The role of ancient genetic variation on human adaptation: Insights from trans-species and introgressed variation

Abstract

Due to human demographic history and the action of natural selection, most genetic variation in present-day humans is of recent origin. However, a smaller number of variants have persisted over hundreds of thousands of years. For example, trans-species polymorphisms (TSPs) can be millions of years old and have origins that predate the separation between closely related species. Balancing selection—the evolutionary pressure to favor genetic diversity at a genetic locus—on alleles involved in the immune system is thought to be a major driver of TSPs between species. However, most TSPs do not have well characterized functions. Studying a set of 125 regions with TSPs between humans and chimpanzees, we identified 60 regions with strong evidence of being under long-term balancing selection (LTBS). Using genome annotation strategies, we identified diverse non-immune functions associated with LTBS targets, including neurological, behavioral, and metabolic traits. Next, we studied another set of ancient genetic variants that originated in archaic hominins (i.e., Neanderthals and Denisovans) and were later introduced in the human genome through introgression. We hypothesized that these archaic alleles influence human circadian function due to the evolution of archaic hominins at high latitudes. We found that introgressed alleles significantly influence the expression levels of circadian genes. Many of these loci are associated with chronotype in the UK Biobank cohort. The most strongly associated variants consistently increase morningness, including two haplotypes that follow a latitudinal cline in Eurasian populations. These results suggest that introgressed alleles from archaic hominins may have helped humans adapt to higher latitudes. Overall, our work leveraged massive databases of human genomes and phenotypes to reveal the diversity of functions that have shaped patterns of genetic variation in our species.