Mandibular Prognathism in Dolang Sheep: Hi-C Evidence for Localized TAD Remodeling at Craniofacial Loci

Mandibular prognathism (Class III malocclusion) is a craniofacial anomaly characterized by an anteriorly positioned mandible, a concave facial profile and impaired mastication, and appears unusually frequently in Dolang sheep (Ovis aries). We combined clinical phenotyping and three-dimensional (3D) genome profiling to investigate this trait in a Dolang sheep flock. We examined 959 animals using standardized criteria, estimated a local prevalence of 10.3%, and assembled a 200 affected/200 unaffected case-control cohort for genomic analyses. As an exploratory pilot study of 3D genome architecture, we generated in situ Hi-C datasets from mandibular bone of two affected and two control sheep. At 40 kb resolution, global topologically associating domain (TAD) organization and boundary strength were broadly conserved between groups, but sliding-window analyses identified a small number of 1 Mb hotspots where affected animals showed increased TAD-boundary density and strengthened insulation. These UNDER-enriched windows lay near genes with plausible roles in craniofacial development, including ROBO2, COL27A1, VRK2 and a cytokine cluster (IL22/IL26/IFNG with MDM1). Together, our data indicate that mandibular prognathism in Dolang sheep is associated with localized remodeling of chromatin insulation at a restricted set of gene-proximal loci and highlight candidate regions and mechanisms for integration with whole-genome sequencing, association and transcriptomic data.