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More than just a pretty face

By Tanita Casci, Nature Rev Genet

15 September 2002: For nearly 20 years, some sheep have flaunted what must be every vain person\\'s dream: a genetic variant that confers beautiful buttocks, commonly known as the callipyge phenotype. More prosaically, the single-locus mutation responsible for the phenotype causes muscle hypertrophy, and it does so through an unusual genetic means, known as polar overdominance. This means that animals only manifest the phenotype if they are heterozygous for the callipygous variant and only if the variant has been inherited from a particular parent (in this case, the father). Freking and colleagues have now pinpointed the single base change in the gene, CLPG, that underlies the callipygous trait. Breeders and geneticists alike have a stake in this discovery: leaner meat could be bred as a result, and we could gain a better understanding of the epigenetic mechanisms that underlie the inheritance of the phenotype.

Previous efforts to map CLPG had localized it genetically to a small (400-kb) telomericregion on chromosome 18 ? small enough to make a direct-sequencing approach to finding the variant a realistic goal. The high level of background polymorphism in sheep, however, made it impossible to detect the causative SNP simply by comparing affected heterozygotes to normal homozygotes. The authors therefore turned to the pedigree of the particular flock they were studying for some help. One callipygous ram in particular was key: the critical region of both copies of chromosome 18 in this ram were probably identical-by-descent, apart from the presence of the CLPG mutation on one copy. Comparing the sequence of the ram to a panel of informative genotypes uncovered 616 polymorphisms, but only one of them ? an A to G change ? could be uniquely assigned to the callipygous trait. The G allele was never found in sheep of diverse breeds, so validating further the pedigree-screening approach as the most robust there is for finding the causative variant of a phenotype.

It\\'s taken ten years, but an important aspect of the callipyge phenotype has now been found, heralding the starting point for understanding what the CLPG variant does. The CLPG region is conserved in cattle, human and mouse genomes, and the variant might be incorporated into an RNA transcript, but little else is known about its function. Initial attempts to detect whether the variant has some regulatory effect ? for example, by altering the imprinting status of the region ? have been unsuccessful. Clearly more work is needed to get to the bottom of this trait.