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:

Imprinted genes and the manipulation of parenting in mammals

Abstract

Genomic imprinting refers to the parent-of-origin expression of genes, which originates from epigenetic events in the mammalian germ line. The evolution of imprinting may reflect a conflict over resource allocation early in life, with silencing of paternal genes in offspring soliciting increased maternal provision and silencing of maternal genes limiting demands on the mother. Parental caregiving has been identified as an area of potential conflict, with several imprinted genes serendipitously found to directly influence the quality of maternal care. Recent systems biology approaches, based on single-cell RNA sequencing data, support a more deliberate relationship, which is reinforced by the finding that imprinted genes expressed in the offspring influence the quality of maternal caregiving. These bidirectional, reiterative relationships between parents and their offspring are critical both for short-term survival and for lifelong wellbeing, with clear implications for human health.

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

Access options

Buy this article

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

Fig. 1: Overall maternal investment and the emergence of genomic imprinting in vertebrates.
Fig. 2: Parenting neural circuitry and suspected imprinted gene action.
Fig. 3: Imprinted genes experimentally demonstrated to affect parenting.

Similar content being viewed by others

References

  1. John, R. M., Lefebvre, L. & Surani, M. A. in Epigenetic Epidemiology (ed. Michels, K. B.) 171–212 (Springer, 2022).

  2. Pires, N. D. & Grossniklaus, U. Different yet similar: evolution of imprinting in flowering plants and mammals. F1000Prime Rep. 6, 63 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hanna, C. W. & Kelsey, G. Genomic imprinting beyond DNA methylation: a role for maternal histones. Genome Biol. 18, 177 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ferguson-Smith, A. C. Genomic imprinting: the emergence of an epigenetic paradigm. Nat. Rev. Genet. 12, 565–575 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Tucci, V., Isles, A. R., Kelsey, G., Ferguson-Smith, A. C. & Erice Imprinting Group. Genomic imprinting and physiological processes in mammals. Cell 176, 952–965 (2019).

    Article  CAS  PubMed  Google Scholar 

  6. Orr, H. A. Somatic mutation favors the evolution of diploidy. Genetics 139, 1441–1447 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Patten, M. M. et al. The evolution of genomic imprinting: theories, predictions and empirical tests. Heredity 113, 119–128 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Trivers, R. L. Parent–offspring conflict. Integr. Comp. Biol. 14, 249–264 (1974).

    Google Scholar 

  9. Moore, T. & Haig, D. Genomic imprinting in mammalian development: a parental tug-of-war. Trends Genet. 7, 45–49 (1991). This article introduces the theory proposing that imprinting evolved because of the conflicting interests of maternal and paternal genes within offspring (mammals and plants).

    Article  CAS  PubMed  Google Scholar 

  10. Cassidy, F. C. & Charalambous, M. Genomic imprinting, growth and maternal-fetal interactions. J. Exp. Biol. 221, jeb.164517 (2018).

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Li, L. et al. Regulation of maternal behavior and offspring growth by paternally expressed Peg3. Science 284, 330–334 (1999). Together with Lefebvre et al. (1998), this study represents one of the first demonstrations of a role for imprinted genes in influencing maternal care, involving, in both cases, paternally expressed genes.

    Article  CAS  PubMed  Google Scholar 

  13. Higgs, M. J., Hill, M. J., John, R. M. & Isles, A. R. Systematic investigation of imprinted gene expression and enrichment in the mouse brain explored at single-cell resolution. BMC Genomics 23, 754 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Higgs, M. J., Webberley, A. E., John, R. M. & Isles, A. R. Parenting deficits in Magel2-null mice predicted from systematic investigation of imprinted gene expression in galanin neurons of the hypothalamus. Preprint at bioRxiv https://doi.org/10.1101/2023.03.27.534088 (2023). This study undertakes a predictive approach followed by experimental validation that paternally expressed Magel2 is involved in both maternal and paternal parenting behaviours.

