Discovery of polar overdominance and its miRNA-dependent molecular basis.


In collaboration with Noelle Cockett from Utah State University, we studied a new muscular hypertrophy of sheep that was first reported in 1983 in Oklahoma in the offspring of a ram called Solid Gold.  We mapped the culprit major gene on sheep chromosome 18, called the phenotype “callipyge” and gene CLPG.  We then discovered in Liège in 1996 that the phenotype was characterized by a unique inheritance pattern in which only heterozygous animals inheriting the CLPG mutation from their father (+/CLPG) express the muscular hypertrophy, a phenomenon which we called polar overdominance.  In the years to come we showed that the CLPG point mutation inactivates a silencer element controlling the expression of the DLK1-GTL2 imprinted gene cluster in skeletal muscle, and that the callipyge phenotype in +/CLPG animals results from ectopic expression of two protein-coding genes (DLK1 and PEG11) that are paternally expressed.  We further showed that CLPG/CLPG animals do not express the phenotype because in these animals DLK1 and PEG11 are post-transcriptionally inhibited by a cluster of maternally expressed miRNAs.  The study of the callipyge phenomenon has pointed towards a miRNA-mediated conflict between the maternal and paternal genomes that normally occurs in the placenta and drives the evolution of parental imprinting.

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Key publications

Ectopic Expression of Retrotransposon-Derived PEG11/RTL1 Contributes to the Callipyge Muscular Hypertrophy. Xu X, Ectors F, Davis EE, Pirottin D, Cheng H, Farnir F, Hadfield T, Cockett N, Charlier C, Georges M, Takeda HPLoS One 10:e0140594 (2015).

Assessing the effect of the CLPG mutation on the microRNA catalog of skeletal muscle using high-throughput sequencing. Caiment F, Charlier C, Hadfield T, Cockett N, Georges M, Baurain DGenome Res 20:1651-1662 (2010).

The callipyge mutation enhances bidirectional long-range DLK1-GTL2 intergenic transcription in cis. Takeda H, Caiment F, Smit M, Hiard S, Tordoir X, Cockett N, Georges M, Charlier C. Proc Natl Acad Sci U S A 103:8119-8124 (2006).

RNAi-mediated allelic trans-interaction at the imprinted Rtl1/Peg11 locus. Davis E, Caiment F, Tordoir X, Cavaillé J, Ferguson-Smith A, Cockett N, Georges M, Charlier C. Curr Biol 15:743-974 (2005).

Ectopic expression of DLK1 protein in skeletal muscle of padumnal heterozygotes causes the callipyge phenotype. Davis E, Jensen CH, Schroder HD, Farnir F, Shay-Hadfield T, Kliem A, Cockett N, Georges M, Charlier CCurr Biol 14:1858-1862 (2004).

The callipyge mutation enhances the expression of coregulated imprinted genes in cis without affecting their imprinting status. Charlier C, Segers K, Karim L, Shay T, Gyapay G, Cockett N, Georges MNat Genet 27:367-369 (2001).

Polar overdominance at the ovine callipyge locus. Cockett NE, Jackson SP, Shay TL, Farnir F, Berghmans S, Snowder GD, Nielsen DM, Georges MScience 273:236-238 (1996).

Chromosomal localization of the callipyge gene in sheep (Ovis aries) using bovine DNA markers. Cockett NE, Jackson SP, Shay TL, Nielsen D, Moore SS, Steele MR, Barendse W, Green RD, Georges M. Proc Natl Acad Sci U S A 91:3019-3023 (1994).

                   

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