PgmNr 1: Novel loci associated with skin pigmentation identified in African populations.
Authors:N. Crawford 1; D. Kelly 1,2; M. Hansen 1; M. Holsbach Beltrame 1; S. Fan 1; S. Bowman 3,4; E. Jewett 5,6; A. Ranciaro 1; S. Thompson 1; S. Pfeifer 7; J. Jensen 7; S. Wata Mpoloka 9; G. Mokone 10; T. Nyambo 11; D. Wolde Meskel 12; G. Belay 12; H. Rothschild 13; Y. Zhou 14,15; M. Kovacs 16; M. Xu 16; E. Oceana 20; Y. Song 5,6,21,22,23; E. Eskin 24; K. Brown 16; M. Marks 3,4; S. Loftus 17; W. Pavan 17; M. Yeager 18,19; S. Chanock 24; S. Tishkoff 1,25
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Affiliations:
1) Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; 2) Genomics and Computational Biology Graduate Program, University of Pennsylvania, Philadelphia, PA, 19104, USA; 3) Department of Pathology & Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104; 4) Department of Pathology & Laboratory Medicine and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; 5) Department of EECS, University of California, Berkeley, CA, 94704; 6) Department of Statistics, University of California, Berkeley, CA, 94704; 7) School of Life Sciences, Arizona State University, Tempe, AZ 85287; 8) Department of Biology, Howard University, Washington D.C.; 9) Department of Biological Sciences, University of Botswana, Gaborone Botswana; 10) Dept. of Biomedical Sciences, University of Botswana School of Medicine, Gaborone, Botswana; 11) Department of Biochemistry, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania; 12) Department of Biology, Addis Ababa University, Addis Ababa, Ethiopia; 13) Stem Cell Program, Division of Hematology/Oncology, Pediatric Hematology Program, Boston Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; 14) Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; 15) Stem Cell Program, Division of Hematology/Oncology, Pediatric Hematology Program, Boston Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; 16) Laboratory of Translational Genomics (LTG), Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute, National Institutes of Health, Bethesda MD 20892; 17) Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; 18) Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD; 19) Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD; 20) Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, RI 02912; 21) Chan Zuckerberg Biohub, San Francisco, CA 94158; 22) Department of Biology, University of Pennsylvania, Philadelphia, PA.; 23) Department of Mathematics, University of Pennsylvania, Philadelphia, PA.; 24) Department of Computer Science, Department of Human Genetics, University of California, Los Angeles, 90095; 25) Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
Despite the wide range of variation in skin pigmentation in Africans, little is known about its genetic basis. To investigate this question we performed a GWAS on pigmentation in 1,593 Africans from populations in Ethiopia, Tanzania, and Botswana. We identify significantly associated loci in or near SLC24A5, MFSD12, TMEM138[DDB1], and OCA2 and HERC2. Allele frequencies at these loci in global populations are strongly correlated with UV exposure. At SLC24A5 we find that a non-synonymous mutation associated with depigmentation in non-Africans was introduced into East Africa by gene flow, and subsequently rose to high frequency. At MFSD12, we identify novel variants that are strongly correlated with dark pigmentation in populations with Nilo-Saharan ancestry. Functional assays reveal that MFSD12 codes for a lysosomal protein that influences pigmentation in cultured melanocytes, zebrafish and mice. CRISPR knockouts of murine Mfsd12 display reduced pheomelanin pigmentation similar to the grizzled mouse mutant (gr/gr). Exome sequencing of gr/gr mice identified a 9 bp in-frame deletion in exon two of Mfsd12. Thus, using human GWAS data we were able to map a classic mouse pigmentation mutant. At TMEM138[DDB1], we identify mutations in melanocyte-specific regulatory regions associated with expression of UV response genes. Variants associated with light pigmentation at this locus show evidence of a selective sweep in Eurasians. At OCA2 and HERC2 we identify novel variants associated with pigmentation and at OCA2, the oculocutaneous albinism II gene, we find evidence for balancing selection maintaining alleles associated with both light and dark skin pigmentation. We observe at all loci that variants associated with dark pigmentation in African populations are identical by descent in southern Asian and Australo-Melanesian populations and did not arise due to convergent evolution. Further, the alleles associated with skin pigmentation at all loci but SLC24A5 are ancient, predating the origin of modern humans. The ancestral alleles at the majority of predicted causal SNPs are associated with light skin, raising the possibility that the ancestors of modern humans could have had relatively light skin color, as is observed in the San population today. This study sheds new light on the evolutionary history of pigmentation in humans.