The contribution of epigenetics to understanding genetic factors in autism

Autism spectrum disorder is a grouping of neurodevelopmental disorders characterized by deficits in social communication and language, as well as by repetitive and stereotyped behaviors. While the environment is believed to play a role in the development of autism spectrum disorder, there is now strong evidence for a genetic link to autism. Despite such evidence, studies investigating a potential single-gene cause for autism, although insightful, have been highly inconclusive. A consideration of an epigenetic approach proves to be very promising in clarifying genetic factors involved in autism. The present article is intended to provide a review of key findings pertaining to epigenetics in autism in such a way that a broader audience of individuals who do not have a strong background in genetics may better understand this highly specific and scientific content. Epigenetics refers to non-permanent heritable changes that alter expression of genes without altering the DNA sequence itself and considers the role of environment in this modulation of gene expression. This review provides a brief description of epigenetic processes, highlights evidence in the literature of epigenetic dysregulation in autism, and makes use of noteworthy findings to illustrate how a consideration of epigenetic factors can deepen our understanding of the development of autism. Furthermore, this discussion will present a promising new way for moving forward in the investigation of genetic factors within autism.

[1]  B. Chung,et al.  Copy number variation and autism: new insights and clinical implications. , 2014, Journal of the Formosan Medical Association = Taiwan yi zhi.

[2]  E. Walker,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[3]  G. I. Gallicano,et al.  Epigenetic Factors and Autism Spectrum Disorders , 2013, NeuroMolecular Medicine.

[4]  Stepan Melnyk,et al.  Complex epigenetic regulation of Engrailed-2 (EN-2) homeobox gene in the autism cerebellum , 2013, Translational Psychiatry.

[5]  David J. Nutt,et al.  GABA system dysfunction in autism and related disorders: From synapse to symptoms , 2012, Neuroscience & Biobehavioral Reviews.

[6]  W. Brown,et al.  Genes associated with autism spectrum disorder , 2012, Brain Research Bulletin.

[7]  Marion Leboyer,et al.  Autism risk factors: genes, environment, and gene-environment interactions , 2012, Dialogues in clinical neuroscience.

[8]  G. Ebers,et al.  Genetic, environmental and stochastic factors in monozygotic twin discordance with a focus on epigenetic differences , 2012, BMC Medicine.

[9]  Scott M. Williams,et al.  Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways. , 2012, Human molecular genetics.

[10]  L. Lambertini,et al.  A Research Strategy to Discover the Environmental Causes of Autism and Neurodevelopmental Disabilities , 2012, Environmental health perspectives.

[11]  G. Anderson Twin Studies in Autism: What Might They Say About Genetic and Environmental Influences , 2012, Journal of autism and developmental disorders.

[12]  Z. Weng,et al.  Epigenetic signatures of autism: trimethylated H3K4 landscapes in prefrontal neurons. , 2012, Archives of general psychiatry.

[13]  D. Gaylor,et al.  Metabolic Imbalance Associated with Methylation Dysregulation and Oxidative Damage in Children with Autism , 2012, Journal of autism and developmental disorders.

[14]  Marios Politis,et al.  Clinical application of stem cell therapy in Parkinson's disease , 2012, BMC Medicine.

[15]  J. LaSalle,et al.  Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples , 2011, Molecular autism.

[16]  D. Schroeder,et al.  15q11.2-13.3 chromatin analysis reveals epigenetic regulation of CHRNA7 with deficiencies in Rett and autism brain. , 2011, Human molecular genetics.

[17]  C. Lajonchere,et al.  Genetic heritability and shared environmental factors among twin pairs with autism. , 2011, Archives of general psychiatry.

[18]  A. Bird,et al.  The role of MeCP2 in the brain. , 2011, Annual review of cell and developmental biology.

[19]  Matthew P. Anderson,et al.  Increased Gene Dosage of Ube3a Results in Autism Traits and Decreased Glutamate Synaptic Transmission in Mice , 2011, Science Translational Medicine.

[20]  M. Oshimura,et al.  Neuron-specific impairment of inter-chromosomal pairing and transcription in a novel model of human 15q-duplication syndrome. , 2011, Human molecular genetics.

[21]  John J. Connolly,et al.  The Genetics of Autism Spectrum Disorders , 2011 .

[22]  M. Sokolowski,et al.  Conservation of gene function in behaviour , 2011, Philosophical Transactions of the Royal Society B: Biological Sciences.

[23]  Janine M. LaSalle,et al.  A genomic point-of-view on environmental factors influencing the human brain methylome , 2011, Epigenetics.

[24]  Ying-Hua Tan,et al.  Analysis of MECP2 Gene Copy Number in Boys With Autism , 2011, Journal of child neurology.

