title: "Selfish spermatogonial selection": a novel mechanism for the association between advanced paternal age and neurodevelopmental disorders.
abstract: There is robust evidence from epidemiological studies that the offspring of older fathers have an increased risk of neurodevelopmental disorders, such as schizophrenia and autism. The authors present a novel mechanism that may contribute to this association. Because the male germ cell undergoes many more cell divisions across the reproductive age range, copy errors taking place in the paternal germline are associated with de novo mutations in the offspring of older men. Recently it has been recognized that somatic mutations in male germ cells that modify proliferation through dysregulation of the RAS protein pathway can lead to within-testis expansion of mutant clonal lines. First identified in association with rare disorders related to paternal age (e.g., Apert syndrome, achondroplasia), this process is known as "selfish spermatogonial selection." This mechanism favors propagation of germ cells carrying pathogenic mutations, increasingly skews the mutational profile of sperm as men age, and enriches de novo mutations in the offspring of older fathers that preferentially affect specific cellular signaling pathways. This mechanism not only offers a parsimonious explanation for the association between advanced paternal age and various neurodevelopmental disorders but also provides insights into the genetic architecture (role of de novo mutations), neurobiological correlates (altered cell cycle), and some epidemiological features of these disorders. The authors outline hypotheses to test this model. Given the secular changes for delayed parenthood in most societies, this hypothesis has important public health implications.
authors: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. j.mcgrath@uq.edu.au
authors: Anne
authors: A
authors: Goriely
authors: John J
authors: JJ
authors: McGrath
authors: Christina M
authors: CM
authors: Hultman
authors: Andrew O M
authors: AO
authors: Wilkie
authors: Dolores
authors: D
authors: Malaspina
mesh_terms: D000367:Age Factors; D002658:Developmental Disabilities / Q000209:etiology* / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000209:etiology / Q000235:genetics; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D010331:Paternal Age; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013091:Spermatogenesis / Q000235:genetics / Q000502:physiology; D013094:Spermatozoa / Q000502:physiology*
references: Mol Psychiatry. 2011 Mar;16(3):286-92
references: 20157312
references: Lancet Oncol. 2011 Jun;12(6):604-8
references: 21498115
references: Arch Gen Psychiatry. 2006 Sep;63(9):1026-32
references: 16953005
references: Schizophr Bull. 2011 Sep;37(5):1039-47
references: 20185538
references: Neurogenetics. 1998 Aug;1(4):277-80
references: 10732803
references: Neuron. 2009 Jan 29;61(2):160-7
references: 19186160
references: Nature. 2012 Apr 04;485(7397):246-50
references: 22495309
references: Dis Model Mech. 2012 Jan;5(1):26-32
references: 21954066
references: PLoS Med. 2009 Mar 10;6(3):e40
references: 19278291
references: Neuron. 2009 May 14;62(3):312-26
references: 19447088
references: Front Mol Neurosci. 2012 Mar 15;5:33
references: 22435049
references: Schizophr Res. 2009 Oct;114(1-3):6-16
references: 19695837
references: Psychiatry Res. 2012 Aug 15;198(3):353-9
references: 22424906
references: Autism Res. 2010 Feb;3(1):30-9
references: 20143326
references: Nature. 2010 Jun 10;465(7299):808-12
references: 20535210
references: Schizophr Res. 2011 Dec;133(1-3):120-4
references: 22000939
references: Neuron. 2011 Jun 9;70(5):886-97
references: 21658582
references: Schizophr Bull. 2009 Mar;35(2):425-36
references: 18990714
references: Arch Gen Psychiatry. 2008 Sep;65(9):1034-40
references: 18762589
references: Nature. 2006 Jul 27;442(7101):471-4
references: 16810178
references: Schizophr Res. 2006 Feb 28;82(2-3):163-73
references: 16406496
references: JAMA Psychiatry. 2013 May;70(5):516-21
references: 23553111
references: Mol Psychiatry. 2011 Dec;16(12):1203-12
references: 21116277
references: PLoS Genet. 2009 Jul;5(7):e1000558
references: 19593369
references: Science. 2003 Aug 1;301(5633):643-6
references: 12893942
references: Nat Rev Genet. 2010 Aug;11(8):589
references: 20634812
references: Cell Calcium. 2011 May;49(5):296-305
references: 21163523
references: Autism. 2011 Nov;15(6):746-60
references: 21610186
references: Schizophr Res. 1999 Dec 21;40(3):211-8
references: 10638859
references: Nat Genet. 2011 Oct 30;43(12):1224-7
references: 22037555
references: Nat Genet. 2009 Nov;41(11):1247-52
references: 19855393
references: Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10143-8
references: 18632557
references: Cereb Cortex. 2012 Jun;22(6):1256-62
references: 21817090
references: Trends Genet. 2000 Dec;16(12):525-6
references: 11102696
references: Adv Anat Embryol Cell Biol. 2007;190:1-65
references: 17432114
references: Schizophr Res. 2011 Aug;130(1-3):282-4
references: 21680154
references: Nature. 2010 Jul 15;466(7304):368-72
references: 20531469
references: Cell. 2012 Jul 20;150(2):402-12
references: 22817899
references: PLoS One. 2009 Dec 30;4(12):e8456
references: 20041141
references: Cell. 2009 Jan 23;136(2):322-36
references: 19167333
references: Am J Hum Genet. 2012 Feb 10;90(2):175-200
references: 22325359
references: Nature. 2012 Aug 23;488(7412):471-5
references: 22914163
references: EMBO J. 2002 May 1;21(9):2139-48
references: 11980711
references: PLoS Genet. 2012;8(2):e1002420
references: 22359510
references: Arch Gen Psychiatry. 2001 Jun;58(6):573-8
references: 11386986
references: J Med Genet. 2011 Nov;48(11):776-8
references: 21969336
references: Nat Genet. 2012 Oct;44(10):1161-5
references: 22922873
references: Mol Psychiatry. 2012 Feb;17(2):142-53
references: 22083728
references: Nat Rev Genet. 2000 Oct;1(1):40-7
references: 11262873
references: Autism Res. 2011 Aug;4(4):302-10
references: 21823244
references: Transl Psychiatry. 2011 Aug 30;1:e34
references: 22832608
references: Soc Psychiatry Psychiatr Epidemiol. 2013 Aug;48(8):1289-95
references: 23104669
references: Nat Rev Cancer. 2007 Apr;7(4):295-308
references: 17384584
references: Br J Psychiatry. 1979 Feb;134:169-77
references: 427333
references: Schizophr Bull. 2013 May;39(3):527-36
references: 22522642
references: Eur J Epidemiol. 2005;20(12):1003-5
references: 16331431
references: PLoS Biol. 2007 Sep;5(9):e224
references: 17760502
references: Curr Opin Neurobiol. 2012 Jun;22(3):405-11
references: 22398399
references: J Epidemiol Community Health. 2006 Oct;60(10):851-3
references: 16973530
references: Schizophr Bull. 2010 Nov;36(6):1157-66
references: 19429845
references: Arch Gen Psychiatry. 2001 Apr;58(4):361-7
references: 11296097
references: Acta Psychiatr Scand. 2008 May;117(5):323-36
references: 18331573
references: Am J Med Genet A. 2010 Mar;152A(3):591-600
references: 20186801
references: Mol Psychiatry. 2009 Jan;14(1):30-6
references: 18813210
references: Eur J Neurosci. 2010 Feb;31(3):556-64
references: 20105239
references: Dis Model Mech. 2010 Nov-Dec;3(11-12):785-98
references: 20699480