Transgenerational Epigenetic Effects and Complex Inheritance Patterns



Mendel’s laws describing the inheritance of simple genetic traits are based on the assumption that genes are transmitted unchanged from parents to offspring. However, this assumption is not always correct as the mammalian genome undergoes massive epigenetic reprogramming during gametogenesis and early embryonic development. Furthermore, stochastic or environmentally induced epigenetic variation may lead to situations where the epigenetic marking of the same allele differs between parents and offspring, among siblings or even monozygotic twins. Epigenetic marks may modify the penetrance of a phenotype and cause “non-Mendelian” inheritance even when the causal genetic variant is transmitted from parent to offspring in perfect Mendelian proportions. In this chapter we focus on a particular type of inheritance where epigenetic marks that are present in parental somatic cells fail to be reset in a proportion of parental germ cells and are transmitted to offspring. Such a transgenerational “epigenetic memory” increases the complexity of the inheritance pattern and therefore is of particular interest for geneticists.


Long Terminal Repeat Epigenetic Mark Primordial Germ Cell Epigenetic Reprogram Transmission Ratio Distortion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The author is grateful to Dr. Celia Greenwood, Mary Fujiwara, and Dr. Kenneth Morgan for helpful discussion.


  1. Allen ND, Norris ML, Surani MA (1990) Epigenetic control of transgene expression and imprinting by genotype-specific modifiers. Cell 61:853–861PubMedGoogle Scholar
  2. Amleh A, Xu BZ, Taketo T (2012) Role of sex chromosomes in mammalian female fertility. In: D’Aquino M, Stallone V (eds) Sex chromosomes: new research. Nova, New York, NYGoogle Scholar
  3. Anway MD, Skinner MK (2006) Epigenetic transgenerational actions of endocrine disruptors. Endocrinology 147:S43–S49PubMedGoogle Scholar
  4. Anway MD, Cupp AS, Uzumcu M, Skinner MK (2005) Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308:1466–1469PubMedGoogle Scholar
  5. Ashe A, Morgan DK, Whitelaw NC, Bruxner TJ, Vickaryous NK, Cox LL, Butterfield NC, Wicking C, Blewitt ME, Wilkins SJ, Anderson GJ, Cox TC, Whitelaw E (2008) A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development. Genome Biol 9:R182PubMedGoogle Scholar
  6. Ashe A, Sapetschnig A, Weick EM, Mitchell J, Bagijn MP, Cording AC, Doebley AL, Goldstein LD, Lehrbach NJ, Le Pen J, Pintacuda G, Sakaguchi A, Sarkies P, Ahmed S, Miska EA (2012) piRNAs can trigger a multigenerational epigenetic memory in the germline of C. elegans. Cell 150:88–99PubMedGoogle Scholar
  7. Bache I, Assche EV, Cingoz S, Bugge M, Tumer Z, Hjorth M, Lundsteen C, Lespinasse J, Winther K, Niebuhr A, Kalscheuer V, Liebaers I, Bonduelle M, Tournaye H, Ayuso C, Barbi G, Blennow E, Bourrouillou G, Brondum-Nielsen K, Bruun-Petersen G, Croquette MF, Dahoun S, Dallapiccola B, Davison V, Delobel B, Duba HC, Duprez L, Ferguson-Smith M, Fitzpatrick DR, Grace E, Hansmann I, Hulten M, Jensen PK, Jonveaux P, Kristoffersson U, Lopez-Pajares I, McGowan-Jordan J, Murken J, Orera M, Parkin T, Passarge E, Ramos C, Rasmussen K, Schempp W, Schubert R, Schwinger E, Shabtai F, Smith K, Stallings R, Stefanova M, Tranebjerg L, Turleau C, van der Hagen CB, Vekemans M, Vokac NK, Wagner K, Wahlstroem J, Zelante L, Tommerup N (2004) An excess of chromosome 1 breakpoints in male infertility. Eur J Hum Genet 12:993–1000PubMedGoogle Scholar
