Progress Towards a Molecular Understanding of Polar Overdominance at the Ovine Callipyge Locus

Michel Georges
Department of Genetics, Faculty of Veterinary Medicine; University of Liege

The callipyge phenotype is a n muscular hypertrophy described in sheep that results from an increase in the proportion and diameter of fast twitch muscle fibers. It is characterized by an unusual mode of inheritance referred to as "polar overdominance": only heterozygous individuals having inherited the CLPG mutation from their sire express the phenotype. We have mapped the callipyge locus to a 400 Kb chromosome segment at the telomeric end of OAR18. This segment has been completely sequenced and annotation of 250 Kb has been completed. This lead to the identification of four genes which are preferentially expressed in skeletal muscle and all undergoing parental imprinting. Two of these are expressed from the paternal allele and code for a protein product: DLK1 and PEG11. The two other ones are expressed from the maternal allele and generate non-coding RNAs: GTL2 and MEG8. We have also identified imprinted anti-sense "anti-MEG11" transcript expressed from exclusively from the maternal allele. We have demonstrated that the CLPG mutation enhances the expression of all these transcripts in skeletal muscle without altering their imprinting status or changing the methylation status of DMR in the corresponding genes. We are in the process of searching for the CLPG mutation by resequencing the corresponding chromosome region, as well as searching for potentially associated epigenetic effects. The potential role of DLK1 and /or PEG11 overexpression in the determinism of the muscular hypertrophy is examined by producing transgenic mice that constitutively overexpress these proteins in skeletal muscle.