title: The expanding genomic landscape of autism: discovering the 'forest' beyond the 'trees'
abstract: Autism spectrum disorders are neurodevelopmental disorders characterized by significant deficits in reciprocal social interactions, impaired communication and restricted, repetitive behaviors. As autism spectrum disorders are among the most heritable of neuropsychiatric disorders, much of autism research has focused on the search for genetic variants in protein-coding genes (i.e., the 'trees'). However, no single gene can account for more than 1% of the cases of autism spectrum disorders. Yet, genome-wide association studies have often identified statistically significant associations of genetic variations in regions of DNA that do not code for proteins (i.e., intergenic regions). There is increasing evidence that such noncoding regions are actively transcribed and may participate in the regulation of genes, including genes on different chromosomes. This article summarizes evidence that suggests that the research spotlight needs to be expanded to encompass far-reaching gene-regulatory mechanisms that include a variety of epigenetic modifications, as well as noncoding RNA (i.e., the 'forest'). Given that noncoding RNA represents over 90% of the transcripts in most cells, we may be observing just the 'tip of the iceberg' or the 'edge of the forest' in the genomic landscape of autism.
authors: Department of Biochemistry & Molecular Medicine, The George Washington University, School of Medicine & Health Sciences, 2300 Eye St., N.W., Washington, DC 20037, USA Tel.: +1 202 994 8431 valhu@gwu.edu.
authors: Valerie W
authors: VW
authors: Hu
keywords: autism spectrum disorder phenotypes; epigenetics; future therapeutic options; genetics; gene–environment interaction; new research paradigm; ‘dark matter’ RNA
references: Environ Health Perspect. 1993 Oct;101(5):386-7
references: 8119246
references: Hum Mol Genet. 2007 Dec 15;16(24):3174-87
references: 17921506
references: EMBO Rep. 2001 Jan;2(1):42-8
references: 11252722
references: Brain Res. 2007 Apr 6;1140:19-25
references: 16427031
references: Nature. 2012 Apr 04;485(7397):246-50
references: 22495309
references: BMC Med. 2009 Oct 22;7:62
references: 19845972
references: Am J Hum Genet. 2010 Mar 12;86(3):411-9
references: 20215007
references: Genome Biol. 2004;5(3):R13
references: 15003116
references: BMC Genomics. 2007 Jun 12;8:166
references: 17565689
references: Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10679-84
references: 17553964
references: J Neurosci Res. 2012 Jan;90(1):1-12
references: 21922512
references: Nature. 2012 Apr 04;485(7397):242-5
references: 22495311
references: PLoS Genet. 2012;8(4):e1002635
references: 22511880
references: Nat Med. 2008 Jul;14(7):723-30
references: 18587408
references: Hum Genet. 1999 Jan;104(1):1-9
references: 10071185
references: Am J Med Genet. 2000 Summer;97(2):153-63
references: 11180223
references: Mol Psychiatry. 2006 Feb;11(2):214-20
references: 16189504
references: Eur Child Adolesc Psychiatry. 2010 Mar;19(3):169-78
references: 19941018
references: J Biol Chem. 2009 Nov 13;284(46):32053-65
references: 19700763
references: PLoS Genet. 2012;8(5):e1002692
references: 22615578
references: Mol Autism. 2010 Apr 08;1(1):8
references: 20678250
references: Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):716-21
references: 18184812
references: Nature. 2007 Jun 14;447(7146):799-816
references: 17571346
references: Neurobiol Learn Mem. 2011 Jul;96(1):89-94
references: 21524708
references: J Biol Chem. 2002 Mar 15;277(11):9118-26
references: 11756408
references: Prostate. 2005 May 1;63(2):187-97
references: 15486987
references: Am J Med Genet. 2000 Summer;97(2):147-52
references: 11180222
references: Transcription. 2012 May-Jun;3(3):106-9
references: 22771943
references: J Biomed Biotechnol. 2009;2009:654346
references: 19841678
references: Sci Transl Med. 2012 Apr 4;4(128):128ra40
references: 22491950
references: Brain Res. 2011 Mar 22;1380:85-97
references: 20868653
references: Nat Genet. 2009 Feb;41(2):178-186
references: 19151715
references: Front Neurosci. 2012 Mar 12;6:30
references: 22416227
references: Neuron. 2003 Dec 18;40(6):1119-31
references: 14687547
references: PLoS One. 2009 Jun 03;4(6):e5775
references: 19492049
references: Autism Res. 2009 Apr;2(2):78-97
references: 19418574
references: Transcription. 2010 Nov;1(3):165-175
references: 21151833
references: FASEB J. 2010 Aug;24(8):3036-51
references: 20375269
references: PLoS One. 2011;6(9):e23356
references: 21915259
references: Autism Res. 2009 Apr;2(2):67-77
references: 19455643
references: Genome Res. 2005 Jul;15(7):987-97
references: 15998911
references: Child Dev. 2013 Jan-Feb;84(1):89-103
references: 22497667
references: Pharmacogenomics. 2011 Sep;12(9):1235-8
references: 21919600
references: Nucleic Acids Res. 2001 Jun 1;29(11):2276-83
references: 11376146
references: Nat Rev Genet. 2011 Nov 18;12(12):861-74
references: 22094949
references: BMC Genomics. 2006 May 18;7:118
