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Imprinted Genes, the Placenta and the Brain

Although imprinted genes comprise only about 1% of the genome, they are disproportionately involved in growth, especially with regard to placental and brain development and function (Tycko & Morison 2002); they are highly pleiotropic in their effects; and they can be dysregulated in more ways than non-imprinted genes. Thus, imprinted-gene expression can be affected by alterations in nucleotide sequence, by epigenetic variation (such as methylation and histone modification), by “imprinter” genes that regulate application, maintenance, and removal of imprints (Wilkins 2005), and by environmentally induced effects on imprinted gene expression (Dolinoy et al. 2006).

Most studies of genomic imprinting have focused on genes expressed during prenatal and neonatal development, where conflict is manifested in aspects of maternal–fetal interactions during placentation and neonatal growth (Angiolini et al. 2006; Crespi & Semeniuk 2004; Haig 1993; 1996; 2004a; 2004b). The placenta has evolved as a focal point for genomic conflict due to its function in the transfer of resources between mutually dependent individuals that bear genes with partially divergent inclusive fitness interests (Coan et al. 2005; Haig 1993; 1996). Many of the common disorders of pregnancy, including gestational diabetes, pre-eclampsia, and fetal growth restriction, arise in part from breakdowns in the dynamically balanced, “tug-of-war” nature of physiological systems subject to maternal–fetal conflict and imprinting effects (Cattanach et al. 2004; Haig 1993; 1996; 1999b; McMinn et al. 2006; Oudejans et al. 2004; Reik et al. 2003).

A considerable proportion of known imprinted genes are expressed exclusively or predominantly in the brain, where they influence aspects of behavior (Curley et al. 2004; Davies et al. 2001; 2005; 2006; Isles et al. 2006; Keverne 2001a; 2001b). The brain can be conceived as analogous to the placenta in that both organs mediate the transfer of fitness-limiting resources in networks of kin (Badcock & Crespi 2006). As in the case of placentation, disruption in systems involving brain-expressed imprinted genes can lead to major neurological and physiological disorders (Badcock 2000; Davies et al. 2001; Haig & Wharton 2003; Isles et al. 2006). Developmental systems regulated by imprinting effects are unusual in that they can be disrupted in two diametrically opposed ways, towards either paternal-gene or maternal-gene bias. Disorders affected by imprinting should thus exhibit diametric phenotypes, as seen clearly, for example, in Beckwith-Wiedemann syndrome involving overgrowth versus the Silver-Russell undergrowth syndrome (Cerrato et al. 2005; Eggermann et al. 2005; 2006). We propose that such diametric effects extend to brain and behavior, and these effects help to account for some of the major features of human cognitive architecture.

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Angiolini, E., Fowden, A., Coan, P., Sandovici, I., Smith, P., Dean, W., Burton, G., Tycko, B., Reik, W., Sibley, C. & Constancia, M. (2006) Regulation of placental efficiency for nutrient transport by imprinted genes. Placenta 27(A):98 – 102. [aBC]

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Badcock, C. R. (2000) Evolutionary psychology: A critical introduction. Polity Press. [aBC]

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Badcock, C. & Crespi, B. (2006) Imbalanced genomic imprinting in brain development: An evolutionary basis for the aetiology of autism. Journal of Evolutionary Biology 19:1007– 32. [aBC]

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Cattanach, B. M., Beechey, C. V. & Peters, J. (2004) Interactions between imprinting effects in the mouse. Genetics 168:397 – 413. [aBC]

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Cerrato, F., Sparago, A., Di Matteo, I., Zou, X., Dean, W., Sasaki, H., Smith, P., Genesio, R., Bruggemann, M., Reik, W. & Riccio, A. (2005) The two-domain hypothesis in Beckwith-Wiedemann syndrome: Autonomous imprinting of the telomeric domain of the distal chromosome 7 cluster. Human Molecular Genetics 14:503 – 11. [aBC]

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Coan, P. M., Burton, G. J. & Ferguson-Smith, A. C. (2005) Imprinted genes in the placenta – A review. Placenta 26(Suppl. A):S10 – 20. [arBC]

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Crespi, B. & Semeniuk, C. (2004) Parent-offspring conflict in the evolution of vertebrate reproductive mode. American Naturalist 163:635 – 53. [aBC]

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Curley, J. P., Barton, S., Surani, A. & Keverne, E. B. (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 – 309. [aBC]

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Davies, W., Isles, A. R., Burgoyne, P. S. & Wilkinson, L. S. (2006) X-linked imprinting: Effects on brain and behaviour. Bioessays 28:35 –44. [aBC]

