Network inference at single-cell resolution reveals morphoregulatory divergence and multilayered buffering in limb evolution

Single-cell gene regulatory network inference across mouse and pig limb development links HOX-, FGF-, and SHH-regulated program divergence to conserved cellular organization, including a PTCH1 regulatory landscape convergence.

• Why it matters: Morphological evolution depends on how conserved developmental genetic programs change, but this is unclear in non-conventional models and at single-cell resolution.
• What they did: The study integrates single-cell transcriptomics and chromatin accessibility with cross-species label transfer and gene regulatory network inference, then tests pathway effects using FGFR inhibition and SHH response perturbations.
• The result: Functional dissection in artiodactyls shows degeneration of a limb regulatory module, conservation of an additional distal enhancer, and extensive cis-regulatory redundancy; reduced Ptch1 dosage is buffered by transcriptional compensation.

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