ABSTRACT Horns are emblematic ruminant cranial appendages, yet their molecular basis and phenotypic diversity remain incompletely understood. Here we built a systematic framework for sheep horn biology by integrating multi‐tissue transcriptomics, cross‐species conservation, fine‐grained tissue comparisons, horn‐type contrasts, and allele‐specific expression (ASE). We first profiled 160 RNA‐seq samples across 16 tissues and identified 1608 horn tissue‐specific genes, revealing horn‐distinct programs strongly enriched in keratinization and epidermal differentiation (e.g., LORICRIN and KRT2 ). Next, cross‐species analyses (sheep, goat, deer, and cattle) defined conserved horn‐associated gene sets that couple epidermal modules with osteogenic components (e.g., COL1A1 and SOX9 ), supporting a composite epidermal–skeletal identity. We then compared horn with skin and periosteum to partition shared versus horn‐specific programs, highlighting both keratinocyte‐related regulators shared with skin and bone‐matrix signals linked to periosteum, alongside horn‐specific metabolic remodeling signatures. Furthermore, differential expression between large‐horned (SHE) and scurred (SCU) individuals identified candidate regulators of horn size variation, including remodeling factors and transcriptional regulators (e.g., MMP9 and SNAI1 ). Finally, ASE analysis uncovered cis‐regulated candidate drivers, including horn‐enriched genes and a horn/skin‐specific enhancer‐linked variant at ABHD5 . Collectively, our study defines a coherent transcriptional blueprint for sheep horn development and provides prioritized genes and regulatory loci underlying horn identity and size diversity.
Li et al. (Thu,) studied this question.