Evolution of Imprinting: Imprinted Gene Function in Human Disease


A subset of genes in mammals, known as imprinted genes, show a conditional expression strategy in which transcription depends on an allele's parental origin. Several explanations have been advanced to explain this phenomenon and these, with varying levels of success, predict the functions of imprinted genes. After outlining these explanations, we summarize what is known about human genetic disorders involving abnormal expression of imprinted genes and ask what this can tell us about the evolution of imprinting.

Keywords: imprinting; kinship; sexual conflict; human behaviour; growth disorders


Abu Allhaija ES and Al‐Khateeb SN (2005) Uvulo‐glosso‐pharyngeal dimensions in different anteroposterior skeletal patterns. The Angle Orthodontist 75(6): 1012–1018.

Abu‐Amero S, Monk D, Frost J et al. (2007) The genetic aetiology of Silver–Russell syndrome. Journal of Medical Genetics [Epub ahead of print] doi:10.1136/jmg.2007.053017.

Allen ND, Logan K, Lally G et al. (1995) Distribution of parthenogenetic cells in the mouse brain and their influence on brain development and behavior. Proceedings of the National Academy of Sciences of the USA 92(23): 10782–10786.

Apostolidou S, Abu‐Amero S, O'Donoghue K et al. (2007) Elevated placental expression of the imprinted PHLDA2 gene is associated with low birth weight. Journal of Molecular Medicine 85(4): 379–387.

Arnaud P, Monk D, Hitchins M et al. (2003) Conserved methylation imprints in the human and mouse GRB10 genes with divergent allelic expression suggests differential reading of the same mark. Human Molecular Genetics 12(9): 1005–1019.

Badcock C and Crespi B (2006) Imbalanced genomic imprinting in brain development: an evolutionary basis for the aetiology of autism. Journal of Evolutionary Biology 19(4): 1007–1032.

Barlow DP (1993) Methylation and imprinting: from host defense to gene regulation? Science 260(5106): 309–310.

Barlow DP, Stoger R, Herrmann BG, Saito K and Schweifer N (1991) The mouse insulin‐like growth factor type‐2 receptor is imprinted and closely linked to the Tme locus. Nature 349(6304): 84–87.

Beaudet AL and Jiang YH (2002) A rheostat model for a rapid and reversible form of imprinting‐dependent evolution. American Journal of Human Genetics 70(6): 1389–1397.

Beechey CV, Cattanach BM, Blake A and Peters J (2007) MRC Mammalian Genetics Unit, Harwell, Oxfordshire. World Wide Web Site – Mouse Imprinting Data and References. http://www.mgu.har.mrc.ac.uk/research/imprinting/

Bittel DC and Butler MG (2005) Prader–Willi syndrome: clinical genetics, cytogenetics and molecular biology. Expert Reviews in Molecular Medicine 7(14): 1–20.

Bliek J, Terhal P, van den Bogaard MJ et al. (2006) Hypomethylation of the H19 gene causes not only Silver–Russell syndrome (SRS) but also isolated asymmetry or an SRS‐like phenotype. American Journal of Human Genetics 78(4): 604–614.

Bourc'his D and Bestor TH (2004) Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431(7004): 96–99.

Bourc'his D, Xu GL, Lin CS, Bollman B and Bestor TH (2001) Dnmt3L and the establishment of maternal genomic imprints. Science 294(5551): 2536–2539.

Brown WM and Consedine NS (2004) Just how happy is the happy puppet? An emotion signaling and kinship theory perspective on the behavioral phenotype of children with Angelman syndrome. Medical Hypotheses 63(3): 377–385.

Caspary T, Cleary MA, Perlman EJ et al. (1999) Oppositely imprinted genes p57(Kip2) and igf2 interact in a mouse model for Beckwith–Wiedemann syndrome. Genes and Development 13(23): 3115–3124.

Cattanach BM and Kirk M (1985) Differential activity of maternally and paternally derived chromosome regions in mice. Nature 315(6019): 496–498.

Charalambous M, Smith FM, Bennett WR et al. (2003) Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2‐independent mechanism. Proceedings of the National Academy of Sciences of the USA 100(14): 8292–8297.

