Skindirectly interacts with the environment at multiple levels, and as such, evolves under various adaptive forces. Skin plays as the first barrier against pathogens and nonbiological external agents and helps regulate internal body temperature. We argue that structural variants likely have a stronger functional impact than single nucleotide variants due to their size.
In a study I led, we found that a common, 32kb deletion of LCE3B and LCE3C genes that is associated with psoriasis, is ancient, predating Human Denisovan divergence. However, it was not clear why negative selection had not removed this deletion from the population. Here, we have shown that the haplotype block that harbors the deletion (i) retains high allele frequency among extant and ancient human populations; (ii) harbors unusually high nucleotide variation (π, P < 4.1 × 10−3); (iii) contains an excess of intermediate frequency variants (Tajima’s D, P < 3.9 × 10−3); and (iv) has an unusually long time to coalescence to the most recent common ancestor (TSel, 0.1 quantile).
Our results are most parsimonious with the scenario where the LCE3BC deletion has evolved under balancing selection in humans. More broadly, this is consistent with the hypothesis that a balance between autoimmunity and natural vaccination through increased exposure to pathogens maintains this deletion in humans. In this study, I led the bioinformatic interrogation of the variation at this locus in modern and ancient human populations. My most profound influence on this work came with the theoretical concept of the link between autoimmunity and natural vaccination.