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.
This project is highly relevant to public health because African Americans (AA) has a higher prevalence and substantial risk of autoimmune diseases such as lupus, but has been largely understudied and the reasons for this health disparity remain elusive. This study will integrate evidence for positive natural selection with biological information to identify adaptive functional variation associated with lupus in AA. Identifying the genetic variations that cause lupus and understanding the role of natural selection in shaping its risk will greatly expand our knowledge about the etiology of lupus in AA and contribute to the development of interventions to reduce risk, improved diagnosis, targeted therapies, and improved outcomes.
