Skip to main content
Log in

BEGAIN: A novel imprinted gene that generates paternally expressed transcripts in a tissue- and promoter-specific manner in sheep

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

In this article we describe the organization of the ovine BEGAIN gene, located 138 kb proximally from the imprinted DLK1 gene and 203 kb from the CLPG mutation that causes the callipyge phenotype. We have shown that in sheep BEGAIN is ubiquitously expressed, including in skeletal muscle, throughout development. We have identified four major BEGAIN transcripts resulting from a combination of alternate promoter usage and alternative splicing. In ovine brain, kidney, liver, and skeletal muscle, these four BEGAIN transcripts exhibited paternal or biallelic expression in a tissue- and promoter-specific manner. Our results indicate that the CLPG mutation does not alter transcript levels of BEGAIN, contrary to its effect on a core cluster of genes in the DLK1-GTL2 domain. Thus, although the BEGAIN gene represents another paternally expressed gene in the ovine DLK1-GTL2 imprinted domain, its expression is not governed by the long-range regulatory element that contains the CLPG mutation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Barlow DP (1995) Gametic imprinting in mammals. Science 270: 1610–1613

    PubMed  Google Scholar 

  • Beechey CV, Cattanach BM, Black A, Peters J (2003) MRC Mammalian Genetics Unit, Harwell, Oxfordshire. Mouse Imprinting Data and References available at http://www.mgu.har.mrc.ac.uk/imprinting/imprinting/html

  • Bidwell CA, Shay TL, Georges M, Beever JE, Berghmans S, et al. (2001) Differential expression of the GTL2 gene within the callipyge region of ovine chromosome 18. Anim Genet 32: 248–256

    Article  PubMed  Google Scholar 

  • Birney E, Andrews D, Bevan P, Coccamo M, Cameron G, et al. (2004) Ensembl 2004. Nucleic Acids Res 32: D468–D470

    Article  PubMed  Google Scholar 

  • Blagitko N, Mergenthaler S, Schulz U, Wollmann HA, Craigen W, et al. (2000) Human GRB10 is imprinted and expressed from the paternal and maternal allele in a highly tissue- and isoform-specific fashion. Hum Mol Genet 9: 1587–1595

    Article  PubMed  Google Scholar 

  • Brudno M, Do CB, Cooper GM, Kim MF, Davydov E, et al. (2003) LAGAN and Multi-LAGAN: Efficient tools for large-scale multiple alignment of genomic DNA. Genome Res 13: 721–731

    Article  PubMed  Google Scholar 

  • Bunzel R, Blumcke I, Cichon S, Normann S, Schramm J, et al. (1998) Polymorphic imprinting of the serotonin-2A (5-HT2A) receptor gene in human adult brain. Brain Res Mol Brain Res 59: 90–92

    Article  PubMed  Google Scholar 

  • Cavaillé J, Seitz H, Paulsen M, Ferguson-Smith AC, Bachellerie J-P (2002) Identification of tandemly-repeated C/D snoRNA genes at the imprinted human 14q32 domain reminiscent of those at the Prader-Willi/Angelman syndrome region. Hum Mol Genet 11: 1527–1538

    Article  PubMed  Google Scholar 

  • Charlier C, Segers K, Wagenaar D, Karim L, Berghmans S, et al. (2001a) Human-ovine comparative sequencing of a 250-kb imprinted domain encompassing the callipyge (clpg) locus and identification of six imprinted transcripts: DLK1, DAT, GTL2, PEG11, antiPEG11, and MEG8. Genome Res 11: 850–862

    Article  Google Scholar 

  • Charlier C, Segers K, Karim L, Shay T, Gyapay G, et al. (2001b) The callipyge mutation enhances the expression of coregulated imprinted genes in cis without affecting their imprinting status. Nat Genet 27: 367–369

    Article  Google Scholar 

  • Chu C, Schwartz S, McPherson E (2004) Paternal uniparental isodisomy for chromosome 14 in a patient with a normal 46, XY karyotype. Am J Med Genet 127A: 167–171

    Article  Google Scholar 

  • Cockett NE, Jackson SP, Shay TL, Farnir F, Berghmans S, et al. (1996) Polar overdominance at the ovine callipyge locus. Science 273: 236–238

