A Human Accelerated Region Drives Opposing Heterochronic Changes in Craniofacial and Limb Development [snRNA-seq]

Human accelerated regions (HARs), which encode transcriptional enhancers with human-specific activity, have been implicated in the evolution of novel human traits. However, their contributions to changes in developmental timing remain unknown.

Using single-nucleus RNA sequencing and developmental trajectory analyses in a genetically humanized mouse model of the HAR HACNS1, we show that HACNS1 drives heterochronic shifts in opposite directions during craniofacial and limb development. In pharyngeal arches, HACNS1 delays chondrocyte differentiation and the expression of genes involved in cartilage and skeletal maturation. In contrast, in the limb buds, HACNS1 accelerates chondrogenesis and promotes earlier expression of differentiation-associated genes.