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.
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.
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McGrath, J. & Solter, D. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37, 179–183 (1984).
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.
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.
Searle, A. G. & Beechey, C. V. Complementation studies with mouse translocations. Cytogenet. Cell Genet. 20, 282–303 (1978).
Snell, G. D. An analysis of translocations in the mouse. Genetics 31, 157–180 (1946).
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.
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).
Bartolomei, M. S., Zemel, S. & Tilghman, S. M. Parental imprinting of the mouse H19 gene. Nature 351, 153–155 (1991).
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.
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).
Moore, T. & Haig, D. Genomic imprinting in mammalian development: a parental tug-of-war. Trends Genet. 7, 45–49 (1991).
Keverne, E. B. & Curley, J. P. Epigenetics, brain evolution and behaviour. Front. Neuroendocrinol. 29, 398–412 (2008).
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).
Barlow, D. P. Genomic imprinting: a mammalian epigenetic discovery model. Annu. Rev. Genet. 45, 379–403 (2011).
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).
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.
Sanz, L. A. et al. A mono-allelic bivalent chromatin domain controls tissue-specific imprinting at Grb10. EMBO J. 27, 2523–2532 (2008).
Chotalia, M. et al. Transcription is required for establishment of germline methylation marks at imprinted genes. Genes Dev. 23, 105–117 (2009).
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).
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).
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).
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.
Williamson, C. M. et al. Uncoupling antisense-mediated silencing and DNA methylation in the imprinted Gnas cluster. PLoS Genet. 7, e1001347 (2011).
Lee, J. T. & Bartolomei, M. S. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell 152, 1308–1323 (2013).
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.
Latos, P. A. et al. Airn transcriptional overlap, but not its lncRNA products, induces imprinted Igf2r silencing. Science 338, 1469–1472 (2012).
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.
Bell, A. C. & Felsenfeld, G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405, 482–485 (2000).
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.
Reik, W. et al. Regulation of supply and demand for maternal nutrients in mammals by imprinted genes. J. Physiol. 547, 35–44 (2003).
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).
Guillemot, F. et al. Genomic imprinting of Mash2, a mouse gene required for trophoblast development. Nature Genet. 9, 235–242 (1995).
Guillemot, F., Nagy, A., Auerbach, A., Rossant, J. & Joyner, A. L. Essential role of Mash-2 in extraembryonic development. Nature 371, 333–336 (1994).
Ono, R. et al. Deletion of Peg10, an imprinted gene acquired from a retrotransposon, causes early embryonic lethality. Nature Genet. 38, 101–106 (2006).
Constancia, M. et al. Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 417, 945–948 (2002).
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).
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).
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).
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).
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).
Brodsky, D. & Christou, H. Current concepts in intrauterine growth restriction. J. Intensive Care Med. 19, 307–319 (2004).
Ishida, M. & Moore, G. E. The role of imprinted genes in humans. Mol. Aspects Med. 34, 826–840 (2013).
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).
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).
Lefebvre, L. et al. Abnormal maternal behaviour and growth retardation associated with loss of the imprinted gene Mest. Nature Genet. 20, 163–169 (1998).
Plagge, A. et al. The imprinted signaling protein XLαs is required for postnatal adaptation to feeding. Nature Genet. 36, 818–826 (2004).
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.
Cattanach, B. M., Peters, J., Ball, S. & Rasberry, C. Two imprinted gene mutations: three phenotypes. Hum. Mol. Genet. 9, 2263–2273 (2000).
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).
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).
Ball, S. T. et al. Gene dosage effects at the imprinted cluster. PLoS ONE 8, e65639 (2013).
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).
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).
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).
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).
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).
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).
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).
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).
Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).
Peters, J. et al. Imprinting control within the compact Gnas locus. Cytogenet. Genome Res. 113, 194–201 (2006).
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).
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).
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.
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).
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).
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.
Haig, D. Huddling: brown fat, genomic imprinting and the warm inner glow. Curr. Biol. 18, R172–R174 (2008).
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).
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).
Fan, W. et al. The central melanocortin system can directly regulate serum insulin levels. Endocrinology 141, 3072–3079 (2000).
Obici, S. et al. Central melanocortin receptors regulate insulin action. J. Clin. Invest. 108, 1079–1085 (2001).
Fujiwara, K. et al. Necdin controls proliferation of white adipocyte progenitor cells. PLoS ONE 7, e30948 (2012).
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).
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).
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).
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).
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.
Ding, F. et al. snoRNA Snord116 (Pwcr1/MBII-85) deletion causes growth deficiency and hyperphagia in mice. PLoS ONE 3, e1709 (2008).
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).
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).
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).
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).
Krechowec, S. & Plagge, A. Physiological dysfunctions associated with mutations of the imprinted Gnas locus. Physiol. (Bethesda) 23, 221–229 (2008).
Howell, J. J. & Manning, B. D. mTOR couples cellular nutrient sensing to organismal metabolic homeostasis. Trends Endocrinol. Metab. 22, 94–102 (2011).
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).
Yu, Y. et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332, 1322–1326 (2011).
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).
Srinivasan, M. & Patel, M. S. Metabolic programming in the immediate postnatal period. Trends Endocrinol. Metab. 19, 146–152 (2008).
