Archaic Introgression Shaped Human Circadian Traits

Abstract

Introduction: When the ancestors of modern Eurasians migrated out of Africa and interbred with Eurasian archaic hominins, namely Neanderthals and Denisovans, DNA of archaic ancestry integrated into the genomes of anatomically modern humans. This process potentially accelerated adaptation to Eurasian environmental factors, including reduced ultra-violet radiation and an increased variation in seasonal dynamics. However, whether these groups differed substantially in circadian biology, and whether archaic introgression adaptively contributed to human chronotypes remains unknown. Results: Here we traced the evolution of chronotype based on genomes from archaic hominin and present-day humans. First, we inferred differences in circadian gene sequences, splicing, and regulation between archaic hominins and modern humans. We identified 28 circadian genes containing variants likely to alter splicing in archaics (e.g.,CLOCK,PER2,RORB,RORC), and 16 circadian genes likely divergently regulated between present-day humans and archaic hominins, includingRORA. These differences suggest the potential for introgression to modify circadian gene expression. Testing this hypothesis, we found that introgressed variants are enriched among eQTLs for circadian genes. Supporting the functional relevance of these regulatory effects, we found that many introgressed alleles have strong associations with chronotype. Strikingly, the strongest introgressed effects on chronotype increase morningness, which is consistent with adaptations to high latitude in other species. Finally, we identified 26 circadian loci with evidence of adaptive introgression, includingPER2andMYBBP1A. Conclusions: These findings identify differences in circadian gene regulation between modern humans and archaic hominins and support the contribution of introgression via coordinated effects on variation in human chronotype.