Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The role of genomic imprinting in biology and disease: an expanding view

Nature Reviews Genetics volume 15, pages 517–530 (2014)Cite this article

Subjects

Key Points

  • Genomic imprinting — an epigenetic phenomenon that results in monoallelic expression according to parental origin — was recognized in mammals around 30 years ago from embryological and genetic studies.

  • Imprinted genes are known to have major effects on prenatal development and placental biology. More recently, they have been shown to exert important effects on postnatal development, growth and survival, as well as on adult phenotypes.

  • Imprinted genes are emerging as key regulators of metabolic processes in both infants and adults. They can influence maintenance of body temperature, food intake and adiposity by acting on multiple tissues and pathways.

  • Many imprinted genes are expressed in the brain and affect diverse aspects of behaviour from birth onwards, from infant feeding to sleep and adult social behaviour.

  • Investigations of mouse mutants have been important in unravelling the roles of imprinted genes and for elucidating some of the pathophysiological mechanisms involved in human imprinted syndromes.

  • Disrupted expression of imprinted genes is an important cause of human disease. In addition to known imprinted syndromes, there is increasing evidence that altered expression of imprinted genes is a contributory factor in a wide range of common diseases, such as intrauterine growth restriction, obesity, diabetes mellitus, psychiatric disorders and cancer.

Abstract

Genomic imprinting is an epigenetic phenomenon that results in monoallelic gene expression according to parental origin. It has long been established that imprinted genes have major effects on development and placental biology before birth. More recently, it has become evident that imprinted genes also have important roles after birth. In this Review, I bring together studies of the effects of imprinted genes from the prenatal period onwards. Recent work on postnatal stages shows that imprinted genes influence an extraordinarily wide-ranging array of biological processes, the effects of which extend into adulthood, and play important parts in common diseases that range from obesity to psychiatric disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Representative mouse imprinted gene clusters.
Figure 2: Imprinted genes affect metabolism.
Figure 3: Imprinted genes regulate behaviours.

Similar content being viewed by others

References

  1. McGrath, J. & Solter, D. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37, 179–183 (1984).

    CAS  PubMed  Google Scholar 

  2. Surani, M. A., Barton, S. C. & Norris, M. L. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 308, 548–550 (1984). References 1 and 2 provide the first recognition of imprinting and show that both the maternal and the paternal genome are needed for normal development of mouse embryos to term.

    CAS  PubMed  Google Scholar 

  3. Cattanach, B. M. & Kirk, M. Differential activity of maternally and paternally derived chromosome regions in mice. Nature 315, 496–498 (1985). This paper shows that imprinting is restricted to some regions of the genome (which implies that genes are involved in the process) and that defects in imprinting could be an important cause of human disease.

    CAS  PubMed  Google Scholar 

  4. Searle, A. G. & Beechey, C. V. Complementation studies with mouse translocations. Cytogenet. Cell Genet. 20, 282–303 (1978).

    CAS  PubMed  Google Scholar 

  5. Snell, G. D. An analysis of translocations in the mouse. Genetics 31, 157–180 (1946).

    PubMed  PubMed Central  Google Scholar 

  6. Nicholls, R. D., Knoll, J. H., Butler, M. G., Karam, S. & Lalande, M. Genetic imprinting suggested by maternal heterodisomy in nondeletion Prader–Willi syndrome. Nature 342, 281–285 (1989). This study is the first to demonstrate a human imprinted syndrome.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Barlow, D. P., Stoger, R., Herrmann, B. G., Saito, K. & Schweifer, N. The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Nature 349, 84–87 (1991).

    CAS  PubMed  Google Scholar 

  8. Bartolomei, M. S., Zemel, S. & Tilghman, S. M. Parental imprinting of the mouse H19 gene. Nature 351, 153–155 (1991).

    CAS  PubMed  Google Scholar 

  9. DeChiara, T. M., Robertson, E. J. & Efstratiadis, A. Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64, 849–859 (1991). Reference 7 describes the first imprinted gene, which is followed shortly afterwards by the description of two more in references 8 and 9.

    CAS  PubMed  Google Scholar 

  10. Xie, W. et al. Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome. Cell 148, 816–831 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Moore, T. & Haig, D. Genomic imprinting in mammalian development: a parental tug-of-war. Trends Genet. 7, 45–49 (1991).

    CAS  PubMed  Google Scholar 

  12. Keverne, E. B. & Curley, J. P. Epigenetics, brain evolution and behaviour. Front. Neuroendocrinol. 29, 398–412 (2008).

    CAS  PubMed  Google Scholar 

  13. Haig, D. Coadaptation and conflict, misconception and muddle, in the evolution of genomic imprinting. Heredity http://dx.doi.org/10.1038/hdy.2013.97 (2013).