  8. Bestor TH (1998) The host defence function of genomic methylation patterns. Novartis Found Symp 214:187–195, discussion 195–189, 228–132PubMedGoogle Scholar
  9. Blewitt ME, Vickaryous NK, Hemley SJ, Ashe A, Bruxner TJ, Preis JI, Arkell R, Whitelaw E (2005) An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse. Proc Natl Acad Sci U S A 102:7629–7634PubMedGoogle Scholar
  10. Blewitt ME, Vickaryous NK, Paldi A, Koseki H, Whitelaw E (2006) Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice. PLoS Genet 2:e49PubMedGoogle Scholar
  11. Bliek J, Terhal P, van den Bogaard MJ, Maas S, Hamel B, Salieb-Beugelaar G, Simon M, Letteboer T, van der Smagt J, Kroes H, Mannens M (2006) Hypomethylation of the H19 gene causes not only Silver-Russell syndrome (SRS) but also isolated asymmetry or an SRS-like phenotype. Am J Hum Genet 78:604–614PubMedGoogle Scholar
  12. Borghol N, Suderman M, McArdle W, Racine A, Hallett M, Pembrey M, Hertzman C, Power C, Szyf M (2012) Associations with early-life socio-economic position in adult DNA methylation. Int J Epidemiol 41:62–74PubMedGoogle Scholar
  13. Bourc’his D, Bestor TH (2004) Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431:96–99PubMedGoogle Scholar
  14. Buiting K, Dittrich B, Gross S, Lich C, Farber C, Buchholz T, Smith E, Reis A, Burger J, Nothen MM, Barth-Witte U, Janssen B, Abeliovich D, Lerer I, van den Ouweland AM, Halley DJ, Schrander-Stumpel C, Smeets H, Meinecke P, Malcolm S, Gardner A, Lalande M, Nicholls RD, Friend K et al(1998) Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: implications for imprint-switch models, genetic counseling, and prenatal diagnosis. Am J Hum Genet 63:170–180PubMedGoogle Scholar
  15. Burgoyne PS, Mahadevaiah SK, Turner JM (2009) The consequences of asynapsis for mammalian meiosis. Nat Rev Genet 10:207–216PubMedGoogle Scholar
  16. Chen ZX, Mann JR, Hsieh CL, Riggs AD, Chedin F (2005) Physical and functional interactions between the human DNMT3L protein and members of the de novo methyltransferase family. J Cell Biochem 95:902–917PubMedGoogle Scholar
  17. Chen CP, Wu PC, Lin CJ, Su YN, Chern SR, Tsai FJ, Lee CC, Town DD, Chen WL, Chen LF, Lee MS, Pan CW, Wang W (2010) Balanced reciprocal translocations detected at amniocentesis. Taiwan J Obstet Gynecol 49:455–467PubMedGoogle Scholar
  18. Chinnusamy V, Zhu JK (2009) Epigenetic regulation of stress responses in plants. Curr Opin Plant Biol 12:133–139PubMedGoogle Scholar
  19. Chong S, Youngson NA, Whitelaw E (2007a) Heritable germline epimutation is not the same as transgenerational epigenetic inheritance. Nat Genet 39:574–575, author reply 575–576PubMedGoogle Scholar
  20. Chong S, Vickaryous N, Ashe A, Zamudio N, Youngson N, Hemley S, Stopka T, Skoultchi A, Matthews J, Scott HS, de Kretser D, O’Bryan M, Blewitt M, Whitelaw E (2007b) Modifiers of epigenetic reprogramming show paternal effects in the mouse. Nat Genet 39:614–622PubMedGoogle Scholar
  21. Cirio MC, Martel J, Mann M, Toppings M, Bartolomei M, Trasler J, Chaillet JR (2008) DNA methyltransferase 1o functions during preimplantation development to preclude a profound level of epigenetic variation. Dev Biol 324:139–150PubMedGoogle Scholar
  22. Clark AT (2007) Establishment and differentiation of human embryonic stem cell derived germ cells. Soc Reprod Fertil Suppl 63:77–86PubMedGoogle Scholar
