Complex adaptive forces shape skin barrier evolution in humans

Skin harbors some of the most significant adaptive variations in humans as our species colonized different ecologies. However, with the exception of pigmentation, the human skin evolution has yet to be investigated in an anthropological genetics framework. Therefore, we investigated the evolutionary trends that shape the genetic variation in the epidermal differentiation complex on chromosome 1, which harbors more than 50 genes with known roles in skin barrier function. Here, we focus on two loci in this complex. First, we found that a common, 32kb deletion of LCE3B and LCE3C genes has remained in the human population since before Human-Denisovan divergence likely due to balancing selection. Second, upstream of the LCE3 locus, we detected a selective sweep, which increased the allele frequency of a distinct haplotype of filaggrin (FLG) gene in Asian populations. We further found that this haplotype is associated with expression levels of multiple nearby genes and microbiome diversity on the skin. Moreover, LCE3BC deletion and the selected FLG haplotype are associated with increased susceptibility to pathologically similar skin diseases, atopic dermatitis and psoriasis, respectively. However, it is not clear why these two common alleles remain in the population for hundreds of thousands of years and not eliminated by negative selection. Interestingly, patients with psoriasis have lower susceptibility to atopic dermatitis, and vice versa. Collectively, we put forward a model of skin evolution where particular disruptions of skin barrier function lead to different microbial compositions of the skin, creating a balance between autoimmunity and natural vaccination.