  15. Creeth, H. D. J. et al. Maternal care boosted by paternal imprinting in mammals. PLoS Biol. 16, e2006599 (2018). This is one of the first reports of an imprinted gene expressed in the offspring influencing maternal behaviour via the regulation of placental hormones with both improvements (decreased Phlda2 levels and increased hormone levels) and deficits (increased Phlda2 levels and decreased hormone levels) in pup-directed behaviours.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. McNamara, G. I. et al. Loss of offspring Peg3 reduces neonatal ultrasonic vocalizations and increases maternal anxiety in wild-type mothers. Hum. Mol. Genet. 27, 440–450 (2018). This study reports that expression of Peg3 in the pup influences maternal behaviour (decreased Peg3 expression and decreased hormone levels) with deficits in pup-directed behaviours and anxiety in the dam, and decreased communication by the pup.

    Article  CAS  PubMed  Google Scholar 

  17. 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 article provides experimental evidence that expression of the paternal allele of Magel2 in the fetus is required for normal sucking.

    Article  CAS  PubMed  Google Scholar 

  18. 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). This is an original proposal of an alternative model to explain why imprinting may have evolved to influence maternal care.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kim, J. et al. Peg3 mutational effects on reproduction and placenta-specific gene families. PLoS ONE 8, e83359 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bosque Ortiz, G. M., Santana, G. M. & Dietrich, M. O. Deficiency of the paternally inherited gene Magel2 alters the development of separation-induced vocalization and maternal behavior in mice. Genes Brain Behav. 21, e12776 (2022). This study reports that expression of the paternal allele of Magel2 in the pup is required for pup communication.

    Article  CAS  PubMed  Google Scholar 

  21. Gross, M. R. The evolution of parental care. Q. Rev. Biol. 80, 37–45 (2005).

    Article  PubMed  Google Scholar 

  22. Doody, J. S., Burghardt, G. M. & Dinets, V. Breaking the social–non‐social dichotomy: a role for reptiles in vertebrate social behavior research? Ethology 119, 95–103 (2013).

    Article  Google Scholar 

  23. Charvet, C. J. & Striedter, G. F. Developmental modes and developmental mechanisms can channel brain evolution. Front. Neuroanat. 5, 4 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Scheiber, I. B. R., Weiß, B. M., Kingma, S. A. & Komdeur, J. The importance of the altricial — precocial spectrum for social complexity in mammals and birds — a review. Front. Zool. 14, 3 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Faust, K. M., Carouso-Peck, S., Elson, M. R. & Goldstein, M. H. The origins of social knowledge in altricial species. Annu. Rev. Dev. Psychol. 2, 225–246 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Rogers, F. D. & Bales, K. L. Mothers, fathers, and others: neural substrates of parental care. Trends Neurosci. 42, 552–562 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gubernick, D. J. & Klopfer, P. H. (eds). Parental Care in Mammals (Springer, 2013).

  28. Creeth, H. D. J., McNamara, G. I., Isles, A. R. & John, R. M. Imprinted genes influencing the quality of maternal care. Front. Neuroendocrinol. 53, 100732 (2019).

    Article  CAS  PubMed  Google Scholar 

  29. Numan, M. Medial preoptic area and maternal behavior in the female rat. J. Comp. Physiol. Psychol. 87, 746–759 (1974).

    Article  CAS  PubMed  Google Scholar 

  30. Bridges, R. S. et al. Endocrine communication between conceptus and mother: placental lactogen stimulation of maternal behavior. Neuroendocrinology 64, 57–64 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Bridges, R. S., Numan, M., Ronsheim, P. M., Mann, P. E. & Lupini, C. E. Central prolactin infusions stimulate maternal behavior in steroid-treated, nulliparous female rats. Proc. Natl Acad. Sci. USA 87, 8003–8007 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Consiglio, A. R. & Bridges, R. S. Circulating prolactin, MPOA prolactin receptor expression and maternal aggression in lactating rats. Behav. Brain Res. 197, 97–102 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Ribeiro, A. C. et al. siRNA silencing of estrogen receptor-α expression specifically in medial preoptic area neurons abolishes maternal care in female mice. Proc. Natl Acad. Sci. USA 109, 16324–16329 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Moffitt, J. R. et al. Molecular, spatial, and functional single-cell profiling of the hypothalamic preoptic region. Science 362, eaau5324 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Wu, Z., Autry, A. E., Bergan, J. F., Watabe-Uchida, M. & Dulac, C. G. Galanin neurons in the medial preoptic area govern parental behaviour. Nature 509, 325–330 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kohl, J. et al. Functional circuit architecture underlying parental behaviour. Nature 556, 326–331 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Numan, M. & Corodimas, K. P. The effects of paraventricular hypothalamic lesions on maternal behavior in rats. Physiol. Behav. 35, 417–425 (1985).