  23. Cooney CA, Dave AA, Wolff GL (2002) Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J Nutr 132:2393S–2400SPubMedGoogle Scholar
  24. Crews D, Gillette R, Scarpino SV, Manikkam M, Savenkova MI, Skinner MK (2012) Epigenetic transgenerational inheritance of altered stress responses. Proc Natl Acad Sci U S A 109:9143–9148PubMedGoogle Scholar
  25. Croteau S, Polychronakos C, Naumova AK (2001) Imprinting defects in mouse embryos: stochastic errors or polymorphic phenotype. Genesis 31:11–16PubMedGoogle Scholar
  26. Croteau S, Freitas-Andrade M, Huang F, Greenwood CMT, Morgan K, Naumova AK (2002) Inheritance patterns of maternal alleles in imprinted regions of the mouse genome at different stages of development. Mamm Genome 13:24–29PubMedGoogle Scholar
  27. Cui H, Horon IL, Ohlsson R, Hamilton SR, Feinberg AP (1998) Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability. Nat Med 4:1276–1280PubMedGoogle Scholar
  28. Davis TL, Trasler JM, Moss SB, Yang GJ, Bartolomei MS (1999) Acquisition of the H19 methylation imprint occurs differentially on the parental alleles during spermatogenesis. Genomics 58:18–28PubMedGoogle Scholar
  29. Davis TL, Yang GJ, McCarrey JR, Bartolomei MS (2000) The H19 methylation imprint is erased and re-established differentially on the parental alleles during male germ cell development. Hum Mol Genet 9:2885–2894PubMedGoogle Scholar
  30. Daxinger L, Whitelaw E (2012) Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat Rev Genet 13:153–162PubMedGoogle Scholar
  31. DeBaun MR, Niemitz EL, Feinberg AP (2003) Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet 72:156–160PubMedGoogle Scholar
  32. Dickies MM (1962) A new viable yellow mutation in the house mouse. J Hered 53:84–86PubMedGoogle Scholar
  33. Dunn LC, Caspari E (1942) Close linkage between mutations with similar effects. Proc Natl Acad Sci U S A 28:205–210PubMedGoogle Scholar
  34. Engler P, Doglio LT, Bozek G, Storb U (1998) A cis-acting element that directs the activity of the murine methylation modifier locus Ssm1. Proc Natl Acad Sci U S A 95:10763–10768PubMedGoogle Scholar
  35. Feinberg AP (2000) DNA methylation, genomic imprinting and cancer. Curr Top Microbiol Immunol 249:87–99PubMedGoogle Scholar
  36. Feng S, Jacobsen SE, Reik W (2010) Epigenetic reprogramming in plant and animal development. Science 330:622–627PubMedGoogle Scholar
  37. Fernandez-Gonzalez R, Ramirez MA, Pericuesta E, Calle A, Gutierrez-Adan A (2010) Histone modifications at the blastocyst Axin1(Fu) locus mark the heritability of in vitro culture-induced epigenetic alterations in mice. Biol Reprod 83:720–727PubMedGoogle Scholar
  38. Follette PJ, Laird CD (1992) Estimating the stability of the proposed imprinted state of the fragile-X mutation when transmitted by females. Hum Genet 88:335–343PubMedGoogle Scholar
  39. Froslev-Friis C, Hjort-Pedersen K, Henriques CU, Krogh LN, Garne E (2011) Improved prenatal detection of chromosomal anomalies. Dan Med Bull 58:A4293PubMedGoogle Scholar
  40. Ginsburg M, Snow MH, McLaren A (1990) Primordial germ cells in the mouse embryo during gastrulation. Development 110:521–528PubMedGoogle Scholar
  41. Golding J, Steer C, Pembrey M (2010) Parental and grandparental ages in the autistic spectrum disorders: a birth cohort study. PLoS One 5:e9939PubMedGoogle Scholar
