Variation at Malaria Resistance Genes in Africans

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DESCRIPTION (provided by applicant): Malaria is a leading cause of death worldwide, affecting approximately 41 % of the world's population. Over 90% of the 1 million deaths per year due to malaria are in sub-Saharan Africa. Although a number of candidate genes have been identified that play a role in resistance to malarial infection, there are few studies of nucleotide variation at these genes without ascertainment bias across geographically diverse ethnic groups, particularly from Africa. Knowledge of patterns of genetic variation and haplotype structure in African populations, and how these patterns are influenced by demographic history and natural selection, will be important for identifying genetic variants that play a role in susceptibility to disease in people of recent African origin. The aims of this study are (1) To identify nucleotide variation and characterize genetic diversity, haplotype structure, and linkage disequilibrium (LD) by resequencing at 12 loci that may play a role in resistance to malarial infection, and at 20 non-coding control regions, in 13 ethnically diverse African populations, and in a comparative sample of Europeans and Asians (2) To genotype Single Nucleotide Polymorphisms (SNPs) with minor allele frequency (MAF) >10% at the candidate loci in a sample of 1100 individuals originating from Africa, and a comparative sample of Europeans and Asians, in order to characterize the geographic distribution of haplotype variability at malarial resistance loci (3) To reconstruct the evolutionary history of candidate genes for malarial resistance and to identify gene regions and haplotypes containing potentially functionally significant variants by screening for signatures of natural selection. This project will contribute to our knowledge of the genetic basis of susceptibility to malarial infection in Africans. Additionally, we will identify markers useful for future association studies of disease susceptibility in populations of African descent. Lastly, we will have a better understanding of the evolutionary history of malarial infection in humans and the role of natural selection and demography on the prevalence and distribution of genetic disease.