Title: Haplotype diversity in candidate genes for susceptibility/resistance to infectious disease among circumpolar Aboriginal populations
Summary of Activity
We will employ a three-pronged approach to assess the contribution of 5 candidate genes (Chemokine receptor 5 (CCR5), Vitamin D receptor (VDR), Killer Immunoglobulin-like receptors (KIR) and the cytokines Tumor Necrosis Factor a (TNFa) and Interferon gamma (IFN?) to the susceptibility/resistance of infectious pathogens in Native North American populations. The identification of gene variants associated with susceptibility to infectious disease among circumpolar Aboriginal groups can contribute to the development of effective treatments for indigenous arctic communities. The three approaches will employ tools from population genetics, direct association studies, and ancient DNA analyses. The genes were chosen because the literature strongly suggests that these genes play a significant role in the active and innate immune response and should be subject to selective forces (pathogens). All genes will be re-sequenced in a diverse panel of circumpolar Aboriginal populations and in specific indigenous communities in North America and Russia that exhibit a high incidence of Tb. 1. The population genetics approach will analyze the distribution, frequency, and relationships among haplotypes in Aboriginal circumpolar groups. The distribution and frequency of haplotypes in these groups should also exhibit a unique pattern at genomic regions that experienced a strong selective pressure (pathogens) during European colonization. These genomic regions likely contain genes associated with resistance to pathogens carried over by European populations during European colonization. 2. The haplotypes identified for the candidate genes in part 1 of the study will then be analyzed in contemporary Aboriginal populations from the circumpolar regions of North American and Russia that exhibit a high frequency of Tb infection. The identification and analysis of haplotypes specific to Native American populations controls for two problems that may exist in previous studies that have typed genetic markers in Aboriginal groups. First, the effects of European admixture in these indigenous communities. By identifying haplotypes that are ancestral to Aboriginal individuals (from part 1) we can exclude haplotypes that are a result of European admixture in the association study. Second, the effects of ascertainment bias because previous genetic markers were largely ascertained from European and Japanese populations. 3. From parts 1 and 2, we will identify haplotypes in the candidate genes that exhibit associations with Tb infection. Once we identify these haplotypes we can directly observe the results of selection for these haplotypes by comparing the frequency of these haplotypes in pre- and post-contact populations. Dr. Larcombe already has permission to analyze DNA from the remains of 20 precontact individuals from indigenous groups in Nunavut. Necessary precautions in ancient DNA analyses will be used.
Dr Pamela Orr
University of Manitoba
GC430-820 Sherbrook Street, Winnipeg, Manitoba Canada
Tel: (204) 78703391
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