  42. Gomperts M, Garcia-Castro M, Wylie C, Heasman J (1994) Interactions between primordial germ cells play a role in their migration in mouse embryos. Development 120:135–141PubMedGoogle Scholar
  43. Grentzinger T, Armenise C, Brun C, Mugat B, Serrano V, Pelisson A, Chambeyron S (2012) piRNA-mediated transgenerational inheritance of an acquired trait. Genome Res 22:1877–1888PubMedGoogle Scholar
  44. Grossniklaus U, Kelly B, Ferguson-Smith AC, Pembrey M, Lindquist S (2013) Transgenerational epigenetic inheritance: how important is it? Nat Rev Genet 14:228–235PubMedGoogle Scholar
  45. Guerrero-Bosagna C, Skinner MK (2012) Environmentally induced epigenetic transgenerational inheritance of phenotype and disease. Mol Cell Endocrinol 354:3–8PubMedGoogle Scholar
  46. Guibert S, Forne T, Weber M (2012) Global profiling of DNA methylation erasure in mouse primordial germ cells. Genome Res 22:633–641PubMedGoogle Scholar
  47. Hackett JA, Reddington JP, Nestor CE, Dunican DS, Branco MR, Reichmann J, Reik W, Surani MA, Adams IR, Meehan RR (2012) Promoter DNA methylation couples genome-defence mechanisms to epigenetic reprogramming in the mouse germline. Development 139:3623–3632PubMedGoogle Scholar
  48. Hackett JA, Sengupta R, Zylicz JJ, Murakami K, Lee C, Down TA, Surani MA (2013) Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science 339:448–452PubMedGoogle Scholar
  49. Hadchouel M, Scotto J, Huret JL, Molinie C, Villa E, Degos F, Brechot C (1985) Presence of HBV DNA in spermatozoa: a possible vertical transmission of HBV via the germ line. J Med Virol 16:61–66PubMedGoogle Scholar
  50. Hajkova P, Erhardt S, Lane N, Haaf T, El-Maarri O, Reik W, Walter J, Surani MA (2002) Epigenetic reprogramming in mouse primordial germ cells. Mech Dev 117:15–23PubMedGoogle Scholar
  51. Hamerton JL, Canning N, Ray M, Smith S (1975) A cytogenetic survey of 14,069 newborn infants. I. Incidence of chromosome abnormalities. Clin Genet 8:223–243PubMedGoogle Scholar
  52. Hancks DC, Kazazian HH Jr (2012) Active human retrotransposons: variation and disease. Curr Opin Genet Dev 22:191–203PubMedGoogle Scholar
  53. Hassold TJ (1980) A cytogenetic study of repeated spontaneous abortions. Am J Hum Genet 32:723–730PubMedGoogle Scholar
  54. Hassold T (1986) Chromosome abnormalities in the human reproductive wastage. Trends Genet 2:105–110Google Scholar
  55. Hiura H, Obata Y, Komiyama J, Shirai M, Kono T (2006) Oocyte growth-dependent progression of maternal imprinting in mice. Genes Cells 11:353–361PubMedGoogle Scholar
  56. Holloway AF, Rao S, Shannon MF (2002) Regulation of cytokine gene transcription in the immune system. Mol Immunol 38:567–580PubMedGoogle Scholar
  57. Homolka D, Ivanek R, Capkova J, Jansa P, Forejt J (2007) Chromosomal rearrangement interferes with meiotic X chromosome inactivation. Genome Res 17:1431–1437PubMedGoogle Scholar
  58. Howell C, Bestor T, Ding F, Latham K, Mertineit C, Trasler J, Chaillet J (2001) Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene. Cell 104:829–838PubMedGoogle Scholar
  59. Howlett SK, Reik W (1991) Methylation levels of maternal and paternal genomes during preimplantation development. Development 113:119–127PubMedGoogle Scholar
  60. Joyce JA, Lam WK, Catchpoole DJ, Jenks P, Reik W, Maher ER, Schofield PN (1997) Imprinting of IGF2 and H19: lack of reciprocity in sporadic Beckwith-Wiedemann syndrome. Hum Mol Genet 6:1543–1548PubMedGoogle Scholar