Wilkinson, L. S., Davies, W. & Isles, A. R. Genomic imprinting effects on brain development and function. Nature Rev. Neurosci. 8, 832–843 (2007).
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).
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).
Bastepe, M. Relative functions of Gαs and its extra-large variant XLαs in the endocrine system. Horm. Metab. Res. 44, 732–740 (2012).
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).
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).
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).
Wilkins, J. F. & Haig, D. Inbreeding, maternal care and genomic imprinting. J. Theor. Biol. 221, 559–564 (2003).
McNamara, P., Dowdall, J. & Auerbach, S. REM sleep, early experience, and the development of reproductive strategies. Human Nature 13, 405–435 (2002).
Kozlov, S. V. et al. The imprinted gene Magel2 regulates normal circadian output. Nature Genet. 39, 1266–1272 (2007).
Powell, W. T. et al. A Prader–Willi locus lncRNA cloud modulates diurnal genes and energy expenditure. Hum. Mol. Genet. 22, 4318–4328 (2013).
Williams, C. A. et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am. J. Med. Genet. A 140A, 413–418 (2006).
Krauchi, K. & Deboer, T. The interrelationship between sleep regulation and thermoregulation. Front. Biosci. (Landmark Ed) 15, 604–625 (2010).
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).
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).
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).
Greer, P. L. et al. The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 140, 704–716 (2010).
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).
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).
Wang, F. et al. Bidirectional control of social hierarchy by synaptic efficacy in medial prefrontal cortex. Science 334, 693–697 (2011).
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).
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).
Plagge, A. et al. Imprinted Nesp55 influences behavioral reactivity to novel environments. Mol. Cell. Biol. 25, 3019–3026 (2005).
Haig, D. Genomic imprinting, sex-biased dispersal, and social behavior. Ann. NY Acad. Sci. 907, 149–163 (2000).
Ubeda, F. & Gardner, A. A model for genomic imprinting in the social brain: juveniles. Evolution 64, 2587–2600 (2010).
Berg, J. S. et al. Imprinted genes that regulate early mammalian growth are coexpressed in somatic stem cells. PLoS ONE 6, e26410 (2011).
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.
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).
Venkatraman, A. et al. Maternal imprinting at the H19–Igf2 locus maintains adult haematopoietic stem cell quiescence. Nature 500, 345–349 (2013).
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).
Lim, D. H. & Maher, E. R. Genomic imprinting syndromes and cancer. Adv. Genet. 70, 145–175 (2010).
Murrell, A. Genomic imprinting and cancer: from primordial germ cells to somatic cells. ScientificWorldJournal 6, 1999–1910 (2006).
Holm, T. M. et al. Global loss of imprinting leads to widespread tumorigenesis in adult mice. Cancer Cell 8, 275–285 (2005).
Riordan, J. D. et al. Identification of Rtl1, a retrotransposon-derived imprinted gene, as a novel driver of hepatocarcinogenesis. PLoS Genet. 9, e1003441 (2013).
Huang, H. S. et al. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature 481, 185–189 (2011).
Babak, T. et al. Global survey of genomic imprinting by transcriptome sequencing. Curr. Biol. 18, 1735–1741 (2008).
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).
Bradley, A. et al. The mammalian gene function resource: the International Knockout Mouse Consortium. Mamm. Genome 23, 580–586 (2012).
Brown, S. D. & Moore, M. W. The International Mouse Phenotyping Consortium: past and future perspectives on mouse phenotyping. Mamm. Genome 23, 632–640 (2012).
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).
Isles, A. R., Davies, W. & Wilkinson, L. S. Genomic imprinting and the social brain. Phil. Trans. R. Soc. B 361, 2229–2237 (2006).
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).
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).
Buiting, K. Prader–Willi syndrome and Angelman syndrome. Am. J. Med. Genet. C. Semin. Med. Genet. 154C, 365–376 (2010).
Schaaf, C. P. et al. Truncating mutations of MAGEL2 cause Prader–Willi phenotypes and autism. Nature Genet. 45, 1405–1408 (2013).
Cattanach, B. M. et al. A candidate model for Angelman syndrome in the mouse. Mamm. Genome 8, 472–478 (1997).
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).
Mackay, D. J. & Temple, I. K. Transient neonatal diabetes mellitus type 1. Am. J. Med. Genet. C. Semin. Med. Genet. 154C, 335–342 (2010).
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).
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).
Kagami, M. et al. Paternal uniparental disomy 14 and related disorders: placental gene expression analyses and histological examinations. Epigenetics 7, 1142–1150 (2012).
Williamson, C. M. et al. Imprinting of distal mouse chromosome 2 is associated with phenotypic anomalies in utero. Genet. Res. 72, 255–265 (1998).
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).
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).
Bush, J. R. & Wevrick, R. Loss of the Prader–Willi obesity syndrome protein necdin promotes adipogenesis. Gene 497, 45–51 (2012).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.
The author declares no competing financial interests.
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.
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.
(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.
Mutations that result in heritable changes in gene expression that are caused by mechanisms other than changes in the underlying DNA sequence.
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.
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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
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