  14. Barlow, D. P. Genomic imprinting: a mammalian epigenetic discovery model. Annu. Rev. Genet. 45, 379–403 (2011).

    CAS  PubMed  Google Scholar 

  15. Charalambous, M. et al. Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism. Proc. Natl Acad. Sci. USA 100, 8292–8297 (2003).

    CAS  PubMed  Google Scholar 

  16. Garfield, A. S. et al. Distinct physiological and behavioural functions for parental alleles of imprinted Grb10. Nature 469, 534–538 (2011). This paper shows the only known example of an imprinted gene that is expressed from maternal and paternal alleles in a tissue-specific manner and the first example of an imprinted gene that affects social behaviour in the mouse.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Sanz, L. A. et al. A mono-allelic bivalent chromatin domain controls tissue-specific imprinting at Grb10. EMBO J. 27, 2523–2532 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Chotalia, M. et al. Transcription is required for establishment of germline methylation marks at imprinted genes. Genes Dev. 23, 105–117 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Henckel, A., Chebli, K., Kota, S. K., Arnaud, P. & Feil, R. Transcription and histone methylation changes correlate with imprint acquisition in male germ cells. EMBO J. 31, 606–615 (2012).

    CAS  PubMed  Google Scholar 

  20. Mancini-Dinardo, D., Steele, S. J., Levorse, J. M., Ingram, R. S. & Tilghman, S. M. Elongation of the Kcnq1ot1 transcript is required for genomic imprinting of neighboring genes. Genes Dev. 20, 1268–1282 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Meng, L., Person, R. E. & Beaudet, A. L. Ube3a-ATS is an atypical RNA polymerase II transcript that represses the paternal expression of Ube3a. Hum. Mol. Genet. 21, 3001–3012 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Sleutels, F., Zwart, R. & Barlow, D. P. The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature 415, 810–813 (2002). This study is the first to show that a lncRNA could silence an imprinted gene.

    CAS  PubMed  Google Scholar 

  23. Williamson, C. M. et al. Uncoupling antisense-mediated silencing and DNA methylation in the imprinted Gnas cluster. PLoS Genet. 7, e1001347 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Lee, J. T. & Bartolomei, M. S. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell 152, 1308–1323 (2013).

    CAS  PubMed  Google Scholar 

  25. Nagano, T. et al. The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science 322, 1717–1720 (2008). This paper provides evidence that a lncRNA product is involved in imprinted gene silencing.

    CAS  PubMed  Google Scholar 

  26. Latos, P. A. et al. Airn transcriptional overlap, but not its lncRNA products, induces imprinted Igf2r silencing. Science 338, 1469–1472 (2012).

    CAS  PubMed  Google Scholar 

  27. Santoro, F. et al. Imprinted Igf2r silencing depends on continuous Airn lncRNA expression and is not restricted to a developmental window. Development 140, 1184–1195 (2013). References 26 and 27 show that transcription of a lncRNA could silence an imprinted gene.

    CAS  PubMed  Google Scholar 

  28. Bell, A. C. & Felsenfeld, G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405, 482–485 (2000).

    CAS  PubMed  Google Scholar 

  29. Hark, A. T. et al. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 405, 486–489 (2000). References 28 and 29 show that an ICR can regulate imprinted gene expression by acting as an insulator.

    CAS  PubMed  Google Scholar 

  30. Reik, W. et al. Regulation of supply and demand for maternal nutrients in mammals by imprinted genes. J. Physiol. 547, 35–44 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Okae, H. et al. Re-investigation and RNA sequencing-based identification of genes with placenta-specific imprinted expression. Hum. Mol. Genet. 21, 548–558 (2012).

    CAS  PubMed  Google Scholar 

  32. Guillemot, F. et al. Genomic imprinting of Mash2, a mouse gene required for trophoblast development. Nature Genet. 9, 235–242 (1995).

    CAS  PubMed  Google Scholar 

  33. Guillemot, F., Nagy, A., Auerbach, A., Rossant, J. & Joyner, A. L. Essential role of Mash-2 in extraembryonic development. Nature 371, 333–336 (1994).

    CAS  PubMed  Google Scholar 

  34. Ono, R. et al. Deletion of Peg10, an imprinted gene acquired from a retrotransposon, causes early embryonic lethality. Nature Genet. 38, 101–106 (2006).