    Article  CAS  PubMed  Google Scholar 

  38. Caldwell, H. K. Oxytocin and vasopressin: powerful regulators of social behavior. Neuroscientist 23, 517–528 (2017).

    Article  CAS  PubMed  Google Scholar 

  39. Yoshihara, C., Numan, M. & Kuroda, K. O. Oxytocin and parental behaviors. Curr. Top. Behav. Neurosci. 35, 119–153 (2018).

    Article  CAS  PubMed  Google Scholar 

  40. Boillot, M. Hunger-activated AgRP neurons inhibit MPOA neurons controlling parenting. J. Neurosci. 39, 6032–6034 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Muzerelle, A. et al. Dorsal raphe serotonin neurotransmission is required for the expression of nursing behavior and for pup survival. Sci. Rep. 11, 6004 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Topilko, T. et al. Edinger-Westphal peptidergic neurons enable maternal preparatory nesting. Neuron 110, 1385–1399.e8 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kohl, J. & Dulac, C. Neural control of parental behaviors. Curr. Opin. Neurobiol. 49, 116–122 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Numan, M. & Young, L. J. Neural mechanisms of mother–infant bonding and pair bonding: similarities, differences, and broader implications. Horm. Behav. 77, 98–112 (2016).

    Article  CAS  PubMed  Google Scholar 

  45. Frey, W. D. et al. Oxytocin receptor is regulated by Peg3. PLoS ONE 13, e0202476 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Stohn, J. P. et al. Increased aggression and lack of maternal behavior in Dio3-deficient mice are associated with abnormalities in oxytocin and vasopressin systems. Genes Brain Behav. 17, 23–35 (2018).

    Article  CAS  PubMed  Google Scholar 

  47. Hoshiya, H., Meguro, M., Kashiwagi, A., Okita, C. & Oshimura, M. Calcr, a brain-specific imprinted mouse calcitonin receptor gene in the imprinted cluster of the proximal region of chromosome 6. J. Hum. Genet. 48, 208–211 (2003). This study is an example of a maternally expressed imprinted gene for which loss of function in the dam resulted in deficits in maternal behaviour.

    Article  CAS  PubMed  Google Scholar 

  48. Yoshihara, C. et al. Calcitonin receptor signaling in the medial preoptic area enables risk-taking maternal care. Cell Rep. 35, 109204 (2021).

    Article  CAS  PubMed  Google Scholar 

  49. Dent, C. L. et al. Mice lacking paternal expression of imprinted Grb10 are risk-takers. Genes Brain Behav. 19, e12679 (2020).

    Article  CAS  PubMed  Google Scholar 

  50. Rienecker, K. D. A., Chavasse, A. T., Moorwood, K., Ward, A. & Isles, A. R. Detailed analysis of paternal knockout Grb10 mice suggests effects on stability of social behavior, rather than social dominance. Genes Brain Behav. 19, e12571 (2020).

    Article  CAS  PubMed  Google Scholar 

  51. Liu, H. et al. Hypothalamic Grb10 enhances leptin signalling and promotes weight loss. Nat. Metab. 5, 147–164 (2023).