  61. Kaati G, Bygren LO, Pembrey M, Sjostrom M (2007) Transgenerational response to nutrition, early life circumstances and longevity. Eur J Hum Genet 15:784–790PubMedGoogle Scholar
  62. Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E, Sasaki H (2004) Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 429:900–903PubMedGoogle Scholar
  63. Kato Y, Kaneda M, Hata K, Kumaki K, Hisano M, Kohara Y, Okano M, Li E, Nozaki M, Sasaki H (2007) Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse. Hum Mol Genet 16:2272–2280PubMedGoogle Scholar
  64. Kearns M, Preis J, McDonald M, Morris C, Whitelaw E (2000) Complex patterns of inheritance of an imprinted murine transgene suggest incomplete germline erasure. Nucleic Acids Res 28:3301–3309PubMedGoogle Scholar
  65. Knock E, Deng L, Wu Q, Leclerc D, Wang XL, Rozen R (2006) Low dietary folate initiates intestinal tumors in mice, with altered expression of G2-M checkpoint regulators polo-like kinase 1 and cell division cycle 25c. Cancer Res 66:10349–10356PubMedGoogle Scholar
  66. Kobayashi H, Sato A, Otsu E, Hiura H, Tomatsu C, Utsunomiya T, Sasaki H, Yaegashi N, Arima T (2007) Aberrant DNA methylation of imprinted loci in sperm from oligospermic patients. Hum Mol Genet 16:2542–2551PubMedGoogle Scholar
  67. Kobayashi H, Hiura H, John RM, Sato A, Otsu E, Kobayashi N, Suzuki R, Suzuki F, Hayashi C, Utsunomiya T, Yaegashi N, Arima T (2009) DNA methylation errors at imprinted loci after assisted conception originate in the parental sperm. Eur J Hum Genet 17:1582–1591PubMedGoogle Scholar
  68. Koike N, Yoo SH, Huang HC, Kumar V, Lee C, Kim TK, Takahashi JS (2012) Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science 338:349–354PubMedGoogle Scholar
  69. Kuff EL, Lueders KK (1988) The intracisternal A-particle gene family: structure and functional aspects. Adv Cancer Res 51:183–276PubMedGoogle Scholar
  70. Laird CD (1987) Proposed mechanism of inheritance and expression of the human fragile-X syndrome of mental retardation. Genetics 117:587–599PubMedGoogle Scholar
  71. Lane N, Dean W, Erhardt S, Hajkova P, Surani A, Walter J, Reik W (2003) Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 35:88–93PubMedGoogle Scholar
  72. Latham KE, Sapienza C, Engel N (2012) The epigenetic lorax: gene-environment interactions in human health. Epigenomics 4:383–402PubMedGoogle Scholar
  73. Lawrance AK, Deng L, Rozen R (2009) Methylenetetrahydrofolate reductase deficiency and low dietary folate reduce tumorigenesis in Apc min/+ mice. Gut 58:805–811PubMedGoogle Scholar
  74. Li E, Bestor TH, Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69:915–926PubMedGoogle Scholar
  75. Lim JP, Brunet A (2013) Bridging the transgenerational gap with epigenetic memory. Trends Genet 29:176–186PubMedGoogle Scholar
  76. Lucifero D, Mann MR, Bartolomei MS, Trasler JM (2004) Gene-specific timing and epigenetic memory in oocyte imprinting. Hum Mol Genet 13:839–849PubMedGoogle Scholar
  77. Mahadevaiah SK, Bourc’his D, de Rooij DG, Bestor TH, Turner JM, Burgoyne PS (2008) Extensive meiotic asynapsis in mice antagonises meiotic silencing of unsynapsed chromatin and consequently disrupts meiotic sex chromosome inactivation. J Cell Biol 182:263–276PubMedGoogle Scholar
  78. Maksakova IA, Mager DL, Reiss D (2008) Keeping active endogenous retroviral-like elements in check: the epigenetic perspective. Cell Mol Life Sci 65:3329–3347PubMedGoogle Scholar
  79. Marques CJ, Carvalho F, Sousa M, Barros A (2004) Genomic imprinting in disruptive spermatogenesis. Lancet 363:1700–1702PubMedGoogle Scholar
