|Freking, Bradley - Brad|
|Smith, Timothy - Tim|
Submitted to: Genome Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/31/2002
Publication Date: 10/21/2002
Citation: Freking, B.A., Murphy, S., Wylie, A., Jirtle, R.L., Rhodes, S., Keele, J.W., Leymaster, K.A., Smith, T.P. 2002. Identification of the single base change causing the callipyge muscle hypertrophy phenotype, the only known example of polar overdominance in animals. Genome Research. 12:1496-1506. Interpretive Summary: A mutation in sheep, named callipyge, with large effects on lean and fat development as well as eating quality of meat was uncovered. Expression of muscle hypertrophy is inherited in a unique parent-of-origin manner referred to as polar overdominance. Specifically, animals exhibiting characteristic muscle hypertrophy must inherit the mutated allele from the sire, and not from the dam, making callipyge a unique phenomenon. We identified the specific causative mutation by sequencing key inbred animals identical-by-descent for a 210-Kb region known to contain the gene. A single base change was revealed as the only variable position in the sequenced region within these two rams that were progeny tested as heterozygous carriers. Additional genotypic information concluded that this variable base completely described the inheritance of the muscle hypertrophy phenotype and was specific to descendants from the animal where the mutation was first observed. Identification of this mutation has led to the subsequent new discovery of a previously unknown expressed gene product. The discovery of this mutation and a new gene product encompassing the mutation will focus new investigations on both genetic and regulatory aspects of this important genomic region.
Technical Abstract: A small genetic region near the telomere of ovine chromosome 18 was previously shown to carry the mutation causing the callipyge muscle hypertrophy phenotype in sheep. Expression of this phenotype is the only known case in mammals of paternal polar overdominance gene action. A region surrounding two positional candidate genes was sequenced in animals of known genotype. Mutation detection focused on an inbred ram of callipyge phenotype postulated to have inherited chromosome segments identical-by-descent with exception of the mutated position. In support of this hypothesis, this inbred ram was homozygous over 210 Kb of sequence, except for a single heterozygous base position. This single polymorphism was genotyped in multiple families segregating the callipyge locus (CLPG), providing 100% concordance with animals of known CLPG genotype, and was unique to descendants of the founder animal. The mutation lies in a region of high homology among mouse, sheep, cattle, and humans, but not in any previously identified expressed transcript. A substantial open reading frame exists in the sheep sequence surrounding the mutation, although this frame is not conserved among species. Initial functional analysis indicates that the sequence encompassing the mutation is part of a novel transcript expressed in sheep fetal muscle.