    PubMed  Google Scholar 

  • Davis E, Harken Jensen C, Schroder HD, Shay T, Kliem A, et al. (2004). Ectopic expression of DLK1 protein in skeletal muscle of padumnal heterozygotes causes the callipyge phenotype. Curr Biol 14: 1858–1862

    Article  PubMed  Google Scholar 

  • Davis E, Caiment F, Tordoir X, Cockett N, Georges M, et al. (2005). RNAi-mediated allelic trans-interaction at the imprinted callipyge locus. Curr Biol 15: 743–749

    Article  PubMed  Google Scholar 

  • Deguchi M, Hata Y, Takeuchi M, Ide N, Hirao K, et al. (1998) BEGAIN (brain-enriched gyanylate kinase-associated protein), a novel neuronal PSD-95/SAP90-binding protein. J Biol Chem 273: 26269–26272

    Article  PubMed  Google Scholar 

  • Ewing B, Green P (1998) Base-calling of automated sequencer traces using phred. II. Error probabilities. Genome Res 8: 186–194

    PubMed  Google Scholar 

  • Ewing G, Hillier L, Wendl MC, Green P (1998) Base-calling of automated sequencer traces using phred. I. Accuracy assessment. Genome Res 8: 175–185

    PubMed  Google Scholar 

  • Fanning AS, Anderson JM (1999) Protein modules as organizers of membrane structure. Curr Opin Cell Biol 11: 432-439

    Article  PubMed  Google Scholar 

  • Freking BA, Murphy SK, Wylie AA, Rhodes SJ, Keele JW, et al. (2002) Identification of the single base change causing the callipyge muscle hypertrophy phenotype, the only known example of polar overdominance in mammals. Genome Res 12: 1496–1506

    Article  PubMed  Google Scholar 

  • Gardiner-Garden M, Frommer M (1987) CpG islands in vertebrate genomes. J Mol Biol 196: 261–282

    Article  PubMed  Google Scholar 

  • Georges M, Charlier C, Cockett N (2003) The callipyge locus: evidence for the trans interaction of reciprocally imprinted genes. Trends Genet 19: 248–252

    Article  PubMed  Google Scholar 

  • Georgiades P, Watkins M, Surani MA, Ferguson-Smith AC (2000) Parental origin-specific developmental defects in mice with uniparental disomy for chromosome 12. Development 127: 4719–4728

    PubMed  Google Scholar 

  • Gordon D, Abajian C, Green P (1998) Consed: a graphical tool for sequence finishing. Genome Res 8: 195–202

    PubMed  Google Scholar 

  • Greally JM (2002) Short interspersed transposable elements (SINEs) are excluded from imprinted regions in the human genome. Proc Natl Acad Sci U S A 99: 327–332

    Article  PubMed  Google Scholar 

  • Hata Y, Takai Y (1999) Roles of postsynaptic density-95/synapse-associated protein 90 and its interacting proteins in the organization of synapses. Cell Mol Life Sci 56: 461–472

    Article  PubMed  Google Scholar 

  • Hayward BE, Moran V, Strain L, Bonthron DT (1998) Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins. Proc Natl Acad Sci U S A 95: 15475–15480

    Article  PubMed  Google Scholar 

  • Heilig R, Eckenberg R, Petit J-L, Fonknechten N, Da Silva C, et al. (2003) The DNA sequence and analysis of human chromosome 14. Nature 421: 601–607

    Article  PubMed  Google Scholar 

  • Hernandez A, Fiering S, Martinez E, Galton VA, St. Germain D (2003) The gene locus encoding iodothyronine deiodinase type 3 (Dio3) is imprinted in the fetus and expresses antisense transcripts. Endocrinology 143: 4483–4486

    Article  Google Scholar 

  • Jinno Y, Yun K, Nishiwaki K, Kubota T, Ogawa O, et al. (1994) Mosaic and polymorphic imprinting of the WT1 gene in humans. Nat Genet 6: 305–309

    Article  PubMed  Google Scholar 

  • Jurka J (2000) Repbase update: a database and an electronic journal of repetitive elements. Trends Genet 16: 418–420

    Article  PubMed  Google Scholar 

  • Kobayashi S, Wagatsuma H, Ono R, Ichikawa H, Yamazaki M, et al. (2000) Mouse Peg9/Dlk1 and human PEG9/DLK1 are paternally expressed imprinted genes closely located to the maternally expressed imprinted genes: mouse Meg3/Gtl2 and human MEG3. Genes Cells 5: 1029–1037

