title: No evidence for cumulative effects in a Dnmt3b hypomorph across multiple generations.
abstract: Observations of inherited phenotypes that cannot be explained solely through genetic inheritance are increasing. Evidence points to transmission of non-DNA molecules in the gamete as mediators of the phenotypes. However, in most cases it is unclear what the molecules are, with DNA methylation, chromatin proteins, and small RNAs being the most prominent candidates. From a screen to generate novel mouse mutants of genes involved in epigenetic reprogramming, we produced a DNA methyltransferase 3b allele that is missing exon 13. Mice that are homozygous for the mutant allele have smaller stature and reduced viability, with particularly high levels of female post-natal death. Reduced DNA methylation was also detected at telocentric repeats and the X-linked Hprt gene. However, none of the abnormal phenotypes or DNA methylation changes worsened with multiple generations of homozygous mutant inbreeding. This suggests that in our model the abnormalities are reset each generation and the processes of transgenerational epigenetic reprogramming are effective in preventing their inheritance.
authors: Queensland Institute of Medical Research, Herston, Brisbane, QLD 4006, Australia. n.youngson@unsw.edu.au
authors: Neil A
authors: NA
authors: Youngson
authors: Trevor
authors: T
authors: Epp
authors: Amity R
authors: AR
authors: Roberts
authors: Lucia
authors: L
authors: Daxinger
authors: Alyson
authors: A
authors: Ashe
authors: Edward
authors: E
authors: Huang
authors: Krystal L
authors: KL
authors: Lester
authors: Sarah K
authors: SK
authors: Harten
authors: Graham F
authors: GF
authors: Kay
authors: Timothy
authors: T
authors: Cox
authors: Jacqueline M
authors: JM
authors: Matthews
authors: Suyinn
authors: S
authors: Chong
authors: Emma
authors: E
authors: Whitelaw
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005091:Exons; D005260:Female; D006720:Homozygote; D008297:Male; D051379:Mice / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010375:Pedigree; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D000097584:DNA Methyltransferase 3B
references: Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14412-7
references: 10588719
references: Epigenomics. 2010 Dec;2(6):797-806
references: 22122083
references: Hum Mol Genet. 2002 Jan 1;11(1):77-86
references: 11773001
references: J Cell Biol. 2004 Aug 16;166(4):493-505
references: 15302854
references: Cell. 1999 Oct 29;99(3):247-57
references: 10555141
references: Mol Cell Biol. 2002 Apr;22(7):2124-35
references: 11884600
references: Genome Biol. 2008;9(12):R182
references: 19099580
references: G3 (Bethesda). 2012 Nov;2(11):1393-6
references: 23173090
references: Mamm Genome. 2011 Apr;22(3-4):235-48
references: 21347845
references: Science. 2011 May 13;332(6031):848-52
references: 21566194
references: Bioinformatics. 2005 Nov 1;21(21):4067-8
references: 16141249
references: Mamm Genome. 2000 May;11(5):347-55
references: 10790532
references: Nat Rev Genet. 2011 Jun 17;12(7):475-86
references: 21681209
references: Epigenetics. 2012 Jun 1;7(6):542-50
references: 22595875
references: EMBO Rep. 2009 Nov;10(11):1235-41
references: 19834512
references: Genome Biol. 2010;11(11):R111
references: 21092094
references: Biol Psychiatry. 2013 Feb 15;73(4):313-20
references: 23062885
references: EMBO J. 1997 Nov 3;16(21):6510-20
references: 9351832
references: Cell. 1992 Jun 12;69(6):915-26
references: 1606615
references: Proc Natl Acad Sci U S A. 2005 May 24;102(21):7629-34
references: 15890782
references: Nature. 2007 Aug 9;448(7154):714-7
references: 17687327
references: Hum Mol Genet. 2011 Jun 1;20(11):2195-203
references: 21421568
references: Nature. 2006 May 25;441(7092):469-74
references: 16724059
references: Nature. 2004 Jun 24;429(6994):900-3
references: 15215868
references: BMC Biol. 2004 Sep 20;2:21
references: 15377381
references: Nat Rev Genet. 2012 Jan 31;13(3):153-62
references: 22290458
references: Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):490-4
references: 22203953
references: Hum Mol Genet. 2008 Mar 1;17(5):690-709
references: 18029387
references: Proc Natl Acad Sci U S A. 2010 May 18;107(20):9281-6
references: 20439742
references: Genomics. 2004 Dec;84(6):952-60
references: 15533712
references: PLoS One. 2010 Sep 30;5(9):
references: 20927350
references: Genome Res. 2012 Apr;22(4):633-41
references: 22357612
references: Nature. 1999 Nov 11;402(6758):187-91
references: 10647011
references: Cytogenet Cell Genet. 1999;84(3-4):245-52
references: 10393442
references: Development. 2006 Mar;133(6):1183-92
references: 16501171
references: Nature. 2009 Jul 23;460(7254):473-8
references: 19525931
references: Mol Cell Endocrinol. 2012 May 6;354(1-2):3-8
references: 22020198
references: Nature. 1987 Oct 1-7;329(6138):454-6
references: 2443854
references: Nat Struct Mol Biol. 2010 Jun;17(6):679-87
references: 20473313
references: Annu Rev Genomics Hum Genet. 2008;9:233-57
references: 18767965
references: Dev Cell. 2012 Aug 14;23(2):265-79
references: 22841499
references: Birth Defects Res A Clin Mol Teratol. 2012 Oct;94(10):849-55
references: 22753363
references: J Med Genet. 2008 Feb;45(2):93-9
references: 17893117
references: Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):11939-44
references: 17609377
references: Nat Genet. 2007 May;39(5):614-22
references: 17450140
references: Nat Genet. 1999 Nov;23(3):314-8
references: 10545949
references: Development. 2009 Nov;136(21):3647-55
references: 19820183
references: Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8786-91
references: 16731628
references: Mamm Genome. 1998 Feb;9(2):150-4
references: 9457677
references: Curr Biol. 2003 May 27;13(11):955-9
references: 12781134
references: Nucleic Acids Res. 2010 Jul;38(13):4246-53
references: 20223770