Cheron G, Servais L, Wagstaff J and Dan B (2005) Fast cerebellar oscillation associated with ataxia in a mouse model of Angelman syndrome. Neuroscience 130(3): 631–637.

Cooper WN, Luharia A, Evans GA et al. (2005) Molecular subtypes and phenotypic expression of Beckwith–Wiedemann syndrome. European Journal of Human Genetics 13(9): 1025–1032.

Crespi B and Semeniuk C (2004) Parent–offspring conflict in the evolution of vertebrate reproductive mode. The American Naturalist 163(5): 635–653.

Curley JP, Barton S, Surani A and Keverne EB (2004) Coadaptation in mother and infant regulated by a paternally expressed imprinted gene. Proceedings of the Royal Society of London Series B – Biological Sciences 271: 1303–1309.

Davies SJ and Hughes HE (1993) Imprinting in Albright's hereditary osteodystrophy. Journal of Medical Genetics 30(2): 101–103.

Davies W, Isles A, Smith R et al. (2005) Xlr3b is a new imprinted candidate for X‐linked parent‐of‐origin effects on cognitive function in mice. Nature Genetics 37(6): 625–629.

Day T and Bonduriansky R (2004) Intralocus sexual conflict can drive the evolution of genomic imprinting. Genetics 167(4): 1537–1546.

DeChiara TM, Robertson EJ and Efstratiadis A (1991) Parental imprinting of the mouse insulin‐like growth factor II gene. Cell 64(4): 849–859.

Dittrich B, Buiting K, Korn B et al. (1996) Imprint switching on human chromosome 15 may involve alternative transcripts of the SNRPN gene. Nature Genetics 14(2): 163–170.

Edwards CA and Ferguson‐Smith AC (2007) Mechanisms regulating imprinted genes in clusters. Current Opinion in Cell Biology 19(3): 281–289.

Engel JR, Smallwood A, Harper A et al. (2000) Epigenotype–phenotype correlations in Beckwith–Wiedemann syndrome. Journal of Medical Genetics 37(12): 921–926.

Filson AJ, Louvi A, Efstratiadis A and Robertson EJ (1993) Rescue of the T‐associated maternal effect in mice carrying null mutations in Igf‐2 and Igf2r, two reciprocally imprinted genes. Development 118(3): 731–736.

Fisher AM, Thomas NS, Cockwell A et al. (2002) Duplications of chromosome 11p15 of maternal origin result in a phenotype that includes growth retardation. Human Genetics 111(3): 290–296.

Frank D, Fortino W, Clark L et al. (2002) Placental overgrowth in mice lacking the imprinted gene Ipl. Proceedings of the National Academy of Sciences of the USA 99(11): 7490–7495.

Genevieve D, Sanlaville D, Faivre L et al. (2005) Paternal deletion of the GNAS imprinted locus (including Gnasxl) in two girls presenting with severe pre‐ and post‐natal growth retardation and intractable feeding difficulties. European Journal of Human Genetics 13(9): 1033–1039.

Geuns E, De Temmerman N, Hilven P et al. (2007) Methylation analysis of the intergenic differentially methylated region of DLK1‐GTL2 in human. European Journal of Human Genetics 15(3): 352–361.

Gicquel C, Rossignol S, Cabrol S et al. (2005) Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver–Russell syndrome. Nature Genetics 37(9): 1003–1007.

Gimelbrant A, Hutchinson JN, Thompson BR and Chess A (2007) Widespread monoallelic expression on human autosomes. Science 318(5853): 1136–1140.

Goos LM and Silverman I (2006) The inheritance of cognitive skills: does genomic imprinting play a role? Journal of Neurogenetics 20(1–2): 19–40.

Grandjean V, Smith J, Schofield PN and Ferguson‐Smith AC (2000) Increased IGF‐II protein affects p57kip2 expression in vivo and in vitro: implications for Beckwith–Wiedemann syndrome. Proceedings of the National Academy of Sciences of the USA 97(10): 5279–5284.

Haig D (1994) Refusing the ovarian time bomb. Trends in Genetics 10(10): 346–347, author reply 348–349.

