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An enhancer:involucrin regulatory module impacts human skin barrier adaptation out-of-Africa and modifies atopic dermatitis risk

Mary Elizabeth Mathyer, Erin A. Brettmann, Alina D. Schmidt, Zane A. Goodwin, Ashley M. Quiggle, Inez Y. Oh, Eric Tycksen, Lisa Zhou, Yeriel D. Estrada, X.F. Colin C. Wong, Simon L.I.J. Denil, Scot A. Matkovich, Avner Shemer, John E. A. Common, Emma Guttman-Yassky, View ORCID ProfileCristina de Guzman Strong
doi: https://doi.org/10.1101/816520
Mary Elizabeth Mathyer
Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USACenter for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USACenter for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110 USA
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Erin A. Brettmann
Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USACenter for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USACenter for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110 USA
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Alina D. Schmidt
Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USACenter for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USACenter for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110 USA
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Zane A. Goodwin
Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USACenter for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USACenter for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110 USA
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Ashley M. Quiggle
Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USACenter for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USACenter for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110 USA
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Inez Y. Oh
Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USACenter for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USACenter for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110 USA
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Eric Tycksen
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA
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Lisa Zhou
Department of Dermatology, Icahn School of Medicine at Mt. Sinai, New York, NY 10029 USA
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Yeriel D. Estrada
Department of Dermatology, Icahn School of Medicine at Mt. Sinai, New York, NY 10029 USA
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X.F. Colin C. Wong
Skin Research Institute of Singapore, A*STAR, Singapore 138648, Singapore
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Simon L.I.J. Denil
Skin Research Institute of Singapore, A*STAR, Singapore 138648, Singapore
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Scot A. Matkovich
Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
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Avner Shemer
Tel-Aviv University, Tel-Aviv, Israel
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John E. A. Common
Skin Research Institute of Singapore, A*STAR, Singapore 138648, Singapore
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Emma Guttman-Yassky
Department of Dermatology, Icahn School of Medicine at Mt. Sinai, New York, NY 10029 USA
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Cristina de Guzman Strong
Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USACenter for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USACenter for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110 USA
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  • ORCID record for Cristina de Guzman Strong
  • For correspondence: cristinastrong@wustl.edu
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ABSTRACT

The genetic modules that contribute to human evolution are poorly understood. We identified positive selection for two independent involucrin (IVL) haplotypes in European (CEU) and Asian (JPT/CHB) populations for skin epidermis. CEU IVL associated with increased IVL and a known epidermal-specific enhancer underwent a recent selective sweep out-of-Africa correlating with increased northern latitude. CRISPR/Cas9 deletion of the mouse enhancer revealed enhancer-mediated cis regulation for Ivl expression with human population-specific enhancer reporter assays confirming the additive effect. Furthermore, IVL enhancer eQTLs associated with decreased IVL together with filaggrin loss-of-function variants are enriched in atopic dermatitis cases vs. controls. Together, our enhancer-IVL cis regulatory module findings reveal an emerging paradigm for recently evolved traits to impact skin disease risk in contemporary populations.

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Posted November 05, 2019.
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An enhancer:involucrin regulatory module impacts human skin barrier adaptation out-of-Africa and modifies atopic dermatitis risk
Mary Elizabeth Mathyer, Erin A. Brettmann, Alina D. Schmidt, Zane A. Goodwin, Ashley M. Quiggle, Inez Y. Oh, Eric Tycksen, Lisa Zhou, Yeriel D. Estrada, X.F. Colin C. Wong, Simon L.I.J. Denil, Scot A. Matkovich, Avner Shemer, John E. A. Common, Emma Guttman-Yassky, Cristina de Guzman Strong
bioRxiv 816520; doi: https://doi.org/10.1101/816520
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An enhancer:involucrin regulatory module impacts human skin barrier adaptation out-of-Africa and modifies atopic dermatitis risk
Mary Elizabeth Mathyer, Erin A. Brettmann, Alina D. Schmidt, Zane A. Goodwin, Ashley M. Quiggle, Inez Y. Oh, Eric Tycksen, Lisa Zhou, Yeriel D. Estrada, X.F. Colin C. Wong, Simon L.I.J. Denil, Scot A. Matkovich, Avner Shemer, John E. A. Common, Emma Guttman-Yassky, Cristina de Guzman Strong
bioRxiv 816520; doi: https://doi.org/10.1101/816520

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