    Article  PubMed  Google Scholar 

  • Kosaki K, Kosaki R, Craigen WJ, Matsuo N (2000) Isoform-specific imprinting of the human PEG1/MEST gene. Am J Hum Genet 66: 309–312

    Article  PubMed  Google Scholar 

  • Lin S-P, Youngson N, Takada S, Seitz H, Reik W, et al. (2003) Asymmetric regulation of imprinting on the maternal and paternal chromosomes at the Dlk1-Gtl2 imprinted cluster on mouse chromosome 12. Nat Genet 35: 97–102

    Article  PubMed  Google Scholar 

  • Lyle R, Watanabe D, te Vruchte D, Lerchner, Smrzka OW, et al. (2000) The imprinted antisense RNA at the Igf2r locus overlaps but does not imprint Mas1. Nat Genet 25: 19–21

    Article  PubMed  Google Scholar 

  • Margulies EH, Blanchette M, NISC Comparative Sequencing Program, Haussler D, Green ED (2003) Identification and characterization of multi-species conserved sequences. Genome Res 13, 2507–2518

  • Miyoshi N, Wagatsum H, Wakana S, Shiroishi T, Nomura M, et al. (2000) Identification of an imprinted gene, Meg3/Gtl2 and its human homologue MEG3, first mapped on mouse distal chromosome 12 and human chromosome 14q. Genes Cells 5: 211–220

    Article  PubMed  Google Scholar 

  • Modrek B, Lee C (2002) A genomic view of alternative splicing. Nat Genet 30: 13–19

    Article  PubMed  Google Scholar 

  • Rebhan M, Chalifa-Caspi V, Prilusky J, Lancet D (1997) GeneCards: integrating information about genes, proteins, and diseases. Trends Genet 13: 163

    Article  PubMed  Google Scholar 

  • Rice P, Longden I, Bleasby A (2000) EMBOSS: the European Molecular Biology Open Software Suite. Trends Genet 16: 276–277

    Article  PubMed  Google Scholar 

  • Roychlik W, Rhoades RE (1989) A computer program for choosing optimal oligonucleotides for filter hybridization, sequencing, and in vitro amplification of DNA. Nucleic Acids Res 17: 8543–8551

    PubMed  Google Scholar 

  • Sakatani T, Wei M, Katoh M, Okita C, Wada D, et al. (2001) Epigenetic heterogeneity at imprinted loci in normal populations. Biochem Biophys Res Commun 283: 1124–1130

    Article  PubMed  Google Scholar 

  • Sanlaville D, Aubry MC, Dumez Y, Nolen MC, Amiel J, et al. (2000) Maternal uniparental heterodisomy of chromosome 14: chromosomal mechanism and clinical follow-up. J Med Genet 37: 525–528

    Article  PubMed  Google Scholar 

  • Schmidt JV, Matteson PG, Jones BK, Guan X-J, Tilghman SM (2000) The Dlk1 and Gtl2 genes are linked and reciprocally imprinted. Genes Dev 14: 1997–2002

    PubMed  Google Scholar 

  • Segers K, Vaiman D, Berghmans S, Shay T, Meyers S, et al. (2000) Construction and characterization of an ovine BAC contig spanning the callipyge locus. Anim Genet 31: 352–359

    Article  PubMed  Google Scholar 

  • Seitz H, Youngson N, Lin S-P, Dalbert S, Paulsen M, et al. (2003) Imprinted microRNA genes transcribed antisense to a reciprocally imprinted retrotransposon-like gene. Nat Genet 34: 261–262

    Article  PubMed  Google Scholar 

  • Seitz H, Royo H, Bortolin M.-L, Lin S-P, Ferguson-Smith AC, et al. (2004) A large imprinted microRNA gene cluster at the mouse Dlk1-Gtl2 domain. Genome Res 14: 1741–1748

    Article  PubMed  Google Scholar 

  • Sheng M (2001) Molecular organization of the postsynaptic specialization. Proc Natl Acad Sci U S A 98: 7058–7061

    Article  PubMed  Google Scholar 

  • Smit M, Segers K, Carrascosa LG, Shay T, Baraldi F, et al. (2003) Mosaicism of Solid Gold supports the causality of a noncoding A-to-G transition in the determinism of the callipyge phenotype. Genetics 163: 453–456