references: 16709250
references: Neuron. 2011 Mar 10;69(5):957-73
references: 21382555
references: Trends Genet. 2005 Feb;21(2):93-102
references: 15661355
references: Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17337-42
references: 17085592
references: Int J Pediatr. 2009;2009:198736
references: 19946417
references: Science. 2005 Sep 2;309(5740):1559-63
references: 16141072
references: J Comp Neurol. 1999 Aug 23;411(2):267-73
references: 10404252
references: Arch Gen Psychiatry. 2011 Nov;68(11):1095-102
references: 21727249
references: Arch Gen Psychiatry. 2011 Nov;68(11):1104-12
references: 21727247
references: Ann Med. 2006;38(8):530-44
references: 17438668
references: Am J Hum Genet. 2008 Feb;82(2):477-88
references: 18252227
references: Brain Res Dev Brain Res. 2001 Feb 28;126(2):201-9
references: 11248354
references: Mol Psychiatry. 2005 Aug;10(8):747-57
references: 15824743
references: Bioessays. 2003 Oct;25(10):930-9
references: 14505360
references: Ment Retard Dev Disabil Res Rev. 2002;8(2):82-6
references: 12112732
references: Nat Genet. 1999 Oct;23(2):185-8
references: 10508514
references: Nature. 2009 Oct 8;461(7265):802-8
references: 19812673
references: Neuron. 2004 Aug 19;43(4):527-37
references: 15312651
references: RNA. 2009 Sep;15(9):1640-51
references: 19617315
references: RNA. 2003 Oct;9(10):1274-81
references: 13130141
references: Environ Health Perspect. 2004 Jun;112(9):944-9
references: 15198913
references: Nat Rev Genet. 2001 Dec;2(12):919-29
references: 11733745
references: Curr Genomics. 2009 May;10(3):154-68
references: 19881909
references: Am J Clin Nutr. 2012 Jul;96(1):80-9
references: 22648721
references: Biochim Biophys Acta. 2008 Aug;1779(8):471-8
references: 18194678
references: Nature. 2010 Jul 15;466(7304):368-72
references: 20531469
references: BMC Biol. 2007 Jan 30;5:4
references: 17263875
references: J Child Psychol Psychiatry. 1977 Sep;18(4):297-321
references: 562353
references: Science. 2003 May 2;300(5620):767-72
references: 12690205
references: BMC Genomics. 2007 Oct 18;8:376
references: 17945006
references: Brain Res. 2010 Jun 18;1338:20-35
references: 20380817
references: Nat Genet. 2011 Jun;43(6):585-9
references: 21572417
references: Hum Mutat. 2000 Apr;15(4):382-3
references: 10737989
references: PLoS One. 2009 Jul 01;4(7):e6121
references: 19568434
references: Biol Psychiatry. 2008 Oct 1;64(7):561-70
references: 18632090
references: Nat Neurosci. 2011 Oct 30;14(12):1499-506
references: 22037497
references: Nature. 2009 May 28;459(7246):528-33
references: 19404256
references: Neurogenetics. 2008 Jul;9(3):153-61
references: 18563458
references: J Cell Mol Med. 2008 Sep-Oct;12(5A):1466-76
references: 18624757
references: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19416-21
references: 18042715
references: PLoS One. 2011 Apr 27;6(4):e19067
references: 21556359
references: Mol Cell Endocrinol. 2012 May 6;354(1-2):3-8
references: 22020198
references: Science. 2005 Nov 4;310(5749):819-23
references: 16272115
references: Am J Med Genet B Neuropsychiatr Genet. 2010 Sep;153B(6):1209-20
references: 20468076
references: Mol Autism. 2010 Feb 22;1(1):3
references: 20678246
references: Hum Mol Genet. 2010 Oct 15;19(20):4072-82
references: 20663923
references: PLoS One. 2008 Jan 23;3(1):e1486
references: 18213394
references: PLoS One. 2011 Feb 16;6(2):e17116
references: 21359227
references: Science. 1995 May 5;268(5211):731-4
references: 7732383
references: J Neurochem. 2006 Mar;96(6):1778-89
references: 16539693
references: Epigenetics. 2011 Jul;6(7):862-9
references: 21617367
references: Hum Mol Genet. 2012 Jun 1;21(11):2399-411
references: 22343140
references: Cell. 2004 Feb 20;116(4):499-509
references: 14980218
references: BMC Biol. 2010 Dec 21;8:149
references: 21176148
references: Neuron. 2012 Apr 26;74(2):285-99
references: 22542183
references: Mol Neurobiol. 2011 Dec;44(3):359-73
references: 21969146
references: Future Neurol. 2009;4(5):591-599
references: 19953194
references: Arch Gen Psychiatry. 2012 Mar;69(3):314-24
references: 22065254
references: Cell. 2008 Oct 31;135(3):391-5
references: 18984147
references: Genome Med. 2010 Apr 07;2(4):23
references: 20374639
references: Nat Chem Biol. 2007 Mar;3(3):166-73
references: 17259978
references: Trends Genet. 2007 May;23(5):243-9
references: 17368621
references: Neurobiol Learn Mem. 2008 Sep;90(2):472-4
references: 18583162
references: Nucleic Acids Res. 2009 May;37(9):2984-95
references: 19304753
references: Nature. 2010 Jul 8;466(7303):253-7
references: 20613842
references: Nature. 2012 Apr 04;485(7397):237-41
references: 22495306
references: Science. 2007 Apr 20;316(5823):445-9
references: 17363630
references: Psychol Med. 1995 Jan;25(1):63-77
references: 7792363
references: Hum Genet. 2012 Apr;131(4):565-79
references: 21996756
references: J Am Acad Child Adolesc Psychiatry. 2003 Jul;42(7):856-63
references: 12819446
references: Autism Res. 2008 Aug;1(4):240-50
references: 19360674
references: Stem Cells Dev. 2010 Jun;19(6):831-41
references: 19757990