A Multi-Omics Atlas of Naturally Occurring Myelomeningocele in a Large-Animal Model Reveals Heritable Architecture.

Neural tube closure relies on tightly coordinated morphogenetic programs integrating convergent extension, apical constriction of the neuroepithelium, and precise cell-cell interactions across germ layers. Disruption of these processes results in myelomeningocele, a severe complex congenital defect with lifelong multisystem consequences whose genetic and epigenetic determinants remain poorly defined. Using a sheep population with naturally occurring myelomeningocele, we quantified substantial heritability (0.42-0.68) and generated the first integrated multi-omics, multi-tissue atlas of this condition in any mammalian species. Genetic, transcriptomic, and whole-genome DNA methylation profiling across ectoderm- and mesoderm-derived tissues revealed shared and lineage-specific perturbations converging on cell-adhesion, cytoskeletal, migratory, inflammatory, and folate-responsive pathways. Chromosome 24 emerged as a multi-omics hotspot enriched for differentially expressed genes, differentially methylated regions, and candidate regulatory loci of GWAS signals, overlapping with human neurological and embryonic development trajectories. Cross-tissue network analyses highlighted coordinated disruption of neurulation-critical gene modules, establishing sheep as a robust translational model for mechanistic dissection of neural tube defect biology.