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

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