Abstract

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. ### Competing Interest Statement The authors have declared no competing interest.