  80. Marques CJ, Francisco T, Sousa S, Carvalho F, Barros A, Sousa M (2009) Methylation defects of imprinted genes in human testicular spermatozoa. Fertil Steril 1:1Google Scholar
  81. Mathieu O, Reinders J, Caikovski M, Smathajitt C, Paszkowski J (2007) Transgenerational stability of the Arabidopsis epigenome is coordinated by CG methylation. Cell 130:851–862PubMedGoogle Scholar
  82. Matzke MA, Matzke AJ (1998) Epigenetic silencing of plant transgenes as a consequence of diverse cellular defence responses. Cell Mol Life Sci 54:94–103PubMedGoogle Scholar
  83. McGowan R, Campbell R, Peterson A, Sapienza C (1989) Cellular mosaicism in the methylation and expression of hemizygous loci in the mouse. Genes Dev 3:1669–1676PubMedGoogle Scholar
  84. Messerschmidt DM, de Vries W, Ito M, Solter D, Ferguson-Smith A, Knowles BB (2012) Trim28 is required for epigenetic stability during mouse oocyte to embryo transition. Science 335:1499–1502PubMedGoogle Scholar
  85. Monk M (1995) Epigenetic programming of differential gene expression in development and evolution. Dev Genet 17:188–197PubMedGoogle Scholar
  86. Morgan HD, Sutherland HG, Martin DI, Whitelaw E (1999) Epigenetic inheritance at the agouti locus in the mouse. Nat Genet 23:314–318PubMedGoogle Scholar
  87. Naumova AK, Kisselev LL (1990) Biological consequences of interactions between hepatitis B virus and human nonhepatic cellular genomes. Biomed Sci 1:233–238PubMedGoogle Scholar
  88. Naumova A, Sapienza C (1994) The genetics of retinoblastoma, revisited. Am J Hum Genet 54:264–273PubMedGoogle Scholar
  89. Naumova AK, Korenev VI, Leonov BV, Tsibinogin VV, Kiselev LL (1986) DNA of the hepatitis B virus in human generative cells. Genetika 22:166–168PubMedGoogle Scholar
  90. Naumova AK, Greenwood CM, Morgan K (2001) Imprinting and deviation from Mendelian transmission ratios. Genome 44:311–320PubMedGoogle Scholar
  91. Nelson VR, Nadeau JH (2010) Transgenerational genetic effects. Epigenomics 2:797–806PubMedGoogle Scholar
  92. Nilsson E, Larsen G, Manikkam M, Guerrero-Bosagna C, Savenkova MI, Skinner MK (2012) Environmentally induced epigenetic transgenerational inheritance of ovarian disease. PLoS One 7:e36129PubMedGoogle Scholar
  93. Obata Y, Kono T (2002) Maternal primary imprinting is established at a specific time for each gene throughout oocyte growth. J Biol Chem 277:5285–5289PubMedGoogle Scholar
  94. Ohtani-Fujita N, Dryja TP, Rapaport JM, Fujita T, Matsumura S, Ozasa K (1997) Hypermethylation in the retinoblastoma gene is associated with unilateral, sporadic retinoblastoma. Cancer Genet Cytogenet 98:43–49PubMedGoogle Scholar
  95. Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257PubMedGoogle Scholar
  96. Ooi SK, Qiu C, Bernstein E, Li K, Jia D, Yang Z, Erdjument-Bromage H, Tempst P, Lin SP, Allis CD, Cheng X, Bestor TH (2007) DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448:714–717PubMedGoogle Scholar
  97. Pembrey ME, Bygren LO, Kaati G, Edvinsson S, Northstone K, Sjostrom M, Golding J, Team AS (2006) Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 14:159–166PubMedGoogle Scholar
  98. Perry WL, Copeland NG, Jenkins NA (1994) The molecular basis for dominant yellow agouti coat color mutations. BioEssays 16:705–707PubMedGoogle Scholar
