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The evolution of uniquely human traits likely entailed changes in developmental gene regulation. Human Accelerated Regions (HARs), which include transcriptional enhancers harboring a significant excess of human-specific sequence changes, are leading candidates for driving gene regulatory modifications in human development. However, insight into whether HARs alter the level, distribution, and timing of endogenous gene expression remains limited. We examined the role of the HAR  HACNS1  (HAR2) in human evolution by interrogating its molecular functions in a genetically humanized mouse model. We find that  HACNS1  maintains its human-specific enhancer activity in the mouse embryo and modifies expression of  Gbx2 , which encodes a transcription factor, during limb development. Using single-cell RNA-sequencing, we demonstrate that  Gbx2  is upregulated in the limb chondrogenic mesenchyme of  HACNS1  homozygous embryos, supporting that  HACNS1  alters gene expression in cell types involved in skeletal patterning. Our findings illustrate that humanized mouse models provide mechanistic insight into how HARs modified gene expression in human evolution.

Modeling uniquely human gene regulatory function via targeted humanization of the mouse genome