    Article  CAS  PubMed  Google Scholar 

  52. Cowley, M. et al. Developmental programming mediated by complementary roles of imprinted Grb10 in mother and pup. PLoS Biol. 12, e1001799 (2014). This study reports a maternally expressed imprinted gene in which loss of function in the pup resulted in increased milk provision by a genetically wild-type dam.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Wolf, J. B. & Hager, R. A maternal-offspring coadaptation theory for the evolution of genomic imprinting. PLoS Biol. 4, e380 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Ubeda, F. Evolution of genomic imprinting with biparental care: implications for Prader-Willi and Angelman syndromes. PLoS Biol. 6, e208 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Anunciado-Koza, R. P., Stohn, J. P., Hernandez, A. & Koza, R. A. Social and maternal behavior in mesoderm specific transcript (Mest)-deficient mice. PLoS ONE 17, e0271913 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Denizot, A. L. et al. A novel mutant allele of Pw1/Peg3 does not affect maternal behavior or nursing behavior. PLoS Genet. 12, e1006053 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Bućan, M. & Abel, T. The mouse: genetics meets behaviour. Nat. Rev. Genet. 3, 114–123 (2002).

    Article  PubMed  Google Scholar 

  58. Champagne, F. A., Curley, J. P., Swaney, W. T., Hasen, N. S. & Keverne, E. B. Paternal influence on female behavior: the role of Peg3 in exploration, olfaction, and neuroendocrine regulation of maternal behavior of female mice. Behav. Neurosci. 123, 469–480 (2009).

    Article  PubMed  Google Scholar 

  59. Peck, L. J. et al. Studying independent Kcna6 knock-out mice reveals toxicity of exogenous LacZ to central nociceptor terminals and differential effects of Kv1.6 on acute and neuropathic pain sensation. J. Neurosci. 41, 9141–9162 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ji, L. et al. Defective neuronal migration and inhibition of bipolar to multipolar transition of migrating neural cells by mesoderm-specific transcript, Mest, in the developing mouse neocortex. Neuroscience 355, 126–140 (2017).

    Article  CAS  PubMed  Google Scholar 

  61. Frey, W. D. & Kim, J. APeg3: regulation of Peg3 through an evolutionarily conserved ncRNA. Gene 540, 251–257 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wilkins, J. F., Ubeda, F. & Van Cleve, J. The evolving landscape of imprinted genes in humans and mice: conflict among alleles, genes, tissues, and kin. Bioessays 38, 482–489 (2016).

    Article  CAS  PubMed  Google Scholar 

  63. Babak, T. et al. Genetic conflict reflected in tissue-specific maps of genomic imprinting in human and mouse. Nat. Genet. 47, 544–549 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Feldman, R. The neurobiology of mammalian parenting and the biosocial context of human caregiving. Horm. Behav. 77, 3–17 (2016).

    Article  PubMed  Google Scholar 

  65. Brown, R. S. E. et al. Prolactin action in the medial preoptic area is necessary for postpartum maternal nursing behavior. Proc. Natl Acad. Sci. USA 114, 10779–10784 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Feldman, R. & Bakermans-Kranenburg, M. J. Oxytocin: a parenting hormone. Curr. Opin. Psychol. 15, 13–18 (2017).

    Article  PubMed  Google Scholar 

  67. Scagliotti, V. et al. Dynamic expression of imprinted genes in the developing and postnatal pituitary gland. Genes 12, 509 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Brown, R. S. E. et al. Prolactin transport into mouse brain is independent of prolactin receptor. FASEB J. 30, 1002–1010 (2016).

    Article  CAS  PubMed  Google Scholar 

  69. Manning, C. J., Dewsbury, D. A., Wakeland, E. K. & Potts, W. K. Communal nesting and communal nursing in house mice, Mus musculus domesticus. Anim. Behav. 50, 741–751 (1995).

    Article  Google Scholar 

  70. Hayes, L. D. To nest communally or not to nest communally: a review of rodent communal nesting and nursing. Anim. Behav. 59, 677–688 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Weber, E. M. & Olsson, I. A. S. Maternal behaviour in Mus musculus sp.: an ethological review. Appl. Anim. Behav. Sci. 114, 1–22 (2008).

    Article  Google Scholar 

  72. Ubeda, F. & Gardner, A. A model for genomic imprinting in the social brain: adults. Evolution 65, 462–475 (2011).

    Article  PubMed  Google Scholar 

  73. Napso, T., Yong, H. E. J., Lopez-Tello, J. & Sferruzzi-Perri, A. N. The role of placental hormones in mediating maternal adaptations to support pregnancy and lactation. Front. Physiol. 9, 1091 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Haig, D. Genetic conflicts in human pregnancy. Q. Rev. Biol. 68, 495–532 (1993).