Haig D (2000) The kinship theory of genomic imprinting. Annual Review of Ecology and Systematics 31: 9–32.

Haig D (2004) Evolutionary conflicts in pregnancy and calcium metabolism – a review. Placenta 25(suppl. A): S10–S15.

Haig D and Westoby M (1989) Parent‐specific gene expression and the triploid endosperm. American Naturalist 134(1): 147–155.

Haig D and Westoby M (2006) An earlier formulation of the genetic conflict hypothesis of genomic imprinting. Nature Genetics 38(3): 271.

Haig D and Wharton R (2003) Prader–Willi syndrome and the evolution of human childhood. American Journal of Human Biology 15(3): 320–329.

Haig D and Wilkins JF (2000) Genomic imprinting, sibling solidarity and the logic of collective action. Philosophical transactions of the Royal Society of London. Series B: Biological Sciences 355(1403): 1593–1597.

Hamilton WD (1964) The genetical evolution of social behaviour. Parts I and II. Journal of Theoretical Biology 7(1): 1–52.

Hayward BE, De Vos M, Judson H et al. (2003) Lack of involvement of known DNA methyltransferases in familial hydatidiform mole implies the involvement of other factors in establishment of imprinting in the human female germline. BMC Genetics 4: 2.

Hayward BE, Moran V, Strain L and Bonthron DT (1998) Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins. Proceedings of the National Academy of Sciences of the USA 95(26): 15475–15480.

Hurst LD and McVean GT (1997) Growth effects of uniparental disomies and the conflict theory of genomic imprinting. Trends in Genetics 13(11): 436–443.

Iwasa Y (1998) The conflict theory of genomic imprinting: how much can be explained? Current Topics in Developmental Biology 40: 255–293.

Iwasa Y and Pomiankowski A (1999) Sex specific X chromosome expression caused by genomic imprinting. Journal of Theoretical Biology 197(4): 487–495.

Iwasa Y and Pomiankowski A (2001) The evolution of X‐linked genomic imprinting. Genetics 158(4): 1801–1809.

Jelinic P and Shaw P (2007) Loss of imprinting and cancer. Journal of Pathology 211(3): 261–268.

Kagami M, Nishimura G, Okuyama T et al. (2005) Segmental and full paternal isodisomy for chromosome 14 in three patients: narrowing the critical region and implication for the clinical features. American Journal of Medical Genetics Part A 138(2): 127–132.

Kagami M, Sekita Y, Nishimura G et al. (2008) Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)‐like phenotypes. Nature Genetics 40(2): 237–242.

Keverne EB, Fundele R, Narasimha M, Barton SC and Surani MA (1996) Genomic imprinting and the differential roles of parental genomes in brain development. Brain Research. Developmental Brain Research 92(1): 91–100.

Kishore S and Stamm S (2006) The snoRNA HBII‐52 regulates alternative splicing of the serotonin receptor 2C. Science 311(5758): 230–232.

Lalande M and Calciano MA (2007) Molecular epigenetics of Angelman syndrome. Cellular and Molecular Life Sciences 64(7–8): 947–960.

Lefebvre L, Viville S, Barton SC et al. (1998) Abnormal maternal behaviour and growth retardation associated with loss of the imprinted gene Mest. Nature Genetics 20(2): 163–169.

Li L, Keverne EB, Aparicio SA et al. (1999) Regulation of maternal behavior and offspring growth by paternally expressed Peg3. Science 284(5412): 330–333.

Lloyd VK, Sinclair DA and Grigliatti TA (1999) Genomic imprinting and position‐effect variegation in Drosophila melanogaster. Genetics 151(4): 1503–1516.

Long DN, McGuire S, Levine MA, Weinstein LS and Germain‐Lee EL (2007) Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) in the development of human obesity. Journal of Clinical Endocrinology and Metabolism 92(3): 1073–1079.

Lossie AC, Whitney MM, Amidon D et al. (2001) Distinct phenotypes distinguish the molecular classes of Angelman syndrome. Journal of Medical Genetics 38(12): 834–845.

Ma D, Shield JP, Dean W et al. (2004) Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM. Journal of Clinical Investigation 114(3): 339–348.