    CAS  PubMed  Google Scholar 

  35. Constancia, M. et al. Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 417, 945–948 (2002).

    CAS  PubMed  Google Scholar 

  36. Jonker, J. W., Wagenaar, E., Van Eijl, S. & Schinkel, A. H. Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol. Cell. Biol. 23, 7902–7908 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Zwart, R., Sleutels, F., Wutz, A., Schinkel, A. H. & Barlow, D. P. Bidirectional action of the Igf2r imprint control element on upstream and downstream imprinted genes. Genes Dev. 15, 2361–2366 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Charalambous, M., da Rocha, S. T. & Ferguson-Smith, A. C. Genomic imprinting, growth control and the allocation of nutritional resources: consequences for postnatal life. Curr. Opin. Endocrinol. Diabetes Obes 14, 3–12 (2007).

    CAS  PubMed  Google Scholar 

  39. Gabory, A., Jammes, H. & Dandolo, L. The H19 locus: role of an imprinted non-coding RNA in growth and development. Bioessays 32, 473–480 (2010).

    CAS  PubMed  Google Scholar 

  40. Ishida, M. et al. Maternal inheritance of a promoter variant in the imprinted PHLDA2 gene significantly increases birth weight. Am. J. Hum. Genet. 90, 715–719 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Brodsky, D. & Christou, H. Current concepts in intrauterine growth restriction. J. Intensive Care Med. 19, 307–319 (2004).

    PubMed  Google Scholar 

  42. Ishida, M. & Moore, G. E. The role of imprinted genes in humans. Mol. Aspects Med. 34, 826–840 (2013).

    CAS  PubMed  Google Scholar 

  43. Richard, N. et al. Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLαs in fetal development. J. Clin. Endocrinol. Metab. 98, E1549–1556 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Curley, J. P., Barton, S., Surani, A. & Keverne, E. B. Coadaptation in mother and infant regulated by a paternally expressed imprinted gene. Proc. Biol. Sci. 271, 1303–1309 (2004).

    PubMed  PubMed Central  Google Scholar 

  45. Lefebvre, L. et al. Abnormal maternal behaviour and growth retardation associated with loss of the imprinted gene Mest. Nature Genet. 20, 163–169 (1998).

    CAS  PubMed  Google Scholar 

  46. Plagge, A. et al. The imprinted signaling protein XLαs is required for postnatal adaptation to feeding. Nature Genet. 36, 818–826 (2004).

    CAS  PubMed  Google Scholar 

  47. Schaller, F. et al. A single postnatal injection of oxytocin rescues the lethal feeding behaviour in mouse newborns deficient for the imprinted Magel2 gene. Hum. Mol. Genet. 19, 4895–4905 (2010). This paper provides an excellent description of feeding behaviour in newborn mice and a possible therapeutic option for treating the suckling deficit in patients with Prader–Willi syndrome.

    CAS  PubMed  Google Scholar 

  48. Cattanach, B. M., Peters, J., Ball, S. & Rasberry, C. Two imprinted gene mutations: three phenotypes. Hum. Mol. Genet. 9, 2263–2273 (2000).

    CAS  PubMed  Google Scholar 

  49. Muscatelli, F. et al. Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader–Willi syndrome. Hum. Mol. Genet. 9, 3101–3110 (2000).

    CAS  PubMed  Google Scholar 

  50. Sun, F. L., Dean, W. L., Kelsey, G., Allen, N. D. & Reik, W. Transactivation of Igf2 in a mouse model of Beckwith–Wiedemann syndrome. Nature 389, 809–815 (1997).

    CAS  PubMed  Google Scholar 

  51. Ball, S. T. et al. Gene dosage effects at the imprinted cluster. PLoS ONE 8, e65639 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Fernandez-Rebollo, E. et al. Loss of XLαs (extra-large αs) imprinting results in early postnatal hypoglycemia and lethality in a mouse model of pseudohypoparathyroidism Ib. Proc. Natl Acad. Sci. USA 109, 6638–6643 (2012).

    CAS  PubMed  Google Scholar 

  53. Frohlich, L. F. et al. Targeted deletion of the Nesp55 DMR defines another Gnas imprinting control region and provides a mouse model of autosomal dominant PHP-Ib. Proc. Natl Acad. Sci. USA 107, 9275–9280 (2010).

    CAS  PubMed  Google Scholar 

  54. Chen, M. et al. Alternative Gnas gene products have opposite effects on glucose and lipid metabolism. Proc. Natl Acad. Sci. USA 102, 7386–7391 (2005).

    CAS  PubMed  Google Scholar 

  55. Kelly, M. L. et al. A missense mutation in the non-neural G-protein α-subunit isoforms modulates susceptibility to obesity. Int. J. Obes (Lond.) 33, 507–518 (2009).

