性风险变异，同时提高我们对自然选择导致的系统性红斑狼疮的遗传基础的理解。为了实现这一目标，拉莫斯博士将(1)使用两个互补的群体遗传学统计数据确定基因组中最近成为再生障碍性贫血(AA)正向自然选择目标的区域，(2)确定易患和正在选择的区域，(3)计算适应性SLE风险变量的全面功能注释，以确定与SLE相关的适应性功能变异。拉莫斯博士是南卡罗来纳医科大学风湿病学系的人类遗传学家。她的长期职业目标是成为一名自身免疫遗传学方面的独立翻译研究员。为了促进她成为一名独立的研究人员，她试图通过培训人口和进化遗传学、生物信息学和分析高维大规模数据集的计算工具来进一步提高她的技能，扩大她的研究的多学科性质。Ramos博士成功的环境来自(1)具有导师记录和支持她的项目所需的各种专业知识的导师团队，(2)来自独特的非裔美国人和非洲人群体的样本的可用性和基础设施的建立，以继续和扩大对这些人群的研究，(3)来自捐赠的炎症和纤维化智能州立中心、非裔美国人风湿性疾病多学科临床研究中心(MCRC)和成长中心基因组医学的支持，以及(4)医学部强有力的导师计划。识别导致再生障碍性贫血SLE风险的功能适应性等位基因将有助于理解积极的自然选择在塑造SLE风险中的作用，并极大地提高对再生障碍性贫血SLE病因学的认识。这些结果将提供关键的初步数据，支持外部应用对序列数据进行重点分析，功能研究，扩展到其他人群和其他自身免疫性疾病。培训将使拉莫斯博士能够实现她的长期目标，即成为一名独立研究员，领导开展自身免疫性疾病创新基因组研究的多学科团队。

 DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a severe autoimmune disorder that disproportionately affects African Americans (AA). Despite tremendous progress in elucidating its genetic etiology, research has been mainly limited to Caucasians, and little progress has been made in the identification of the specific disease-predisposing functional variations. Since the genome structure of a population is influenced by environmental pressures, and immune responses are particularly sensitive to the environment, it is possible that, throughout evolution, population-specific positive natural selection has led to a increased frequency of alleles that also predispose to autoimmune diseases like SLE. The goal of this project is to discover functional SLE risk variants in AAs while improving our understanding of the genetic basis of SLE that is due to natural selection. In order to accomplish this, Dr. Ramos will (1) identify regions of the genome that have been the target of recent positive natural selection in AA using two complementary population genetics statistics, (2) identify regions that are both predisposing to SLE and under selection, and (3) compute thorough functional annotation of the adaptive SLE risk variants to identify adaptive functional variation associated with SLE. Dr. Ramos is a human geneticist in the Division of Rheumatology at the Medical University of South Carolina (MUSC). Her long-term career goal is to become an independent translational researcher in the genetics of autoimmunity. To facilitate her transition into an independent investigator, she seeks to further her skills and broaden the multidisciplinary nature of her research by training in population and evolutionary genetics, and bioinformatics and computational tools for the analysis of high-dimensional large-scale datasets. The environment for the success of Dr. Ramos is provided by (1) a mentorship team with the mentorship track record and varied expertise needed to support her project, (2) the availability of samples from unique African American and African populations and the established infrastructure to continue and expand studies on these populations, (3) support from the endowed Smart State Center in Inflammation and Fibrosis, the Multidisciplinary Clinical Research Center (MCRC) for Rheumatic Diseases in African Americans, and the growing Center Genomic Medicine, and (4) the Department of Medicine's robust mentorship program. The identification of functional adaptive alleles that contribute to SLE risk in AA will contributeto an understanding of the role of positive natural selection in shaping SLE risk and vastly improve knowledge about the etiology of SLE in AA. These results will provide critical preliminary data supporting extramural applications to conduct focused analysis of sequence data, functional studies, expand to other populations and to other autoimmune diseases. The training will enable Dr. Ramos to achieve her long-term objective of becoming an independent investigator leading multidisciplinary teams conducting innovative genomic research in autoimmune disease.