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

McMinn J, Wei M, Schupf N et al. (2006) Unbalanced placental expression of imprinted genes in human intrauterine growth restriction. Placenta 27(6–7): 540–549.

Meguro M, Mitsuya K, Sui H et al. (1997) Evidence for uniparental, paternal expression of the human GABAA receptor subunit genes, using microcell‐mediated chromosome transfer. Human Molecular Genetics 6(12): 2127–2133.

Milunsky J, Huang XL, Wyandt HE and Milunsky A (1999) Schizophrenia susceptibility gene locus at Xp22.3. Clinical Genetics 55(6): 455–460.

Monk D, Arnaud P, Apostolidou S et al. (2006) Limited evolutionary conservation of imprinting in the human placenta. Proceedings of the National Academy of Sciences of the USA 103(17): 6623–6628.

Moon YS, Smas CM, Lee K et al. (2002) Mice lacking paternally expressed Pref‐1/Dlk1 display growth retardation and accelerated adiposity. Molecular and cellular biology 22(15): 5585–5592.

Moore T and Haig D (1991) Genomic imprinting in mammalian development: a parental tug‐of‐war. Trends in Genetics 7(2): 45–49.

Nowaczyk MJ, Carter MT, Xu J et al. (2008) Paternal deletion 6q24.3: a new congenital anomaly syndrome associated with intrauterine growth failure, early developmental delay and characteristic facial appearance. American Journal of Medical Genetics A 146(3): 354–360.

Oliver C, Horsler K, Berg K et al. (2007) Genomic imprinting and the expression of affect in Angelman syndrome: what's in the smile? Journal of Child Psychology and Psychiatry 48(6): 571–579.

Ono R, Nakamura K, Inoue K et al. (2006) Deletion of Peg10, an imprinted gene acquired from a retrotransposon, causes early embryonic lethality. Nature Genetics 38(1): 101–106.

Plagge A, Gordon E, Dean W et al. (2004) The imprinted signaling protein XL alpha s is required for postnatal adaptation to feeding. Nature Genetics 36(8): 818–826.

Plagge A, Isles AR, Gordon E et al. (2005) Imprinted Nesp55 influences behavioral reactivity to novel environments. Molecular and Cellular Biology 25(8): 3019–3026.

Raefski AS and O'Neill MJ (2005) Identification of a cluster of X‐linked imprinted genes in mice. Nature Genetics 37(6): 620–624.

Schaefer CB, Ooi SK, Bestor TH and Bourc'his D (2007) Epigenetic decisions in mammalian germ cells. Science 316(5823): 398–399.

Schonherr N, Meyer E, Roos A et al. (2007) The centromeric 11p15 imprinting centre is also involved in Silver–Russell syndrome. Journal of Medical Genetics 44(1): 59–63.

Sekita Y, Wagatsuma H, Nakamura K et al. (2008) Role of retrotransposon‐derived imprinted gene, Rtl1, in the feto‐maternal interface of mouse placenta. Nature Genetics 40(2): 243–248.

Skuse DH, James RS, Bishop DV et al. (1997) Evidence from Turner's syndrome of an imprinted X‐linked locus affecting cognitive function. Nature 387(6634): 705–708.

Sleutels F and Barlow DP (2002) The origins of genomic imprinting in mammals. Advances in Genetics 46: 119–163.

Smith FM, Garfield AS and Ward A (2006) Regulation of growth and metabolism by imprinted genes. Cytogenetic and Genome Research 113(1–4): 279–291.

Solter D (1988) Differential imprinting and expression of maternal and paternal genomes. Annual Review of Genetics 22: 127–146.

Surani MA, Barton SC and Norris ML (1984) Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 308(5959): 548–550.

Sutton VR and Shaffer LG (2000) Search for imprinted regions on chromosome 14: comparison of maternal and paternal UPD cases with cases of chromosome 14 deletion. American Journal of Medical Genetics 93(5): 381–387.

Temple IK and Shield JP (2002) Transient neonatal diabetes, a disorder of imprinting. Journal of Medical Genetics 39(12): 872–875.

