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Science 16 December 2005:
Vol. 310. no. 5755, pp. 1782 - 1786
DOI: 10.1126/science.1116238
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Research Articles

SLC24A5, a Putative Cation Exchanger, Affects Pigmentation in Zebrafish and Humans

Rebecca L. Lamason,1* Manzoor-Ali P.K. Mohideen,1{dagger} Jason R. Mest,1 Andrew C. Wong,1{ddagger} Heather L. Norton,6 Michele C. Aros,1 Michael J. Jurynec,8 Xianyun Mao,6 Vanessa R. Humphreville,1§ Jasper E. Humbert,2,9 Soniya Sinha,2 Jessica L. Moore,1|| Pudur Jagadeeswaran,10 Wei Zhao,3 Gang Ning,7 Izabela Makalowska,7 Paul M. McKeigue,11 David O'Donnell,11 Rick Kittles,12 Esteban J. Parra,13 Nancy J. Mangini,14 David J. Grunwald,8 Mark D. Shriver,6 Victor A. Canfield,4 Keith C. Cheng1,4,5

Lighter variations of pigmentation in humans are associated with diminished number, size, and density of melanosomes, the pigmented organelles of melanocytes. Here we show that zebrafish golden mutants share these melanosomal changes and that golden encodes a putative cation exchanger slc24a5 (nckx5) that localizes to an intracellular membrane, likely the melanosome or its precursor. The human ortholog is highly similar in sequence and functional in zebrafish. The evolutionarily conserved ancestral allele of a human coding polymorphism predominates in African and East Asian populations. In contrast, the variant allele is nearly fixed in European populations, is associated with a substantial reduction in regional heterozygosity, and correlates with lighter skin pigmentation in admixed populations, suggesting a key role for the SLC24A5 gene in human pigmentation.

1 Jake Gittlen Cancer Research Foundation, Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
2 Intercollege Graduate Degree Program in Genetics, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
3 Department of Health Evaluation Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
4 Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
5 Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
6 Department of Anthropology, The Pennsylvania State University, University Park, PA 16802, USA.
7 The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
8 Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
9 Department of Genetics, Weis Center for Research, Danville, PA 17822, USA.
10 Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA.
11 Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
12 Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH 43210, USA.
13 Department of Anthropology, University of Toronto at Mississauga, Mississauga, ON L5L 1C6, Canada.
14 Department of Anatomy and Cell Biology, Indiana University School of Medicine-Northwest, Gary, IN 46408, USA.

* Present address: The Graduate Program in Immunology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

{dagger} Present address: Health System Management Center, Case Western Reserve University, Cleveland, OH 44106, USA.

{ddagger} Present address: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.

§ Present address: The Pennsylvania State University College of Medicine, H060, 500 University Drive, Hershey, PA 17033, USA.

|| Present address: Department of Biology, University of South Florida, Tampa, FL 33620, USA.

To whom correspondence should be addressed. E-mail: kcheng{at}psu.edu

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