Polar Overdominance as an Evolutionary Tug-of-War: The CLPG Paradigm for Imprinted Allelic Conflict and Precision Breeding
Abstract
The Callipyge (CLPG) phenotype in sheep represents the only known example of polar overdominance in mammals, yet its evolutionary origins and broader implications for breeding remain poorly understood. Here, we propose the Imprinted Allelic Conflict (IAC) model, which reinterprets CLPG polar overdominance as an extreme manifestation of the kinship theory of genomic imprinting—a single A→G transition within the DLK1-GTL2 imprinted cluster that disrupts the evolutionary equilibrium between maternally and paternally derived alleles. Through CRISPR/Cas9-mediated recapitulation of the CLPG mutation in the homozygous state, combined with multi-omics analyses, we demonstrate a defined hierarchy of molecular perturbations: (i) increased DNA methylation at the GTL2 promoter with reduced chromatin accessibility at its CpG island; (ii) GTL2 expression is profoundly suppressed, while DLK1 and PEG11 show no significant differential upregulation in the homozygous state; (iii) altered myofiber characteristics (finer fibers with increased density); and (iv) the carcass traits reported in natural CLPG heterozygotes (dressing 55.9% vs. 51.7%, lean meat 71.3% vs. 64.0%, fat 24.3% vs. 31.5%) are from published literature. We emphasize that the homozygous mutation generated in this study provides partial validation of the IAC model’s epigenetic predictions, but the polar overdominance and parent-of-origin-specific predictions await confirmation in heterozygous animals. The IAC model further predicts the existence of “cryptic imprinted conflicts” at five additional loci across the sheep genome (IGF2/H19, SNRPN, IGF2R, PEG3, KCNQ1OT1), offering an untapped reservoir for precision genome editing.
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