AbstractMammal hybridization is a speciation mechanism and an evolutionary driver. Goat-sheep, especially buck-ewe hybrids, are very rare with only one case reported in 2016, which is the subject of the work presented here. Blood transcriptome analysis revealed that the hybrid largely deviated from imprinting schemes previously described in sheep and other mammals. Furthermore, transcriptome regulation seems to differ from the parent transcriptomes, which is most likely a product of partially incompatible imprinting mechanisms from two closely related species. To gain a deeper understanding of hybridization in mammals we re-analyzed the RNA sequencing data of the buck-ewe hybrid and its parents. We found parent-of-origin-specific expression of genes that functionally clustered, which we explain with the Dobzhansky–Muller incompatibility (DMI) model. According to the DMI model, proteins which interact have a high probability of being barrier loci and hence are prone to monoallelic expression. We discovered enrichment of genes uniquely expressed by the buck-ewe hybrid, which implicate that it suffered from an NF-κB lymphoproliferative autoimmune disorder. Similar findings were reported in the F1 generation of hybrid mice. We propose that hybridization of two related species may lead to an autoimmune phenotype, due to immunoglobulin incompatibilities and incomplete silencing of barrier loci.