    PubMed  Google Scholar 

  • Takada S, Tevendale M, Baker J, Georgiades P, Campbell E, et al. (2000) Delta-like and Gtl2 are reciprocally expressed, differentially methylated linked imprinted genes on mouse chromosome 12. Curr Biol 10: 1135–1138

    Article  PubMed  Google Scholar 

  • Takada S, Paulsen M, Tevendale M, Tsai C-E, Kelsey G, et al. (2002) Epigenetic analysis of the Dlk1-Gtl2 imprinted domain on mouse chromosome 12: implications for imprinting control from comparison with Igf2-H19. Hum Mol Genet 11: 77–86

    Article  PubMed  Google Scholar 

  • Tsai C-E, Lin S-P, Ito M, Takagi N, Takada S, et al. (2002) Genomic imprinting contributes to thyroid hormone metabolism in the mouse embryo. Curr Biol 12: 1221–1226

    Article  PubMed  Google Scholar 

  • Uejima H, Lee MP, Cui H, Feinberg AP (2000) Hot-stop PCR: a simple and general assay for linear quantitation of allele ratios. Nat Genet 25: 375–376

    Article  PubMed  Google Scholar 

  • Vaiman D, Billault A, Tabet-Aoul K, Schibler L, Vilette D, et al. (1999) Construction and characterization of a sheep BAC library of three genome equivalents. Mamm Genome 10: 585–587

    Article  PubMed  Google Scholar 

  • Verona RI, Mann MRW, Bartolomei MS (2003) Genomic Imprinting: Intricacies of epigenetic regulation in clusters. Annu Rev Cell Dev Biol 19: 237–259

    Article  PubMed  Google Scholar 

  • Vu TH, Hoffman AR (1994) Promoter-specific imprinting of the human insulin-like growth factor-II gene. Nature 371: 714–717

    Article  PubMed  Google Scholar 

  • Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, et al. (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420: 520–562

    Article  PubMed  Google Scholar 

  • Weinstein LS (2001) The role of tissue-specific imprinting as a source of phenotypic heterogeneity in human disesase. Biol Psychiatry 50: 927–931

    Article  PubMed  Google Scholar 

  • Weinstein LS, Yu S, Ecelbarger CA (2000) Variable imprinting of the heterotrimeric G protein Gs α-subunit within different segments of the nephron. Am J Physiol Renal Physiol 278: F507–F514

    PubMed  Google Scholar 

  • Wylie AA, Murphy SK, Orton TC, Jirtle RL (2000) Novel imprinted DLK1/GTL2 domain on human chromosome 14 contains motifs that mimic those implicated in IGF2/H19 regulation. Genome Res 10: 1711–1718

    Article  PubMed  Google Scholar 

  • Xu Y, Goodyer CG, Deal C, Polychronakos C (1993) Functional polymorphism in the parental imprinting of the human IGF2R gene. Biochem Biophys Res Commun 197: 747–754

    Article  PubMed  Google Scholar 

  • Yao I, Iida J, Nishimura W, Hata Y (2002) Synaptic and nuclear localization of brain-enriched guanylate kinase-associated protein. J Neurosci 22: 5354–5364

    PubMed  Google Scholar 

  • Yevtodiyenko A, Carr MS, Patel N, Schmidt JV (2002) Analysis of candidate imprinted genes linked to Dlk1-Gtl2 using a congenic mouse line. Mamm Genome 13: 633–638

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by grants from the FRFC (No. 2.4525.96), Crédit aux Chercheurs (No. 1.5.134.00) from the FNRS, Crédit à la Recherche from the University of Liège, the SSTC (No. 0135), USDA/NRICGP grants Nos. 94-04358, 96-35205, 98-03455, and 01-03332, and the Utah Agricultural Experiment Station, Utah State University, Logan, UT. Carole Charlier is Chercheur Qualifié FNRS.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michel Georges.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Smit, M.A., Tordoir, X., Gyapay, G. et al. BEGAIN: A novel imprinted gene that generates paternally expressed transcripts in a tissue- and promoter-specific manner in sheep. Mamm Genome 16, 801–814 (2005). https://doi.org/10.1007/s00335-004-2415-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-004-2415-z

Keywords

Navigation