    CAS  Google Scholar 

  56. Weinstein, L. S., Xie, T., Qasem, A., Wang, J. & Chen, M. The role of GNAS and other imprinted genes in the development of obesity. Int. J. Obes (Lond.) 34, 6–17 (2010).

    CAS  Google Scholar 

  57. Nicholls, R. D., Ohta, T. & Gray, T. A. Genetic abnormalities in Prader–Willi syndrome and lessons from mouse models. Acta Paediatr. Suppl. 88, 99–104 (1999).

    CAS  PubMed  Google Scholar 

  58. Price, S. M., Stanhope, R., Garrett, C., Preece, M. A. & Trembath, R. C. The spectrum of Silver–Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria. J. Med. Genet. 36, 837–842 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Curley, J. P. et al. Increased body fat in mice with a targeted mutation of the paternally expressed imprinted gene Peg3. FASEB J. 19, 1302–1304 (2005).

    CAS  PubMed  Google Scholar 

  60. Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    CAS  PubMed  Google Scholar 

  61. Peters, J. et al. Imprinting control within the compact Gnas locus. Cytogenet. Genome Res. 113, 194–201 (2006).

    CAS  PubMed  Google Scholar 

  62. Xie, T. et al. Severe obesity and insulin resistance due to deletion of the maternal Gsα allele is reversed by paternal deletion of the Gsα imprint control region. Endocrinology 149, 2443–2450 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Yu, S. et al. Paternal versus maternal transmission of a stimulatory G-protein α subunit knockout produces opposite effects on energy metabolism. J. Clin. Invest. 105, 615–623 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Lassi, G. et al. Loss of Gnas imprinting differentially affects REM/NREM sleep and cognition in mice. PLoS Genet. 8, e1002706 (2012). This study shows that imprinting is required for normal sleep homeostasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Nunn, N., Feetham, C. H., Martin, J., Barrett-Jolley, R. & Plagge, A. Elevated blood pressure, heart rate and body temperature in mice lacking the XLαs protein of the Gnas locus is due to increased sympathetic tone. Exp. Physiol. 98, 1432–1445 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Tseng, Y. H. et al. Prediction of preadipocyte differentiation by gene expression reveals role of insulin receptor substrates and necdin. Nature Cell Biol. 7, 601–611 (2005).

    CAS  PubMed  Google Scholar 

  67. Charalambous, M. et al. Imprinted gene dosage is critical for the transition to independent life. Cell. Metab. 15, 209–221 (2012). This paper shows that there is a second wave of brown fat recruitment in the mouse and that imprinted genes are required for this process.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Haig, D. Huddling: brown fat, genomic imprinting and the warm inner glow. Curr. Biol. 18, R172–R174 (2008).

    CAS  PubMed  Google Scholar 

  69. Chen, M. et al. Gsα deficiency in the paraventricular nucleus of the hypothalamus partially contributes to obesity associated with Gsα mutations. Endocrinology 153, 4256–4265 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Chen, M. et al. Central nervous system imprinting of the G protein Gsα and its role in metabolic regulation. Cell. Metab. 9, 548–555 (2009).

    PubMed  PubMed Central  Google Scholar 

  71. Fan, W. et al. The central melanocortin system can directly regulate serum insulin levels. Endocrinology 141, 3072–3079 (2000).

    CAS  PubMed  Google Scholar 

  72. Obici, S. et al. Central melanocortin receptors regulate insulin action. J. Clin. Invest. 108, 1079–1085 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Fujiwara, K. et al. Necdin controls proliferation of white adipocyte progenitor cells. PLoS ONE 7, e30948 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Moon, Y. S. et al. Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity. Mol. Cell. Biol. 22, 5585–5592 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Takahashi, M., Kamei, Y. & Ezaki, O. Mest/Peg1 imprinted gene enlarges adipocytes and is a marker of adipocyte size. Am. J. Physiol. Endocrinol. Metab. 288, E117–E124 (2005).

    CAS  PubMed  Google Scholar 

  76. Resnick, J. L., Nicholls, R. D. & Wevrick, R. Recommendations for the investigation of animal models of Prader–Willi syndrome. Mamm. Genome 24, 165–178 (2013).

    CAS  PubMed  Google Scholar 

  77. Bischof, J. M., Stewart, C. L. & Wevrick, R. Inactivation of the mouse Magel2 gene results in growth abnormalities similar to Prader–Willi syndrome. Hum. Mol. Genet. 16, 2713–2719 (2007).

    CAS  PubMed  Google Scholar 

  78. Mercer, R. E. et al. Magel2 is required for leptin-mediated depolarization of POMC neurons in the hypothalamic arcuate nucleus in mice. PLoS Genet. 9, e1003207 (2013). References 69, 70 and 78 indicate that misexpression of imprinted genes can lead to defective melanocortin signalling in obesity.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Ding, F. et al. snoRNA Snord116 (Pwcr1/MBII-85) deletion causes growth deficiency and hyperphagia in mice. PLoS ONE 3, e1709 (2008).

