Positional programs in early murine facial development and their role in human facial shape variability.

The face is a complex, variable structure shaped by environmental and functional adaptations. In humans, the remarkable diversity of facial shapes underpins identity and mutual recognition. The developmental process from cranial neural crest cell migration to facial prominence fusion is conserved and essential for determining facial shape. However, the molecular and cellular underpinnings are not fully understood. We reconstruct facial development in the mouse model at the single-cell level, and show that the facial mesenchyme exhibits a remarkable molecular heterogeneity predominantly driven by positional programs. We then explore the role of these spatially defined murine mesenchymal populations in the extraordinary diversity of human facial shapes. By integrating molecular and spatial coordinates with human genome-wide association studies and genes linked to abnormal human facial shapes, we link genetic variants associated with facial features to individual cell populations and transcriptional signatures. This integrative approach provides a framework for exploring evolutionary processes behind facial variation and offers new insights into congenital facial syndromes.