  99. Pickard B, Dean W, Engemann S, Bergmann K, Fuermann M, Jung M, Reis A, Allen N, Reik W, Walter J (2001) Epigenetic targeting in the mouse zygote marks DNA for later methylation: a mechanism for maternal effects in development. Mech Dev 103:35–47PubMedGoogle Scholar
  100. Rainier S, Johnson LA, Dobry CJ, Ping AJ, Grundy PE, Feinberg AP (1993) Relaxation of imprinted genes in human cancer. Nature 362:747–749PubMedGoogle Scholar
  101. Rakyan VK, Blewitt ME, Druker R, Preis JI, Whitelaw E (2002) Metastable epialleles in mammals. Trends Genet 18:348–351PubMedGoogle Scholar
  102. Rakyan VK, Chong S, Champ ME, Cuthbert PC, Morgan HD, Luu KV, Whitelaw E (2003) Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc Natl Acad Sci U S A 100:2538–2543PubMedGoogle Scholar
  103. Reed SC (1937) The inheritance and expression of fused, a new mutation in the house mouse. Genetics 22:1–13PubMedGoogle Scholar
  104. Reik W, Collick A, Norris ML, Barton SC, Surani MA (1987) Genomic imprinting determines methylation of parental alleles in transgenic mice. Nature 328:248–251PubMedGoogle Scholar
  105. Reik W, Brown KW, Schneid H, Le Bouc Y, Bickmore W, Maher ER (1995) Imprinting mutations in the Beckwith-Wiedemann syndrome suggested by altered imprinting pattern in the IGF2-H19 domain. Hum Mol Genet 4:2379–2385PubMedGoogle Scholar
  106. Saferali A, Berlivet S, Schimenti J, Bartolomei MS, Taketo T, Naumova AK (2010) Defective imprint resetting in carriers of Robertsonian translocation Rb (8.12). Mamm Genome 21:377–387PubMedGoogle Scholar
  107. Sapienza C (1991) Genome imprinting and carcinogenesis. Biochim Biophys Acta 1072:51–61PubMedGoogle Scholar
  108. Sapienza C, Peterson AC, Rossant J, Balling R (1987) Degree of methylation of transgenes is dependent on gamete of origin. Nature 328:251–254PubMedGoogle Scholar
  109. Satake A, Iwasa Y (2012) A stochastic model of chromatin modification: cell population coding of winter memory in plants. J Theor Biol 302:6–17PubMedGoogle Scholar
  110. Scrable H, Cavenee W, Ghavimi F, Lovell M, Morgan K, Sapienza C (1989) A model for embryonal rhabdomyosarcoma tumorigenesis that involves genome imprinting. Proc Natl Acad Sci U S A 86:7480–7484PubMedGoogle Scholar
  111. Scrable HJ, Sapienza C, Cavenee WK (1990) Genetic and epigenetic losses of heterozygosity in cancer predisposition and progression. Adv Cancer Res 54:25–62PubMedGoogle Scholar
  112. Skinner GR (1976) Transformation of primary hamster embryo fibroblasts by type 2 simplex virus: evidence for a “hit and run” mechanism. Br J Exp Pathol 57:361–376PubMedGoogle Scholar
  113. Smallwood SA, Tomizawa S, Krueger F, Ruf N, Carli N, Segonds-Pichon A, Sato S, Hata K, Andrews SR, Kelsey G (2011) Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. Nat Genet 43:811–814PubMedGoogle Scholar
  114. Swain JL, Stewart TA, Leder P (1987) Parental legacy determines methylation and expression of an autosomal transgene: a molecular mechanism for parental imprinting. Cell 50:719–727PubMedGoogle Scholar
  115. Szabo PE, Mann JR (1995) Biallelic expression of imprinted genes in the mouse germ line: implications for erasure, establishment, and mechanisms of genomic imprinting. Genes Dev 9:1857–1868PubMedGoogle Scholar
  116. Toppings M, Castro C, Mills PH, Reinhart B, Schatten G, Ahrens ET, Chaillet JR, Trasler JM (2008) Profound phenotypic variation among mice deficient in the maintenance of genomic imprints. Hum Reprod 23:807–818PubMedGoogle Scholar