    Article  CAS  PubMed  Google Scholar 

  75. Vrana, P. B. et al. Genomic imprinting of a placental lactogen gene in Peromyscus. Dev. Genes Evol. 211, 523–532 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. John, R. M. Imprinted genes and the regulation of placental endocrine function: pregnancy and beyond. Placenta 56, 86–90 (2017).

    Article  CAS  PubMed  Google Scholar 

  77. Georgescu, T., Swart, J. M., Grattan, D. R. & Brown, R. S. E. The prolactin family of hormones as regulators of maternal mood and behavior. Front. Glob. Womens Health 2, 767467 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Soares, M. J., Konno, T. & Alam, S. M. K. The prolactin family: effectors of pregnancy-dependent adaptations. Trends Endocrinol. Metab. 18, 114–121 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Shingo, T. et al. Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science 299, 117–120 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Soares, M. J. The prolactin and growth hormone families: pregnancy-specific hormones/cytokines at the maternal-fetal interface. Reprod. Biol. Endocrinol. 2, 51 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Bridges, R. S. Neuroendocrine regulation of maternal behavior. Front. Neuroendocrinol. 36, 178–196 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Menzies, B. R., Pask, A. J. & Renfree, M. B. Placental expression of pituitary hormones is an ancestral feature of therian mammals. EvoDevo 2, 16 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Cindrova-Davies, T. et al. RNA-seq reveals conservation of function among the yolk sacs of human, mouse, and chicken. Proc. Natl Acad. Sci. USA 114, E4753–E4761 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hemberger, M., Hanna, C. W. & Dean, W. Mechanisms of early placental development in mouse and humans. Nat. Rev. Genet. 21, 27–43 (2020).

    Article  CAS  PubMed  Google Scholar 

  85. Tunster, S. J., Van De Pette, M. & John, R. M. Isolating the role of elevated Phlda2 in asymmetric late fetal growth restriction in mice. Dis. Model. Mech. 7, 1185–1191 (2014).

    PubMed  PubMed Central  Google Scholar 

  86. Tunster, S. J., Creeth, H. D. & John, R. M. The imprinted Phlda2 gene modulates a major endocrine compartment of the placenta to regulate placental demands for maternal resources. Dev. Biol. 409, 251–260 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Harrison, D. J. et al. Placental endocrine insufficiency programs anxiety, deficits in cognition and atypical social behaviour in offspring. Hum. Mol. Genet. 30, 1863–1880 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Suzuki, S., Shaw, G., Kaneko-Ishino, T., Ishino, F. & Renfree, M. B. Characterisation of marsupial PHLDA2 reveals eutherian specific acquisition of imprinting. BMC Evol. Biol. 11, 244 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Tunster, S. J. et al. Peg3 deficiency results in sexually dimorphic losses and gains in the normal repertoire of placental hormones. Front. Cell Dev. Biol. 6, 123 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Tunster, S. J., Van de Pette, M. & John, R. M. Fetal overgrowth in the Cdkn1c mouse model of Beckwith-Wiedemann syndrome. Dis. Model. Mech. 4, 814–821 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Tanaka, M., Gertsenstein, M., Rossant, J. & Nagy, A. Mash2 acts cell autonomously in mouse spongiotrophoblast development. Dev. Biol. 190, 55–65 (1997).

    Article  CAS  PubMed  Google Scholar 

  92. Tunster, S. J., McNamara, G. I., Creeth, H. D. & John, R. M. Increased dosage of the imprinted Ascl2 gene restrains two key endocrine lineages of the mouse Placenta. Dev. Biol. 418, 55–65 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Cleaton, M. A. et al. Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction. Nat. Genet. 48, 1473–1480 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lopez-Tello, J. et al. Fetal manipulation of maternal metabolism is a critical function of the imprinted Igf2 gene. Cell Metab. 35, 1195–1208.e6 (2023).

