Positional Cloning of the Callipyge Gene: A Step Towards Understanding a Novel Form of Dominant Negative Imprinting

Carole Charlier
Genetic, B43, Faculty of Veterinary Medicine; University of Liege

The Callipyge (CLPG) gene is responsible of a muscular hypertrophy in sheep. This phenotype is characterized by a non-mendelian mode of inheritance referred as "polar overdominance". Only heterozygous individuals receiving the CLPG mutation from their father express the phenotype. The CLPG locus has been mapped by linkage analysis to the telomeric end of ovine chromosome (chr) 18. Comparative studies allowed us to identify the orthologous regions in human and mouse. These correspond respectively to distal chr 14q in man and distal chr 12 in the mouse. Maternal and paternal uniparental disomies (UPD) in human and mouse point towards imprinting of these chromosomal regions in these species as well. Moreover, recent characterization of an insertional mutation on mouse distal chr 12, the Gt12lacZ gene trap insertion, supports the existence of a new imprinted domain in this region. Positionally cloning the CLPG locus will be the starting point of this domain characterization. We refined the genetic mapping of the CLPG locus to a 3 cM interval and constructed a complete BAC contig of this region. It has a physical size < 1000 kb and contains at least four known genes including the ovine orthologue of Gt12. However, recombinations between CLPG and Gtl2 allow us to exclude Gtl2 as causing the callipyge phenotype. We are in the process of developing new genetic markers to refine the map position of the CLPG gene based on twenty-five remaining recombinants. A collaboration has been initiated with Dr. Weissenbach, Ferguson-Smith and Gossler to sequence the corresponding genomic region in human, mouse and sheep in order to facilitate the study of this new imprinted domain.