But genetics would be too simple if this law was always applied to the letter. The callipyge phenomenon follows its own rules and does not comply with the Mendelian mode of inheritance. In order for an animal to present with the muscular hypertrophy that characterizes this phenotype, it must be the carrier of a unique version of the mutated gene and this must come from the father. This mode of inheritance had never been observed before its discovery in 1996 and was given the name “polar overdominance”.   This observation was published by Noelle Cockett and Michel Georges in the journal Science.  Since then, experts think that this mode of inheritance could be much more frequent than was previously thought. It could also contribute to a predisposition to genetically complex common illnesses in humans. 

When the alleles come into conflict

Haruko Takeda joined Michel Georges’ team in 2002, and, for the last nine years, has been specifically concentrating on the study of the mechanisms underlying the polar overdominance of the callipyge phenotype.  Why does an individual inheriting the mutation from the father express the phenotype while an individual inheriting the mutation from the mother does not? Why does an individual inheriting the mutation from his father and mother not present with the characteristics of the callipyge phenotype? These are the questions that scientists have been trying to answer for years. Discoveries in relation to this subject are fascinating and the mechanisms involved are astonishing. The researchers notably identified the involvement of an area of the genome subjected to what is called the “parental imprint”.  “The genes subjected to this imprint are genes of which only the paternal or maternal version is expressed”, explains Haruko Takeda. “The CLPG mutation – which is responsible for the callipyge phenomenon – affects the expression of the two genes (DLK1 and PEG11) that code for proteins from the paternal chromosome and a large number of non-coding genes from the maternal chromosome”, she continues. “Over time, we have shown that polar overdominance is in fact the reflection of a conflict between maternal and paternal alleles during which the micro-RNAs produced from the maternal allele target the coding genes for the proteins produced from the paternal allele”. This is the main reason why the individuals which are carriers of two mutated CLPG alleles do not express the callipyge phenotype: the mutation situated on the paternal allele is neutralized by the excess of the micro-RNAs produced by the mutated maternal allele. 

Getting to the bottom of the mystery

Haruko Takeda and her colleagues have recently published new results in the journal PLOS ONE (1). “We had already demonstrated that the expression of the DLK1 gene causes a muscular hypertrophy in transgenic mice. However, we did not yet know if the second gene (PEG11) affected by the CLPG mutation also played a role in the appearance of the phenotype”, says the scientist. In order to verify that, the researchers created a line of transgenic mice that expressed the PEG11 protein in the skeletal muscles of the mice pups. “In this way, we were able to demonstrate, by means of measurements and histological analyses of the muscles, that these mice clearly presented a muscular hypertrophy”, reveals Haruko Takeda. These results suggest that the PEG11 gene plays a non-negligible role in the callipyge phenotype observed in sheep. Moreover, later results that have not yet been published by the researchers, suggest that the two genes DLK1 and PEG11 could be acting in synergy with each other.

Despite decades of research and discoveries about the callipyge phenotype, the latter has still not revealed its secrets. “We would particularly like to understand which intermediary leads to the muscular hypertrophy through the expression of the DLK1 and PEG11 genes”, continues Haruko Takeda. “But also, on a broader level, we would like to know at which point polar overdominance becomes a frequent genetic phenomenon, what its contribution to natural selection or the predisposition to disease in humans is”. Can the callipyge phenomenon be classed as a scientific curiosity? Certainly, but it is a curiosity that could provide a lot of unexpected answers to genetic mysteries. 

 (1) Xuewen Xu, Fabien Ectors, Erica E. Davis, Dimitri Pirottin, Huijun Cheng, Frédéric Farnir, Tracy Hadfield, Noelle Cockett, Carole Charlier, Michel Georges, Haruko Takeda. Ectopic Expression of Retrotransposon-Derived PEG11/RTL1 Contributes to the Callipyge Muscular Hypertrophy. PLOS ONE.10.1371/journal.pone.0140594