Davies, W., Isles, A. R., Smith, R., Karunadasa, D., Burrmann, D., Humby, T., Ojarikre, O., Biggin, C., Skuse, D., Burgoyne, P. & Wilkinson, L. (2005) Xlr3b is a new imprinted candidate for X-linked parent-of-origin effects on cognitive function in mice. Nature Genetics 37:625 –29. [aBC]

Davies, W., Isles, A. R. & Wilkinson, L. S. (2001) Imprinted genes and mental dysfunction. Annals of Medicine 33:428 – 36. [aBC]

[Davies, W., Isles, A. R. & Wilkinson, L. S.] (2005) Imprinted gene expression in the brain. Neuroscience and Biobehavioral Reviews 29:421 – 30. [BJAD]

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Dolinoy, D. C., Weidman, J. R. & Jirtle, R. L. (2006) Epigenetic gene regulation: Linking early developmental environment to adult disease. Reproductive Toxicology 23:297 – 307. [aBC]

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Eggermann, T., Meyer, E., Obermann, C., Heil, I., Schuler, H., Ranke, M. B., Eggermann, K. & Wollmann, H. A. (2005) Is maternal duplication of 11p15 associated with Silver-Russell syndrome? Journal of Medical Genetics 42:e26. [aBC]

Eggermann, T., Schonherr, N., Meyer, E., Obermann, C., Mavany, M., Eggermann, K., Ranke, M. B. & Wollmann, H. A. (2006) Epigenetic mutations in 11p15 in Silver-Russell syndrome are restricted to the telomeric imprinting domain. Journal of Medical Genetics 43:615 – 16. [aBC]

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Haig, D. (1993) Genetic conflicts in human pregnancy. Quarterly Review of Biology 68:495 – 532. [aBC]

[Haig, D.] (1996) Placental hormones, genetic imprinting, and maternal-fetal communication. Journal of Evolutionary Biology 9:357. [aBC]

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[Haig, D.] (1999b) Genetic conflicts of pregnancy and childhood. In: Evolution in health and disease, ed. C. Stearns, pp. 77 – 90. Oxford University Press. [aBC]

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[Haig, D.] (2004a) Evolutionary conflicts in pregnancy and calcium metabolism – A review. Placenta 25(Suppl. A):S10 – S15. [aBC]

[Haig, D.] (2004b) Genomic imprinting and kinship: How good is the evidence? Annual Review of Genetics 38:553 – 85. [aBC]

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Haig, D. & Wharton, R. (2003) Prader-Willi syndrome and the evolution of human childhood. American Journal of Human Biology 15:320 – 29. [arBC]

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Isles, A. R., Davies, W. & Wilkinson, L. S. (2006) Genomic imprinting and the social brain. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 361(1476):2229– 37. [aBC, WD]

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Keverne, E. B., Fundele, R., Narasimha, M., Barton, S. C. & Surani, M. A. (1996) Genomic imprinting and the differential roles of parental genomes in brain development. Brain Research, Developmental Brain Research 92:91– 100. [rBC, BJAD, LMG]

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McMinn, J., Wei, M., Schupf, N., Cusmai, J., Johnson, E. B., Smith, A. C., Weksberg, R., Thaker, H. M. & Tycko, B. (2006) Unbalanced placental expression of imprinted genes in human intrauterine growth restriction. Placenta 27:540– 49. [aBC]

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Oudejans, C. B. M., Mulders, J., Lachmeijer, A. M. A., van Dijk, M., Konst, A. A. M., Westerman, B. A., van Wijk, I. J., Leegwater, P. A. J., Kato, H. D., Matsuda, T., Wake, N., Dekker, G. A., Pals, G., ten Kate, L. P. & Blankenstein, M. A. (2004) The parent-of-origin effect of 10q22 in pre-eclamptic females coincides with two regions clustered for genes with down-regulated expression in androgenetic placentas. Molecular Human Reproduction 10:589– 98. [aBC]

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Reik, W., Constancia, M., Fowden, A., Anderson, N., Dean, W., Ferguson-Smith, A., Tycko, B. & Sibley, C. (2003) Regulation of supply and demand for maternal nutrients in mammals by imprinted genes. Journal of Physiology 547:35 – 44. [aBC]

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Tycko, B. & Morison, I. M. (2002) Physiological functions of imprinted genes. Journal of Cellular Physiology 192:245 – 58. [aBC]

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Wilkins, J. F. (2005) Genomic imprinting and methylation: Epigenetic canalization and conflict. Trends in Genetics 21:356 – 65. [aBC]

-- Bernard Crespi , Christopher Badcock

from "Psychosis and autism as diametrical disorders of the social brain"

Quoted on Sun Jul 1st, 2012