    Article  CAS  PubMed  Google Scholar 

  95. Janssen, A. B. et al. Maternal prenatal depression is associated with decreased placental expression of the imprinted gene PEG3. Psychol. Med. 46, 2999–3011 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Caldwell, H. K., Aulino, E. A., Freeman, A. R., Miller, T. V. & Witchey, S. K. Oxytocin and behavior: lessons from knockout mice. Dev. Neurobiol. 77, 190–201 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  98. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  100. 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).

    Article  PubMed  Google Scholar 

  101. Yan, Y., Frisén, J., Lee, M. H., Massagué, J. & Barbacid, M. Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development. Genes Dev. 11, 973–983 (1997).

    Article  CAS  PubMed  Google Scholar 

  102. 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).

    Article  CAS  PubMed  Google Scholar 

  103. Lau, M. M. et al. Loss of the imprinted IGF2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality. Genes Dev. 8, 2953–2963 (1994).

    Article  CAS  PubMed  Google Scholar 

  104. D’Amato, F. R., Scalera, E., Sarli, C. & Moles, A. Pups call, mothers rush: does maternal responsiveness affect the amount of ultrasonic vocalizations in mouse pups. Behav. Genet. 35, 103–112 (2005).

    Article  PubMed  Google Scholar 

  105. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  106. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Berg, E. L. et al. Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome. Transl. Psychiatry 10, 39 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Spencer, H. G. & Clark, A. G. Non-conflict theories for the evolution of genomic imprinting. Heredity 113, 112–118 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Santoni, F. A. et al. Detection of imprinted genes by single-cell allele-specific gene expression. Am. J. Hum. Genet. 100, 444–453 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Akbari, V. et al. Genome-wide detection of imprinted differentially methylated regions using nanopore sequencing. eLife 11, e77898 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Van de Pette, M. et al. Visualizing changes in Cdkn1c expression links early-life adversity to imprint mis-regulation in adults. Cell Rep. 18, 1090–1099 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Van de Pette, M. et al. Epigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice. Nat. Commun. 13, 2464 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Fukumitsu, K. et al. Amylin-calcitonin receptor signaling in the medial preoptic area mediates affiliative social behaviors in female mice. Nat. Commun. 13, 709 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  115. Charalambous, M. et al. Maternally-inherited Grb10 reduces placental size and efficiency. Dev. Biol. 337, 1–8 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Takahashi, K., Kobayashi, T. & Kanayama, N. p57(Kip2) regulates the proper development of labyrinthine and spongiotrophoblasts. Mol. Hum. Reprod. 6, 1019–1025 (2000).

    Article  CAS  PubMed  Google Scholar 

  117. Aykroyd, B. R. L., Tunster, S. J. & Sferruzzi-Perri, A. N. Igf2 deletion alters mouse placenta endocrine capacity in a sexually dimorphic manner. J. Endocrinol. 246, 93–108 (2020).

    Article  CAS  PubMed  Google Scholar 

  118. Cao, W. et al. Origin and evolution of marsupial-specific imprinting clusters through lineage-specific gene duplications and acquisition of promoter differential methylation. Mol. Biol. Evol. 40, msad022 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Numan, M. The Parental Brain: Mechanisms, Development, and Evolution (Oxford Univ. Press, 2020).

  120. Guthrie, S. et al. Pregnancy Research Review: Policy Report (RAND Corporation, 2020).

  121. Bauer, A., Knapp, M. & Parsonage, M. Lifetime costs of perinatal anxiety and depression. J. Affect. Disord. 192, 83–90 (2016).

    Article  PubMed  Google Scholar 

  122. Henrichs, J. et al. Maternal psychological distress and fetal growth trajectories: the Generation R Study. Psychol. Med. 40, 633–643 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. Liu, Y. et al. Depression in pregnancy, infant birth weight and DNA methylation of imprint regulatory elements. Epigenetics 7, 735–746 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Savory, K. et al. Prenatal symptoms of anxiety and depression associated with sex differences in both maternal perceptions of one year old infant temperament and researcher observed infant characteristics. J. Affect. Disord. 264, 383–392 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Field, T. Prenatal depression effects on early development: a review. Infant Behav. Dev. 34, 1–14 (2011).