    PubMed  PubMed Central  Google Scholar 

  80. Font de Mora, J. et al. Ras–GRF1 signaling is required for normal β-cell development and glucose homeostasis. EMBO J. 22, 3039–3049 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Lee, K. et al. Inhibition of adipogenesis and development of glucose intolerance by soluble preadipocyte factor-1 (Pref-1). J. Clin. Invest. 111, 453–461 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Xie, T. et al. The alternative stimulatory G protein α-subunit XLαs is a critical regulator of energy and glucose metabolism and sympathetic nerve activity in adult mice. J. Biol. Chem. 281, 18989–18999 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Krechowec, S. O. et al. Postnatal changes in the expression pattern of the imprinted signalling protein XLαs underlie the changing phenotype of deficient mice. PLoS ONE 7, e29753 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Krechowec, S. & Plagge, A. Physiological dysfunctions associated with mutations of the imprinted Gnas locus. Physiol. (Bethesda) 23, 221–229 (2008).

    CAS  Google Scholar 

  85. Howell, J. J. & Manning, B. D. mTOR couples cellular nutrient sensing to organismal metabolic homeostasis. Trends Endocrinol. Metab. 22, 94–102 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Hsu, P. P. et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332, 1317–1322 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Yu, Y. et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332, 1322–1326 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Medina, M. C. et al. The thyroid hormone-inactivating type III deiodinase is expressed in mouse and human β-cells and its targeted inactivation impairs insulin secretion. Endocrinology 152, 3717–3727 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Srinivasan, M. & Patel, M. S. Metabolic programming in the immediate postnatal period. Trends Endocrinol. Metab. 19, 146–152 (2008).

    CAS  PubMed  Google Scholar 

  90. Wilkinson, L. S., Davies, W. & Isles, A. R. Genomic imprinting effects on brain development and function. Nature Rev. Neurosci. 8, 832–843 (2007).

    CAS  Google Scholar 

  91. Colas, D., Wagstaff, J., Fort, P., Salvert, D. & Sarda, N. Sleep disturbances in Ube3a maternal-deficient mice modeling Angelman syndrome. Neurobiol. Dis. 20, 471–478 (2005).

    CAS  PubMed  Google Scholar 

  92. da Rocha, S. T. et al. Gene dosage effects of the imprinted delta-like homologue 1 (dlk1/pref1) in development: implications for the evolution of imprinting. PLoS Genet. 5, e1000392 (2009).

    PubMed  Google Scholar 

  93. Bastepe, M. Relative functions of Gαs and its extra-large variant XLαs in the endocrine system. Horm. Metab. Res. 44, 732–740 (2012).

    CAS  PubMed  Google Scholar 

  94. Germain-Lee, E. L. et al. A mouse model of albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene. Endocrinology 146, 4697–4709 (2005).

    CAS  PubMed  Google Scholar 

  95. Jiang, Y. H. et al. Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3. PLoS ONE 5, e12278 (2010).

    PubMed  PubMed Central  Google Scholar 

  96. Nakatani, J. et al. Abnormal behavior in a chromosome-engineered mouse model for human 15q11–13 duplication seen in autism. Cell 137, 1235–1246 (2009).

    PubMed  PubMed Central  Google Scholar 

  97. Wilkins, J. F. & Haig, D. Inbreeding, maternal care and genomic imprinting. J. Theor. Biol. 221, 559–564 (2003).

    PubMed  Google Scholar 

  98. McNamara, P., Dowdall, J. & Auerbach, S. REM sleep, early experience, and the development of reproductive strategies. Human Nature 13, 405–435 (2002).

    PubMed  Google Scholar 

  99. Kozlov, S. V. et al. The imprinted gene Magel2 regulates normal circadian output. Nature Genet. 39, 1266–1272 (2007).

    CAS  PubMed  Google Scholar 

  100. Powell, W. T. et al. A Prader–Willi locus lncRNA cloud modulates diurnal genes and energy expenditure. Hum. Mol. Genet. 22, 4318–4328 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Williams, C. A. et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am. J. Med. Genet. A 140A, 413–418 (2006).

    Google Scholar 

  102. Krauchi, K. & Deboer, T. The interrelationship between sleep regulation and thermoregulation. Front. Biosci. (Landmark Ed) 15, 604–625 (2010).

