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A molecular basis for classic blond hair color in Europeans

Nature Genetics 46, 748–752 (2014) | Download Citation

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Abstract

Hair color differences are among the most obvious examples of phenotypic variation in humans. Although genome-wide association studies (GWAS) have implicated multiple loci in human pigment variation, the causative base-pair changes are still largely unknown1. Here we dissect a regulatory region of the KITLG gene (encoding KIT ligand) that is significantly associated with common blond hair color in northern Europeans2. Functional tests demonstrate that the region contains a regulatory enhancer that drives expression in developing hair follicles. This enhancer contains a common SNP (rs12821256) that alters a binding site for the lymphoid enhancer-binding factor 1 (LEF1) transcription factor, reducing LEF1 responsiveness and enhancer activity in cultured human keratinocytes. Mice carrying ancestral or derived variants of the human KITLG enhancer exhibit significant differences in hair pigmentation, confirming that altered regulation of an essential growth factor contributes to the classic blond hair phenotype found in northern Europeans.

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Acknowledgements

We thank R. Moon (University of Washington) for the XE237 LEF1 expression plasmid, R. Nusse (Stanford University) for the SuperTOPFlash plasmid, C. Lowe (Stanford University) for help with statistical and 1000 Genomes Project analysis and members of the Kingsley laboratory for useful comments on the manuscript. This work was supported in part by the University of Georgia Research Foundation (M.A.B.) and by US National Institutes of Health grants GM65393 (M.A.B.), R01-NS050835 (L.L.) and a Center of Excellence in Genomic Science award 5P50HG2568 (D.M.K.). L.L. and D.M.K. are investigators of the Howard Hughes Medical Institute.

Author information

    • Bosiljka Tasic

    Present address: Allen Institute for Brain Science, Seattle, Washington, USA.

Affiliations

  1. Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, USA.

    • Catherine A Guenther
    •  & David M Kingsley

  2. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA.

    • Catherine A Guenther
    • , Bosiljka Tasic
    • , Liqun Luo
    •  & David M Kingsley

  3. Department of Biology, Stanford University, Stanford, California, USA.

    • Bosiljka Tasic
    •  & Liqun Luo

  4. Department of Genetics, University of Georgia, Athens, Georgia, USA.

    • Mary A Bedell

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Contributions

C.A.G. and D.M.K. conceived and oversaw the project. M.A.B. isolated and sequenced the Slpan breakpoint. B.T. and L.L. provided advice, reagents and mice for generating site-specific integrants. C.A.G. performed the gene expression analysis in Slpan mutants, carried out the transgenic analysis of the blond-associated GWAS interval, identified the hair follicle enhancer and performed in vitro and in vivo tests of the effects of the rs12821256 polymorphism. C.A.G. and D.M.K. wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David M Kingsley.

Integrated supplementary information

Supplementary figures

  1. 1.

    H2 transgenic embryos.

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    H2b transgenic embryos.

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    HFE transgenic embryos.

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    H2-BLD transgenic embryos.

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    H2-DEL transgenic embryos.

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    Additional pigmentation phenotypes seen in hair enhancer-Kitl mice.

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    Analysis of pigment levels in zigzag hairs from site-specific transgenic mice.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–7 and Supplementary Tables 1 and 2

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DOI

https://doi.org/10.1038/ng.2991