Thomas NS, Sharp AJ, Browne CE et al. (1999) Xp deletions associated with autism in three females. Human Genetics 104(1): 43–48.

Thornhill AR and Burgoyne PS (1993) A paternally imprinted X chromosome retards the development of the early mouse embryo. Development 118(1): 171–174.

Trivers RL (1974) Parent–offspring conflict. American Zoologist 14(1): 249–264.

Tycko B and Morison IM (2002) Physiological functions of imprinted genes. Journal of Cellular Physiology 192(3): 245–258.

Umlauf D, Goto Y, Cao R et al. (2004) Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes. Nature Genetics 36(12): 1296–1300.

Varmuza S and Mann M (1994) Genomic imprinting – defusing the ovarian time bomb. Trends in Genetics 10(4): 118–123.

Varrault A, Gueydan C, Delalbre A et al. (2006) Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth. Developmental Cell 11(5): 711–722.

Wagschal A and Feil R (2006) Genomic imprinting in the placenta. Cytogenetic and Genome Research 113(1–4): 90–98.

Wang ZQ, Fung MR, Barlow DP and Wagner EF (1994) Regulation of embryonic growth and lysosomal targeting by the imprinted Igf2/Mpr gene. Nature 372(6505): 464–467.

Webster KE, O'Bryan MK, Fletcher S et al. (2005) Meiotic and epigenetic defects in Dnmt3L‐knockout mouse spermatogenesis. Proceedings of the National Academy of Sciences of the USA 102(11): 4068–4073.

Weisstein AE and Spencer HG (2003) The evolution of genomic imprinting via variance minimization: an evolutionary genetic model. Genetics 165(1): 205–222.

Wells JC (2007) Sexual dimorphism of body composition. Best Practice and Research Clinical Endocrinology and Metabolism 21(3): 415–430.

Wilkin TJ and Murphy MJ (2006) The gender insulin hypothesis: why girls are born lighter than boys, and the implications for insulin resistance. International Journal of Obesity 30(7): 1056–1061.

Wilkins JF (2006) Tissue‐specific reactivation of gene expression at an imprinted locus. Journal of Theoretical Biology 240(2): 277–287.

Wilkins JF and Haig D (2003a) Inbreeding, maternal care and genomic imprinting. Journal of Theoretical Biology 221(4): 559–564.

Wilkins JF and Haig D (2003b) What good is genomic imprinting: the function of parent‐specific gene expression. Nature Reviews. Genetics 4(5): 359–368.

Wolf JB and Hager R (2006) A maternal‐offspring coadaptation theory for the evolution of genomic imprinting. PLoS Biology 4(12): e380.

Wood AJ and Oakey RJ (2006) Genomic imprinting in mammals: emerging themes and established theories. PLoS Genetics 2(11): e147.

Yu S, Yu D, Lee E et al. (1998) Variable and tissue‐specific hormone resistance in heterotrimeric Gs protein alpha‐subunit (Gsalpha) knockout mice is due to tissue‐specific imprinting of the gsalpha gene. Proceedings of the National Academy of Sciences of the USA 95(15): 8715–8720.

Further Reading

Burt A and Trivers R (2006) Genes in Conflict. Chapter 4: Genomic Imprinting, pp. 96–141. Cambridge, MA: The Belnap Press of Harvard University Press.

Feil R and Berger F (2007) Convergent evolution of genomic imprinting in plants and mammals. Trends in Genetics 23(4): 192–199.

Haig D (2004) Genomic imprinting and kinship: how good is the evidence? Annual Review of Genetics 38: 553–585.

Keverne EB (2007) Genomic imprinting and the evolution of sex differences in mammalian reproductive strategies. Advances in Genetics 59: 217–243.

Pardo‐Manuel de Villena F, de la Casa‐Esperon E and Sapienza C (2000) Natural selection and the function of genome imprinting: beyond the silenced minority. Trends in Genetics 16(12): 573–579.

Tilghman SM (1999) The sins of the fathers and mothers: genomic imprinting in mammalian development. Cell 96(2): 185–193.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Dickins, Benjamin JA, and Kelsey, Gavin(Jul 2008) Evolution of Imprinting: Imprinted Gene Function in Human Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021014]