Complex genetic architecture underlies human hand and foot evolution

The transition to bipedal locomotion is a key event in human evolution, involving substantial changes to the skeleton, including the bones of the hands and feet (autopods). Hominins evolved a more muscular and opposable thumb while the other fingers are relatively shorter, enhancing manipulative capacity. The feet evolved robust first toes and short lateral toes to meet the challenges of bipedal walking and running. While adaptations in the hand and foot have often been considered separately, the fore- and hind limbs of primates are morphologically integrated, serially homologous structures, raising the possibility that natural selection on either autopod may have driven corresponding changes in the other. To explore the genetic architecture underlying human autopod evolution, we used functional genomics methods to identify regulatory elements and gene expression patterns in the developing phalanges and metacarpals of the human hand and foot. We find that gene expression and regulation differ along the proximal-distal axis and between timepoints but not between limb types or individual digits. We show that thousands of human-specific genomic features fall within autopod regulatory elements, some accessible in multiple tissues, others with tissue-specific accessibility. Our results highlight the complex genomic basis of human autopod evolution.