    Article  PubMed  Google Scholar 

  126. Muzik, M. & Borovska, S. Perinatal depression: implications for child mental health. Ment. Health Fam. Med. 7, 239–247 (2010).

    PubMed  PubMed Central  Google Scholar 

  127. Sumption, L. A., Garay, S. M. & John, R. M. Low serum placental lactogen at term is associated with postnatal symptoms of depression and anxiety in women delivering female infants. Psychoneuroendocrinology 116, 104655 (2020).

    Article  CAS  PubMed  Google Scholar 

  128. Jin, Y. et al. Chromosomal architecture and placental expression of the human growth hormone gene family are targeted by pre-pregnancy maternal obesity. Am. J. Physiol. Endocrinol. Metab. 315, E435–E445 (2018).

    Article  CAS  PubMed  Google Scholar 

  129. Steinig, J., Nagl, M., Linde, K., Zietlow, G. & Kersting, A. Antenatal and postnatal depression in women with obesity: a systematic review. Arch. Womens Ment. Health 20, 569–585 (2017).

    Article  PubMed  Google Scholar 

  130. Fernandez-Jimenez, N. et al. A meta-analysis of pre-pregnancy maternal body mass index and placental DNA methylation identifies 27 CpG sites with implications for mother-child health. Commun. Biol. 5, 1313 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Wesseler, K., Kraft, F. & Eggermann, T. Molecular and clinical opposite findings in 11p15.5 associated imprinting disorders: characterization of basic mechanisms to improve clinical management. Int. J. Mol. Sci. 20, 4219 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  132. McMinn, J. et al. Unbalanced placental expression of imprinted genes in human intrauterine growth restriction. Placenta 27, 540–549 (2006).

    Article  CAS  PubMed  Google Scholar 

  133. Isles, A. R. Genomic imprinting; the cost of mother’s care. Bioessays 33, 924–926 (2011).

    Article  PubMed  Google Scholar 

  134. Haig, D. Troubled sleep: night waking, breastfeeding and parent–offspring conflict. Evol. Med. Public Health 2014, 32–39 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Oliver, C., Demetriades, L. & Hall, S. Effects of environmental events on smiling and laughing behavior in Angelman syndrome. Am. J. Ment. Retard. 107, 194–200 (2002).

    Article  PubMed  Google Scholar 

  136. Mount, R., Oliver, C., Berg, K. & Horsler, K. Effects of adult familiarity on social behaviours in Angelman syndrome. J. Intellect. Disabil. Res. 55, 339–350 (2011).

    Article  CAS  PubMed  Google Scholar 

  137. Brown, W. M. & Consedine, N. S. Just how happy is the happy puppet? An emotion signaling and kinship theory perspective on the behavioral phenotype of children with Angelman syndrome. Med. Hypotheses 63, 377–385 (2004).

    Article  PubMed  Google Scholar 

  138. Oliver, C. et al. Genomic imprinting and the expression of affect in Angelman syndrome: what’s in the smile? J. Child Psychol. Psychiatry 48, 571–579 (2007).

    Article  PubMed  Google Scholar 

  139. Mehr, S. A. & Krasnow, M. M. Parent-offspring conflict and the evolution of infant-directed song. Evol. Hum. Behav. 38, 674–684 (2017).

    Article  Google Scholar 

  140. Kotler, J., Mehr, S. A., Egner, A., Haig, D. & Krasnow, M. M. Response to vocal music in Angelman syndrome contrasts with Prader-Willi syndrome. Evol. Hum. Behav. 40, 420–426 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Mehr, S. A., Kotler, J., Howard, R. M., Haig, D. & Krasnow, M. M. Genomic imprinting is implicated in the psychology of music. Psychol. Sci. 28, 1455–1467 (2017).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Rosalind M. John.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Genetics thanks Gavin Kelsey, Kumi O. Kuroda and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

John, R.M., Higgs, M.J. & Isles, A.R. Imprinted genes and the manipulation of parenting in mammals. Nat Rev Genet 24, 783–796 (2023). https://doi.org/10.1038/s41576-023-00644-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41576-023-00644-3

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