[25]  V. Eapen Genetic basis of autism: is there a way forward? , 2011, Current opinion in psychiatry.

[26]  G. Pedraza-Alva,et al.  In sickness and in health: the role of methyl-CpG binding protein 2 in the central nervous system , 2011, The European journal of neuroscience.

[27]  C. Betancur,et al.  Etiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting , 2011, Brain Research.

[28]  E. Kavalali,et al.  Role of MeCP2, DNA methylation, and HDACs in regulating synapse function , 2011, Journal of Neurodevelopmental Disorders.

[29]  Alistair T. Pagnamenta,et al.  Novel method for combined linkage and genome-wide association analysis finds evidence of distinct genetic architecture for two subtypes of autism , 2011, Journal of Neurodevelopmental Disorders.

[30]  M. Esteller,et al.  Epigenetic modifications and human disease , 2010, Nature Biotechnology.

[31]  A. Gropman,et al.  Epigenetics, Copy Number Variation, and Other Molecular Mechanisms Underlying Neurodevelopmental Disabilities: New Insights and Diagnostic Approaches , 2010, Journal of developmental and behavioral pediatrics : JDBP.

[32]  B. Chung,et al.  Autism spectrum disorders and epigenetics. , 2010, Journal of the American Academy of Child and Adolescent Psychiatry.

[33]  T. Rauch,et al.  Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[34]  Luigi Ferrucci,et al.  Abundant Quantitative Trait Loci Exist for DNA Methylation and Gene Expression in Human Brain , 2010, PLoS genetics.

[35]  Jingping Zhao,et al.  Association analysis of CNTNAP2 polymorphisms with autism in the Chinese Han population , 2010, Psychiatric genetics.

[36]  Michael L. Gonzales,et al.  The Role of MeCP2 in Brain Development and Neurodevelopmental Disorders , 2010, Current psychiatry reports.

[37]  Nancy J. Cox,et al.  Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism , 2009, Molecular Psychiatry.

[38]  M. Cuccaro,et al.  Genomic and epigenetic evidence for oxytocin receptor deficiency in autism , 2009, BMC medicine.

[39]  J. LaSalle,et al.  Evolving role of MeCP2 in Rett syndrome and autism. , 2009, Epigenomics.

[40]  P. Curatolo,et al.  Syndromic autism: causes and pathogenetic pathways , 2009, World journal of pediatrics : WJP.

[41]  R. Delorme,et al.  Screening for Genomic Rearrangements and Methylation Abnormalities of the 15q11-q13 Region in Autism Spectrum Disorders , 2009, Biological Psychiatry.

[42]  R. Prakash,et al.  Ube3a is required for experience-dependent maturation of the neocortex , 2009, Nature Neuroscience.

[43]  Gustavo Turecki,et al.  Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse , 2009, Nature Neuroscience.

[44]  Jennette D. Driscoll,et al.  Chromosome 15q11–13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number , 2008, Journal of Medical Genetics.

[45]  E. Bacchelli,et al.  Analysis of X chromosome inactivation in autism spectrum disorders , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[46]  V. Preedy,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2008 .

[47]  I. Hertz-Picciotto,et al.  MECP2 promoter methylation and X chromosome inactivation in autism , 2008, Autism research : official journal of the International Society for Autism Research.

[48]  D. Geschwind,et al.  Advances in autism genetics: on the threshold of a new neurobiology , 2008, Nature Reviews Genetics.

[49]  Timothy M. DeLorey,et al.  Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: A potential model of autism spectrum disorder , 2008, Behavioural Brain Research.

[50]  B. O’Roak,et al.  Autism genetics: strategies, challenges, and opportunities , 2008, Autism research : official journal of the International Society for Autism Research.

[51]  J. Sebat,et al.  Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. , 2008, American journal of human genetics.

[52]  Tanya M. Teslovich,et al.  A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. , 2008, American journal of human genetics.

[53]  M. Bieda,et al.  Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes , 2007, Proceedings of the National Academy of Sciences.

[54]  J. Lamb,et al.  Autism: the quest for the genes , 2007, Expert Reviews in Molecular Medicine.

[55]  J. R. Kurian,et al.  Sex Difference in Mecp2 Expression During a Critical Period of Rat Brain Development , 2007, Epigenetics.

[56]  B. Migeon Why females are mosaics, X-chromosome inactivation, and sex differences in disease. , 2007, Gender medicine.

[57]  E. Whitelaw,et al.  Epigenetic mechanisms in the context of complex diseases , 2007, Cellular and Molecular Life Sciences.

[58]  Kenny Q. Ye,et al.  Strong Association of De Novo Copy Number Mutations with Autism , 2007, Science.