    Google Scholar 

  103. d'Isa, R. et al. Mice lacking Ras–GRF1 show contextual fear conditioning but not spatial memory impairments: convergent evidence from two independently generated mouse mutant lines. Front. Behav. Neurosci. 5, 78 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Mabb, A. M., Judson, M. C., Zylka, M. J. & Philpot, B. D. Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes. Trends Neurosci. 34, 293–303 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. McNamara, G. I. & Isles, A. R. Dosage-sensitivity of imprinted genes expressed in the brain: 15q11–q13 and neuropsychiatric illness. Biochem. Soc. Trans. 41, 721–726 (2013).

    CAS  PubMed  Google Scholar 

  106. Greer, P. L. et al. The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 140, 704–716 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Fradin, D. et al. Parent-of-origin effects in autism identified through genome-wide linkage analysis of 16,000 SNPs. PLoS ONE 5, e12513 (2010).

    PubMed  PubMed Central  Google Scholar 

  108. Lamb, J. A. et al. Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects. J. Med. Genet. 42, 132–137 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Wang, F. et al. Bidirectional control of social hierarchy by synaptic efficacy in medial prefrontal cortex. Science 334, 693–697 (2011).

    CAS  PubMed  Google Scholar 

  110. Davis, J. F., Krause, E. G., Melhorn, S. J., Sakai, R. R. & Benoit, S. C. Dominant rats are natural risk takers and display increased motivation for food reward. Neuroscience 162, 23–30 (2009).

    CAS  PubMed  Google Scholar 

  111. Dent, C. L. & Isles, A. R. Brain-expressed imprinted genes and adult behaviour: the example of Nesp and Grb10. Mamm. Genome 25, 87–93 (2014).

    CAS  PubMed  Google Scholar 

  112. Plagge, A. et al. Imprinted Nesp55 influences behavioral reactivity to novel environments. Mol. Cell. Biol. 25, 3019–3026 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Haig, D. Genomic imprinting, sex-biased dispersal, and social behavior. Ann. NY Acad. Sci. 907, 149–163 (2000).

    CAS  PubMed  Google Scholar 

  114. Ubeda, F. & Gardner, A. A model for genomic imprinting in the social brain: juveniles. Evolution 64, 2587–2600 (2010).

    PubMed  Google Scholar 

  115. Berg, J. S. et al. Imprinted genes that regulate early mammalian growth are coexpressed in somatic stem cells. PLoS ONE 6, e26410 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Ferron, S. R. et al. Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis. Nature 475, 381–385 (2011). This paper shows that loss of imprinting in a brain subregion is required for neurogenesis, which indicates the importance of the control of expressed gene dosage for normal development.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Ratajczak, M. Z., Shin, D. M., Schneider, G., Ratajczak, J. & Kucia, M. Parental imprinting regulates insulin-like growth factor signaling: a Rosetta Stone for understanding the biology of pluripotent stem cells, aging and cancerogenesis. Leukemia 27, 773–779 (2013).

    CAS  PubMed  Google Scholar 

  118. Venkatraman, A. et al. Maternal imprinting at the H19–Igf2 locus maintains adult haematopoietic stem cell quiescence. Nature 500, 345–349 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Zacharek, S. J. et al. Lung stem cell self-renewal relies on BMI1-dependent control of expression at imprinted loci. Cell Stem Cell 9, 272–281 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Lim, D. H. & Maher, E. R. Genomic imprinting syndromes and cancer. Adv. Genet. 70, 145–175 (2010).

    CAS  PubMed  Google Scholar 

  121. Murrell, A. Genomic imprinting and cancer: from primordial germ cells to somatic cells. ScientificWorldJournal 6, 1999–1910 (2006).

    Google Scholar 

  122. Holm, T. M. et al. Global loss of imprinting leads to widespread tumorigenesis in adult mice. Cancer Cell 8, 275–285 (2005).

    CAS  PubMed  Google Scholar 

  123. Riordan, J. D. et al. Identification of Rtl1, a retrotransposon-derived imprinted gene, as a novel driver of hepatocarcinogenesis. PLoS Genet. 9, e1003441 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Huang, H. S. et al. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature 481, 185–189 (2011).

    PubMed  PubMed Central  Google Scholar 

  125. Babak, T. et al. Global survey of genomic imprinting by transcriptome sequencing. Curr. Biol. 18, 1735–1741 (2008).

    CAS  PubMed  Google Scholar 

  126. DeVeale, B., van der Kooy, D. & Babak, T. Critical evaluation of imprinted gene expression by RNA-seq: a new perspective. PLoS Genet. 8, e1002600 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Bradley, A. et al. The mammalian gene function resource: the International Knockout Mouse Consortium. Mamm. Genome 23, 580–586 (2012).