  117. Trasler JM (2009) Epigenetics in spermatogenesis. Mol Cell Endocrinol 306:33–36PubMedGoogle Scholar
  118. Tsuei DJ, Chang MH, Chen PJ, Hsu TY, Ni YH (2002) Characterization of integration patterns and flanking cellular sequences of hepatitis B virus in childhood hepatocellular carcinomas. J Med Virol 68:513–521PubMedGoogle Scholar
  119. Valenza-Schaerly P, Pickard B, Walter J, Jung M, Pourcel L, Reik W, Gauguier D, Vergnaud G, Pourcel C (2001) A dominant modifier of transgene methylation is mapped by QTL analysis to mouse chromosome 13. Genome Res 11:382–388PubMedGoogle Scholar
  120. Van Assche E, Bonduelle M, Tournaye H, Joris H, Verheyen G, Devroey P, Van Steirteghem A, Liebaers I (1996) Cytogenetics of infertile men. Hum Reprod 11(Suppl 4):1–24, discussion 25–26PubMedGoogle Scholar
  121. Van Guelpen B, Hultdin J, Johansson I, Hallmans G, Stenling R, Riboli E, Winkvist A, Palmqvist R (2006) Low folate levels may protect against colorectal cancer. Gut 55:1461–1466PubMedGoogle Scholar
  122. Vasicek TJ, Zeng L, Guan XJ, Zhang T, Costantini F, Tilghman SM (1997) Two dominant mutations in the mouse fused gene are the result of transposon insertions. Genetics 147:777–786PubMedGoogle Scholar
  123. Wang D, Li LB, Hou ZW, Kang XJ, Xie QD, Yu XJ, Ma MF, Ma BL, Wang ZS, Lei Y, Huang TH (2011) The integrated HIV-1 provirus in patient sperm chromosome and its transfer into the early embryo by fertilization. PLoS One 6:e28586PubMedGoogle Scholar
  124. Waterland RA, Jirtle RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23:5293–5300PubMedGoogle Scholar
  125. Waterland RA, Dolinoy DC, Lin JR, Smith CA, Shi X, Tahiliani KG (2006) Maternal methyl supplements increase offspring DNA methylation at Axin Fused. Genesis 44:401–406PubMedGoogle Scholar
  126. Waterland RA, Travisano M, Tahiliani KG (2007) Diet-induced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female. FASEB J 21:3380–3385PubMedGoogle Scholar
  127. Weng A, Magnuson T, Storb U (1995) Strain-specific transgene methylation occurs early in mouse development and can be recapitulated in embryonic stem cells. Development 121:2853–2859PubMedGoogle Scholar
  128. Wolff GL (1965) Body composition and coat color correlation in different phenotypes of “viable yellow” mice. Science 147:1145–1147PubMedGoogle Scholar
  129. Wolff GL (1978) Influence of maternal phenotype on metabolic differentiation of agouti locus mutants in the mouse. Genetics 88:529–539PubMedGoogle Scholar
  130. Wolff GL, Kodell RL, Moore SR, Cooney CA (1998) Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J 12:949–957PubMedGoogle Scholar
  131. Yang L, Andrade MF, Labialle S, Moussette S, Geneau G, Sinnett D, Belisle A, Greenwood CM, Naumova AK (2008) Parental effect of DNA (cytosine-5) methyltransferase 1 on grandparental-origin-dependent transmission ratio distortion in mouse crosses and human families. Genetics 178:35–45PubMedGoogle Scholar
  132. Zamudio NM, Scott HS, Wolski K, Lo CY, Law C, Leong D, Kinkel SA, Chong S, Jolley D, Smyth GK, de Kretser D, Whitelaw E, O’Bryan MK (2011) DNMT3L is a regulator of X chromosome compaction and post-meiotic gene transcription. PLoS One 6:e18276PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Departments of Obstetrics and Gynecology and Human GeneticsMcGill UniversityMontrealCanada
  2. 2.The Research Institute of the McGill University Health CentreMcGill UniversityMontrealCanada

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