The Genetic Architecture Of Skin Pigmentation In Southern Africa. A. R. Martin1, J. M. Granka2, C. R. Gignoux3, M. Möller4, C. J. Werely4, J. M. Kidd5, M. W. Feldman6, E. G. Hoal4, C. D. Bustamante1, B. M. Henn7 1) Stanford University, Genetics Department, Stanford, CA; 2) Ancestry.com, San Francisco, CA; 3) University of California, Pharmaceutical Sciences, San Francisco, CA; 4) Stellenbosch University, Health Sciences, Tygerberg, South Africa; 5) University of Michigan, Department of Human Genetics, Ann Arbor, MI; 6) Stanford University, Department of Biological Sciences, Stanford, CA; 7) SUNY, Deptartment of Ecology and Evolution, Stony Brook, NY.

   Skin pigmentation is one of the most recognizably diverse phenotypes in humans across the globe, but its highly genetic basis has mainly been studied in northern European and Asian populations. The Eurasian pigmentation alleles are among the most differentiated variants in the genome, suggesting strong positive selection for light skin pigmentation. Light skin pigmentation is also observed in the far southern latitudes of Africa, among KhoeSan hunter-gatherers of the Kalahari Desert and other populations. The KhoeSan hunter-gatherers, believed to have diverged from other populations 100,000 years ago, maintain extraordinary levels of genetic diversity, but it is unknown whether light skin pigmentation represents convergent evolution or the ancestral human phenotype. We have collected saliva samples, ethnographic information, and pigmentation phenotypes from 123 individuals in the Khomani San from the Kalahari. To understand the genetic basis for light skin pigmentation, we have genotyped and exome sequenced 91 Khomani San individuals to high coverage, generating one of the largest indigenous African exome datasets sequenced outside of 1000 Genomes. Because linkage disequilibrium decay is rapid in this population, we have assessed parameters influencing phasing and imputation accuracy since ideal reference panels do not exist. We have also pursued multiple genotype/phenotype mapping methods, including a mixed model approach, admixture mapping, and linkage mapping. After controlling for admixture from European and Bantu-speaking populations, we find that globally common variants are not significantly associated with pigmentation. Rather, our results indicate that there are a multitude of rare variants in known pigmentation genes, and suggest that previously unidentified genes acting in canonical pigmentation pathways may be involved. Our results highlight the strength of diverse population studies to explain phenotypic variation in the context of human evolutionary history.

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