The callipyge mutation enhances bidirectional long-range DLK1-GTL2 intergenic transcription in cis

*Unit of Animal Genetics, Faculty of Veterinary Medicine and Centre of Biomedical Integrative Genoproteomics (CBIG), University of Liège (B43), 20 Boulevard de Colonster, 4000-Liège, Belgium;
^†Animal, Dairy, and Veterinary Sciences, College of Agriculture, Utah State University, Logan, UT 84322-4700; and
^‡Research Unit in Systems and Modelling, Department of Electrical Engineering and Computer Science and CBIG, Faculty of Applied Sciences, University of Liège (B29), 4000-Liège, Belgium

Communicated by James E. Womack, Texas A&M University, College Station, TX, April 7, 2006 (received for review February 2, 2006)

Abstract

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, long-range 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.

Footnotes

^§To whom correspondence should be addressed. E-mail: michel.georges{at}ulg.ac.be
Author contributions: H.T., M.G., and C.C. designed research; H.T., F.C., and M.S. performed research; M.S., S.H., X.T., and N.C. contributed new reagents/analytic tools; H.T., M.S., M.G., and C.C. analyzed data; and H.T., M.G., and C.C. wrote the paper.
Conflict of interest statement: No conflicts declared.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AF354168 and DQ378061).
Abbreviations:

Abbreviations:

DHS,

DNase-I hypersensitive site;

IG,

intergenic;

LCR,

locus control region;

miRNA,

microRNA;

RT,

reverse transcriptase.