Human-Specific Gain of Function in a Developmental Enhancer

TLDR

Gene‑regulatory changes are believed to drive human developmental evolution, yet in‑vivo evidence for uniquely human regulatory function has been lacking. A rapidly evolved human enhancer, HACNS1, drives stronger limb expression in transgenic mice than its chimpanzee and macaque counterparts, and 13 human‑specific substitutions within an 81‑bp module are sufficient to confer this limb‑specific activity.

Abstract

Changes in gene regulation are thought to have contributed to the evolution of human development. However, in vivo evidence for uniquely human developmental regulatory function has remained elusive. In transgenic mice, a conserved noncoding sequence ( HACNS1 ) that evolved extremely rapidly in humans acted as an enhancer of gene expression that has gained a strong limb expression domain relative to the orthologous elements from chimpanzee and rhesus macaque. This gain of function was consistent across two developmental stages in the mouse and included the presumptive anterior wrist and proximal thumb. In vivo analyses with synthetic enhancers, in which human-specific substitutions were introduced into the chimpanzee enhancer sequence or reverted in the human enhancer to the ancestral state, indicated that 13 substitutions clustered in an 81–base pair module otherwise highly constrained among terrestrial vertebrates were sufficient to confer the human-specific limb expression domain.