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

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Received Date: 10th October 19

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-mediatedcis 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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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature