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.

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