The Evolution and Functional Impact of Human Deletion Variants Shared with Archaic Hominin Genomes

Abstract

Allele sharing between modern and archaic hominin genomes has been variously interpreted to have originated from ancestral genetic structure or through non-African introgression from archaic hominins. However, evolution of polymorphic human deletions that are shared with archaic hominin genomes has yet to be studied. We identified 427 polymorphic human deletions that are shared with archaic hominin genomes, approximately 87% of which originated before the Human–Neandertal divergence (ancient) and only approximately 9% of which have been introgressed from Neandertals (introgressed). Recurrence, incomplete lineage sorting between human and chimp lineages, and hominid-specific insertions constitute the remaining approximately 4% of allele sharing between humans and archaic hominins. We observed that ancient deletions correspond to more than 13% of all common (>5% allele frequency) deletion variation among modern humans. Our analyses indicate that the genomic landscapes of both ancient and introgressed deletion variants were primarily shaped by purifying selection, eliminating large and exonic variants. We found 17 exonic deletions that are shared with archaic hominin genomes, including those leading to three fusion transcripts. The affected genes are involved in metabolism of external and internal compounds, growth and sperm formation, as well as susceptibility to psoriasis and Crohn’s disease. Our analyses suggest that these “exonic” deletion variants have evolved through different adaptive forces, including balancing and population-specific positive selection. Our findings reveal that genomic structural variants that are shared between humans and archaic hominin genomes are common among modern humans and can influence biomedically and evolutionarily important phenotypes.

Evolution of the rapidly mutating human salivary agglutinin gene ( DMBT1 ) and population subsistence strategy

“…One study has highlighted DMBT1 to be a strong candidate for ancient balancing selection in the genome (49). Another recent study has identified the region upstream of DMBT1 to show unusually negative Tajima's D (in the fifth percentile genome wide) in Europeans, supporting our model of selection (50). However, the effect on SNP diversity of a rapidly mutating CNV undergoing fluctuating geographically structured selection remains unclear.…”

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

“…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 green boxes represent π and Tajima’s D scores calculated for the size-matched downstream regions of non-exonic ancient deletions. These deletions are comparable to the LCE3BC deletion in the sense that they were also found to have evolved before Human Neanderthal/Denisovan divergence and that they are similarly high in allele frequency [58]. P -values (Wilcoxon Test) are shown on top of the comparisons …”

“…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.…”

The Strength of Selection against Neanderthal Introgression

“…a higher rate of genetic drift [5]. This suggests that weakly deleterious exonic alleles may have been effectively neutral and drifted up in frequency in Neanderthals [28–30], only to be slowly selected against after introgressing into modern human populations of larger effective size. To test this hypothesis, we simulated a simple model of a population split between AMH and Neanderthals, using a range of plausible Neanderthal population sizes after the split.…”