    PubMed  PubMed Central  Google Scholar 

  128. Brown, S. D. & Moore, M. W. The International Mouse Phenotyping Consortium: past and future perspectives on mouse phenotyping. Mamm. Genome 23, 632–640 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Murray, S. A., Eppig, J. T., Smedley, D., Simpson, E. M. & Rosenthal, N. Beyond knockouts: Cre resources for conditional mutagenesis. Mamm. Genome 23, 587–599 (2012).

    PubMed  PubMed Central  Google Scholar 

  130. Isles, A. R., Davies, W. & Wilkinson, L. S. Genomic imprinting and the social brain. Phil. Trans. R. Soc. B 361, 2229–2237 (2006).

    CAS  PubMed  Google Scholar 

  131. Kelsey, G. Imprinting on chromosome 20: tissue-specific imprinting and imprinting mutations in the GNAS locus. Am. J. Med. Genet. C. Semin. Med. Genet. 154C, 377–386 (2010).

    CAS  PubMed  Google Scholar 

  132. Williamson, C. M. et al. A cis-acting control region is required exclusively for the tissue-specific imprinting of Gnas. Nature Genet. 36, 894–899 (2004).

    CAS  PubMed  Google Scholar 

  133. Buiting, K. Prader–Willi syndrome and Angelman syndrome. Am. J. Med. Genet. C. Semin. Med. Genet. 154C, 365–376 (2010).

    CAS  PubMed  Google Scholar 

  134. Schaaf, C. P. et al. Truncating mutations of MAGEL2 cause Prader–Willi phenotypes and autism. Nature Genet. 45, 1405–1408 (2013).

    CAS  PubMed  Google Scholar 

  135. Cattanach, B. M. et al. A candidate model for Angelman syndrome in the mouse. Mamm. Genome 8, 472–478 (1997).

    CAS  PubMed  Google Scholar 

  136. Zhang, P. et al. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith–Wiedemann syndrome. Nature 387, 151–158 (1997).

    CAS  PubMed  Google Scholar 

  137. Mackay, D. J. & Temple, I. K. Transient neonatal diabetes mellitus type 1. Am. J. Med. Genet. C. Semin. Med. Genet. 154C, 335–342 (2010).

    CAS  PubMed  Google Scholar 

  138. Ma, D. et al. Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM. J. Clin. Invest. 114, 339–348 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. da Rocha, S. T., Edwards, C. A., Ito, M., Ogata, T. & Ferguson-Smith, A. C. Genomic imprinting at the mammalian Dlk1–Dio3 domain. Trends Genet. 24, 306–316 (2008).

    PubMed  Google Scholar 

  140. Kagami, M. et al. Paternal uniparental disomy 14 and related disorders: placental gene expression analyses and histological examinations. Epigenetics 7, 1142–1150 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Williamson, C. M. et al. Imprinting of distal mouse chromosome 2 is associated with phenotypic anomalies in utero. Genet. Res. 72, 255–265 (1998).

    CAS  PubMed  Google Scholar 

  142. Yu, S. et al. Variable and tissue-specific hormone resistance in heterotrimeric Gs protein α-subunit (Gsα) knockout mice is due to tissue-specific imprinting of the Gsα gene. Proc. Natl Acad. Sci. USA 95, 8715–8720 (1998).

    CAS  PubMed  Google Scholar 

  143. Eaton, S. A. et al. New mutations at the imprinted Gnas cluster show gene dosage effects of Gsα in postnatal growth and implicate XLαs in bone and fat metabolism but not in suckling. Mol. Cell. Biol. 32, 1017–1029 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Bush, J. R. & Wevrick, R. Loss of the Prader–Willi obesity syndrome protein necdin promotes adipogenesis. Gene 497, 45–51 (2012).

    CAS  PubMed  Google Scholar 

  145. Tennese, A. A. & Wevrick, R. Impaired hypothalamic regulation of endocrine function and delayed counterregulatory response to hypoglycemia in Magel2-null mice. Endocrinology 152, 967–978 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Skryabin, B. V. et al. Deletion of the MBII-85 snoRNA gene cluster in mice results in postnatal growth retardation. PLoS Genet. 3, e235 (2007).

    PubMed  PubMed Central  Google Scholar 

  147. Jones, B. K., Levorse, J. & Tilghman, S. M. Deletion of a nuclease-sensitive region between the Igf2 and H19 genes leads to Igf2 misregulation and increased adiposity. Hum. Mol. Genet. 10, 807–814 (2001).

    CAS  PubMed  Google Scholar 

  148. Clapcott, S. J., Peters, J., Orban, P. C., Brambilla, R. & Graham, C. F. Two ENU-induced mutations in Rasgrf1 and early mouse growth retardation. Mamm. Genome 14, 495–505 (2003).

