Multiple HLA loci and energy metabolism genes are targeted by recent positive selection in an Ethiopian population. F. Tekola-Ayele1, A. Adeyemo1, E. Hailu2, A. Aseffa2, G. Davey3, M. J. Newport3, CN. Rotimi1 1) National Human Genome Research Institute, National Institutes of Health, Bethesda, MD; 2) Armauer Hansen Research Institute, Addis Ababa, Ethiopia; 3) Brighton and Sussex Medical School, Brighton, UK.

   The genetic, population demographic, ecological, and socio-cultural diversity of African populations is a useful resource to capture genomic regions targeted by specific local selection pressures, and to refine and interpret the putative selective forces. However, only a handful of African population groups have been represented in studies involving genome-wide scans of selection. Here, we performed a genome-wide scan to identify regions that show evidence of recent positive selection in a sample of 120 individuals from the Wolaita ethnic group from southern Ethiopia. The Wolaita people have inhabited the mid- and high-lands of southern Ethiopia for millennia and inhabit one of the most densely populated regions in the country. To identify selection signal in this ethnic group, we included 988 unrelated individuals from 11 global populations in the HapMap 3 database. We performed three types of analyses: the integrated haplotype score (iHS), cross-population extended haplotype homozygosity (XP-EHH), and fixation index (FST). We found enrichment of signals of recent positive selection in several genes in the HLA locus (p<0.00001). Our selection signals overlapped with loci that showed genome-wide significant association with several inflammatory diseases including podoconiosis, a devastating lymphedema of the lower legs resulting from massive inflammatory response to chronic exposure of feet to irritant soils in poor barefoot individuals. Podoconiosis is endemic in the Wolaita area. Second, we found selection signals in energy metabolism genes including PPAR-alpha that plays a key adaptive role in energy metabolism during prolonged food deprivation. This finding is consistent with the historical consumption of enset (Ensete ventricosum) as a main food source in the Wolaita area. Enset, also known as The Tree against Hunger, has high carbohydrate and starch but low fat and protein content, and is used as a staple and co-staple food source. Therefore, the putatively advantageous selected allele may inhibit PPAP-alpha expression, resulting in reduced oxidation of lipids which is balanced by enhanced carbohydrate oxidation. We also found a novel selection signal in CDKAL1, a gene known to be associated with type 2 diabetes. In all, we found evidence of strong selection for HLA and metabolism genes in an Ethiopian population probably due to adaptive response to burden of pathogens and nutritional composition of the staple diet.

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