A Human Accelerated Region Drives Opposing Heterochronic Changes in Craniofacial and Limb Development

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Abstract Many human developmental processes proceed over a prolonged timescale compared to other primates, a phenomenon known as heterochrony. 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. Consistent with these transcriptomic shifts, SOX9-expressing pre-cartilaginous domains are more diffuse in the pharyngeal arches, but the condensed domains are expanded in the limb buds. Gene regulatory network inference suggests that HACNS1 -driven heterochronic shifts are due to changes in the expression of its target gene Gbx2 and resulting downstream effects on the regulatory networks through which Gbx2 functions. Our findings demonstrate that a single human-specific gene regulatory change can alter developmental timing, providing a potential mechanism for how uniquely human genetic changes reshaped conserved developmental programs.

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