    CAS  PubMed  Google Scholar 

  149. Smith, F. M. et al. Mice with a disruption of the imprinted Grb10 gene exhibit altered body composition, glucose homeostasis, and insulin signaling during postnatal life. Mol. Cell. Biol. 27, 5871–5886 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Cattanach, B. M., Beechey, C. V., Rasberry, C., Jones, J. & Papworth, D. Time of initiation and site of action of the mouse chromosome 11 imprinting effects. Genet. Res. 68, 35–44 (1996).

    CAS  PubMed  Google Scholar 

  151. Shiura, H. et al. Meg1/Grb10 overexpression causes postnatal growth retardation and insulin resistance via negative modulation of the IGF1R and IR cascades. Biochem. Biophys. Res. Commun. 329, 909–916 (2005).

    CAS  PubMed  Google Scholar 

  152. Shiura, H. et al. Paternal deletion of Meg1/Grb10 DMR causes maternalization of the Meg1/Grb10 cluster in mouse proximal chromosome 11 leading to severe pre- and postnatal growth retardation. Hum. Mol. Genet. 18, 1424–1438 (2009).

    CAS  PubMed  Google Scholar 

  153. Hernandez, A., Martinez, M. E., Fiering, S., Galton, V. A. & St Germain, D. Type 3 deiodinase is critical for the maturation and function of the thyroid axis. J. Clin. Invest. 116, 476–484 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author thanks B. Cattanach, G. Moore, A. Plagge and V. Tucci for discussions and comments. Given the broad scope of this Review, the author apologizes to colleagues whose work was not cited owing to space limitations.

Author information

Authors and Affiliations

  1. Medical Research Council Mammalian Genetics Unit, Harwell Science and Innovation Campus, OX11 0RD, Oxfordshire, UK

    Jo Peters

Authors
  1. Jo Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jo Peters.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

PowerPoint slides

Glossary

Pronuclear

Pertaining to the pronucleus (that is, the haploid nucleus from a male or female gamete).

Gene dosage

The number of expressed copies of a gene in a cell.

CCCTC-binding factor

(CTCF). A highly conserved zinc-finger protein that influences chromatin organization and architecture; it is implicated in diverse regulatory functions, including transcriptional activation, repression and insulation.

Epigenetic

Pertaining to heritable but potentially reversible changes in gene expression that are caused by mechanisms other than changes in the underlying DNA sequence.

Uniparental disomy

(UPD). A cellular or organismal phenomenon in which both chromosome homologues are derived from one parent and none from the other parent. It can be the result of fertilization that involves a disomic gamete and a gamete that is nullisomic for the homologue.

Metabolic syndrome

A group of metabolic conditions that occur together and that increase the risk of developing cardiovascular disease, stroke and diabetes.

Metabolic programming

The response to adverse conditions during early development that results in resetting of metabolic responses and predisposition to metabolic syndrome in adulthood.

Rapid eye movement

(REM). A phase of sleep that is characterized by rapid and random movement of the eyes, low muscle tone and a rapid low-voltage electroencephalogram. It is associated with dreaming, and many brain areas are active during REM sleep.

Non-REM

(NREM). A phase of sleep that is characterized by slow or no eye movement. Non-REM sleep is divided into three stages, which have distinct brain wave patterns, and deep or slow wave sleep occurs in stage three. There is relatively little dreaming in non-REM sleep.

Fear conditioning

A behavioural paradigm in which organisms learn to predict adverse events.

Facial barbering

The trimming and plucking of the whiskers and fur of one mouse by another.

Tube test

A test of social dominance in which two unfamiliar mice are placed head first at opposite ends of a tube. The socially dominant mouse remains in the tube, whereas the more submissive mouse retreats from the tube.

Complete hydatidiform mole

A conceptus that lacks a set of normal maternal chromosomes and that forms a tumour-like mass. Known causes include a failure to set imprints in the female germ line and the occurrence of a conceptus that has both sets of chromosomes of paternal origin.

Epimutations

Mutations that result in heritable changes in gene expression that are caused by mechanisms other than changes in the underlying DNA sequence.

Retrotransposon

A genetic element that can be transposed to a new site in the genome by forming an RNA transcript that can be copied to DNA using reverse transcriptase, which can then be integrated into the genome.

Reciprocal hybrids

F1 hybrid mice produced from reciprocal crosses between two mouse strains or between Mus musculus subspecies.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Peters, J. The role of genomic imprinting in biology and disease: an expanding view. Nat Rev Genet 15, 517–530 (2014). https://doi.org/10.1038/nrg3766

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg3766

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing