The callipyge mutation (CLPG) is an A to G transition that affects a muscle-specific long-range control element located in the middle of the 90-kb DLK1-GTL2 intergenic (IG) region. It causes ectopic expression of a 327-kb cluster of imprinted genes in skeletal muscle, resulting in the callipyge muscular hypertrophy and its non-Mendelian inheritance pattern known as polar overdominance. We herein demonstrate that the CLPG mutation alters the muscular epigenotype of the DLK1-GTL2 IG region in cis, including hypomethylation, acquisition of novel DNase-I hypersentivite sites, and, most strikingly, strongly enhanced bidirectional, longrange IG transcription. The callipyge phenotype thus emerges as a unique model to study the functional significance of IG transcription, which recently has proven to be a widespread, yet elusive, feature of the mammalian genome.DNA methylation ͉ DNase-I hypersensitivity ͉ intergenic region ͉ noncoding RNA T he callipyge phenotype is an inherited muscular hypertrophy of sheep. It is characterized by polar overdominance, an unusual mode of inheritance in which only heterozygotes having received the CLPG mutation from their sire express the phenotype (1). The CLPG mutation is an A-to-G transition in a conserved dodecamer motif located in the 90-kb intergenic (IG) region separating the imprinted DLK1 and GTL2 genes on sheep chromosome 18 (refs. 2 and 3; Fig. 1). This motif was assumed to be part of a muscle-specific locus control region (LCR), because the CLPG mutation causes ectopic expression of a core cluster of neighboring genes in postnatal skeletal muscle, a tissue in which these genes are normally silenced (6, 7). Genes whose expression is affected by the CLPG mutation include (i) the paternally expressed protein encoding DLK1 and PEG11 genes, located, respectively, 64 kb proximally and 88 kb distally from the CLPG mutation, and (ii) the maternally expressed noncoding RNA genes GTL2, antiPEG11, MEG8, and MIRG, located between 33 and 262 kb distally from the CLPG mutation, as well as their multiple C͞D small nucleolar RNA and microRNA (miRNA) guests (8, 9). With the exception of PEG11, all these genes are transcribed toward the telomere. The effect of the CLPG mutation is cis-restricted and subordinate to imprinting control because it does not perturb the monoallelic expression of the target genes (6).It was recently shown that the callipyge phenotype can be caused by ectopic expression of DLK1 protein in skeletal muscle as observed in ϩ͞C Pat individuals (10). The lack of phenotypic expression in C͞C animals is postulated to be due to translational inhibition of padumnal DLK1 transcripts by noncoding madumnal transcripts (11). A direct role for miRNAs in this trans effect is suggested by the demonstration of RNA interference-mediated degradation of padumnal PEG11 transcripts by miRNAs processed from madumnal antiPEG11 transcripts (12).How the CLPG mutation operates such profound, tissuespecific inf luence on the expression of genes, which can be as far as 262 kb away, remains unknown...

Ovine hereditary chondrodysplasia, or spider lamb syndrome (SLS), is a genetic disorder that is characterized by severe skeletal abnormalities and has resulted in substantial economic losses for sheep producers. Here we demonstrate that a non-synonymous T>A transversion in the highly conserved tyrosine kinase II domain of a positional candidate gene, fibroblast growth factor receptor 3 (FGFR3), is responsible for SLS. We also demonstrate that the mutant FGFR3 allele has an additive effect on long-bone length, calling into question the long-standing belief that SLS is inherited as a strict monogenic, Mendelian recessive trait. Instead, we suggest that SLS manifestation is determined primarily by the presence of the mutant FGFR3 allele, but it is also influenced by an animal's genetic background. In contrast to FGFR3 mutations causing dwarfism in humans, this single-base change is the only known natural mutation of FGFR3 that results in a skeletal overgrowth phenotype in any species.

Genetic strategies to improve the profitability of sheep operations have generally focused on traits for reproduction. However, natural mutations exist in sheep that affect muscle growth and development, and the exploitation of these mutations in breeding strategies has the potential to significantly improve lamb-meat quality. The best-documented mutation for muscle development in sheep is callipyge (CLPG), which causes a postnatal muscle hypertrophy that is localized to the pelvic limbs and loin. Enhanced skeletal muscle growth is also observed in animals with the Carwell (or rib-eye muscling) mutation, and a double-muscling phenotype has been documented for animals of the Texel sheep breed. However, the actual mutations responsible for these muscular hypertrophy phenotypes in sheep have yet to be identified, and further characterization of the genetic basis for these phenotypes will provide insight into the biological control of muscle growth and body composition.

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-Genetic strategies to improve the profitability of sheep operations have generally focused on traits for reproduction. However, natural mutations exist in sheep that affect muscle growth and development, and the exploitation of these mutations in breeding strategies has the potential to significantly improve lamb-meat quality. The best-documented mutation for muscle development in sheep is callipyge (CLPG), which causes a postnatal muscle hypertrophy that is localized to the pelvic limbs and loin. Enhanced skeletal muscle growth is also observed in animals with the Carwell (or rib-eye muscling) mutation, and a double-muscling phenotype has been documented for animals of the Texel sheep breed. However, the actual mutations responsible for these muscular hypertrophy phenotypes in sheep have yet to be identified, and further characterization of the genetic basis for these phenotypes will provide insight into the biological control of muscle growth and body composition.sheep / muscle / hypertrophy / callipyge / mutation