The psoriasis-associated deletion of late cornified envelope genes LCE3B and LCE3C has been maintained under balancing selection since Human Denisovan divergence

Abstract

Background

A common, 32kb deletion of LCE3B and LCE3C genes is strongly associated with psoriasis. We recently found that this deletion is ancient, predating Human-Denisovan divergence. However, it was not clear why negative selection has not removed this deletion from the population.

Results

Here, we show 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).

Conclusions

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.

Background

Genomic structural variants (SVs), which are deletions, duplications, inversions and translocations of genomic segments, account for the majority of variable base pairs in primate genomes [1, 2]. Because of their sheer size, SVs can have strong effects on gene function and regulation if they overlap with protein-coding (eg, [3]) or regulatory sequences (eg, [4]). Indeed, several studies have revealed important roles that SVs play in human evolution [2, 5] and adaptation [6, 7].

Disruption of a gene’s function by deletion of its coding sequence likely reduces fitness and predisposes humans to several genetic disorders (eg, [8–10]). Consistent with this notion, deletion variants among humans are distributed significantly away from coding sequences [11] and most exonic deletions are found in very low frequencies in human populations [12]. In a recent study, we searched for unusually old deletion variants that affect coding sequences. Specifically, we identified exonic deletions that evolved before Human-Neanderthal divergence (>500-1,000KYA) [13]. We surmised that it is unlikely for a loss-of-function gene deletion to be maintained for this long, especially under negative selection. Thus, we hypothesized that a number of these ancient deletion variants have been evolving under balancing selection.

Balancing selection has enjoyed a renewed interest in the evolutionary genomics community. In its most basic form, balancing selection can be thought of as the combination of adaptive forces that maintain variation longer than expected under neutrality [14, 15]. Based on the analyses of recently available human and nonhuman primate genomes, several variants have been shown to be evolving under long-term balancing selection in the human-chimpanzee lineage [16, 17]. In addition, multiple instances of balancing selection within the human gene pool have been reported in the last decade [18–23].

In this paper, we investigate the evolution of an ancient gene deletion (LCE3BC deletion). This ~32kb deletion variant overlaps 2 genes, LCE3B and LCE3C, which are both involved in skin tissue repair. We recently showed that this deletion variant is derived in the Homo lineage and that the deletion is present in the Denisovan genome, but absent in the Neanderthal genome [13]. In the same study, we were able to rule out archaic introgression and concluded that incomplete lineage sorting best explains the observed allele sharing at this locus. The deletion is very common in humans, reaching up to 70% in some European populations. Moreover, this deletion has been strongly associated with psoriasis susceptibility, with odds ratios ranging from 1.3 (The Italian population) to 1.9 (The Chinese population) [24–27]. However, the adaptive reasons for why this deletion remains in the population are unknown.