Shared genetic foundation of the DHEAS pathway indicate similar extended childhoods in Neanderthals and modern humans

Adrenarche, the pre-pubertal rise in adrenal androgens, particularly dehydroepiandrosterone (DHEA) and its sulfated form DHEAS, is a critical driver of middle childhood cognitive and social development in modern humans. Compared to other apes, modern human adrenarche is more prolonged, with higher DHEAS levels. Whether this uniquely prolonged human adrenarche is a derived trait of Homo sapiens or has deeper hominin roots remains unresolved. Here, we examine the Neanderthal genetic variation in five key DHEAS biosynthesis genes (HSD3B2, CYP17A1, POR, CYB5A, SULT2A1). We also examine archaic introgression in these genes by comparing high-coverage Neanderthal genomes with globally diverse modern human sequences from the 1000 Genomes Project. We identify 29 Neanderthal-derived single nucleotide variants across these genes. Key steroidogenic genes in the biosynthesis pathway show no evidence of introgression, consistent with selection on pleiotropic regulators of steroidogenesis. In contrast, accessory genes carried introgressed Neanderthal haplotypes at moderate frequencies in non-African human populations, indicating Neanderthal variants are compatible with the human DHEAS synthesis pathway. All Neanderthal-specific variants were in non-coding regions, with three variants associated with reduced enzyme efficiency or DHEAS production in adults. Additionally, for all 29 positions, the modern human major allele is ancestral, and there is no evidence for a suite of novel adrenarche-extending variants. We conclude that the genetic foundation for extended adrenarche is shared between Homo sapiens and Neanderthals, and may have deeper hominin roots. Any phenotypic variation in adrenarche between modern humans and Neanderthals is more likely attributable to differential gene expression than to divergence in protein-coding sequences.