[59]  L. Chadwick,et al.  MeCP2 in Rett syndrome: transcriptional repressor or chromatin architectural protein? , 2007, Current opinion in genetics & development.

[60]  R. Jirtle,et al.  Epigenetic gene regulation: linking early developmental environment to adult disease. , 2007, Reproductive toxicology.

[61]  Julie Daniels,et al.  The epidemiology of autism spectrum disorders. , 2007, Annual review of public health.

[62]  J. LaSalle,et al.  15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. , 2007, Human molecular genetics.

[63]  Thomas Bourgeron,et al.  Mapping autism risk loci using genetic linkage and chromosomal rearrangements , 2007, Nature Genetics.

[64]  J. LaSalle The Odyssey of MeCP2 and Parental Imprinting , 2007, Epigenetics.

[65]  Elysa J. Marco,et al.  Autism-lessons from the X chromosome. , 2006, Social cognitive and affective neuroscience.

[66]  R. Ghosh,et al.  Multiple Modes of Interaction between the Methylated DNA Binding Protein MeCP2 and Chromatin , 2006, Molecular and Cellular Biology.

[67]  J. LaSalle,et al.  Reduced MeCP2 Expression is Frequent in Autism Frontal Cortex and Correlates with Aberrant MECP2 Promoter Methylation , 2006, Epigenetics.

[68]  N. C. Schanen,et al.  Epigenetics of autism spectrum disorders. , 2006, Human molecular genetics.

[69]  T. Bourgeron,et al.  Searching for ways out of the autism maze: genetic, epigenetic and environmental clues , 2006, Trends in Neurosciences.

[70]  P. Levitt,et al.  Polymorphic GGC repeat differentially regulates human reelin gene expression levels , 2006, Journal of Neural Transmission.

[71]  A. Bird,et al.  Genomic DNA methylation: the mark and its mediators. , 2006, Trends in biochemical sciences.

[72]  E. Lopez-Rangel,et al.  Loud and clear evidence for gene silencing by epigenetic mechanisms in autism spectrum and related neurodevelopmental disorders , 2005, Clinical genetics.

[73]  Z. Talebizadeh,et al.  Brief Report: Non-Random X Chromosome Inactivation in Females with Autism , 2005, Journal of autism and developmental disorders.

[74]  A. Razin,et al.  MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression. , 2005, Human molecular genetics.

[75]  J. LaSalle,et al.  Homologous pairing of 15q11-13 imprinted domains in brain is developmentally regulated but deficient in Rett and autism samples. , 2005, Human molecular genetics.

[76]  Rodney C Samaco,et al.  Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. , 2005, Human molecular genetics.

[77]  S. Scherer,et al.  Molecular Cytogenetics of Autism , 2004 .

[78]  Rodney C. Samaco,et al.  Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders. , 2004, Human molecular genetics.

[79]  Rachel A. Horowitz-Scherer,et al.  Chromatin Compaction by Human MeCP2 , 2003, Journal of Biological Chemistry.

[80]  A. Bird,et al.  Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals , 2003, Nature Genetics.

[81]  E. Li Chromatin modification and epigenetic reprogramming in mammalian development , 2002, Nature Reviews Genetics.

[82]  D. Ledbetter,et al.  Allele-specific expression analysis by RNA-FISH demonstrates preferential maternal expression of UBE3A and imprint maintenance within 15q11- q13 duplications. , 2002, Human molecular genetics.

[83]  H. Zoghbi,et al.  Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. , 2002, Human molecular genetics.

[84]  J. LaSalle,et al.  Quantitative localization of heterogeneous methyl-CpG-binding protein 2 (MeCP2) expression phenotypes in normal and Rett syndrome brain by laser scanning cytometry. , 2001, Human molecular genetics.

[85]  M. Groudine,et al.  Looping versus linking: toward a model for long-distance gene activation. , 1999, Genes & development.

[86]  H. Zoghbi,et al.  Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 , 1999, Nature Genetics.

[87]  M. Linnoila,et al.  Nonhuman primate model of alcohol abuse: effects of early experience, personality, and stress on alcohol consumption. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[88]  M. Lyon Gene Action in the X-chromosome of the Mouse (Mus musculus L.) , 1961, Nature.

[89]  E. Rogaev,et al.  Epigenetics in the Human Brain , 2013, Neuropsychopharmacology.

[90]  Valerie W. Hu From genes to environment: using integrative genomics to build a "systems-level" understanding of autism spectrum disorders. , 2013, Child development.

[91]  J. LaSalle,et al.  Epigenetic Epidemiology of Autism and Other Neurodevelopmental Disorders , 2012 .

[92]  T. Bourgeron Genetics and Epigenetics of Autism Spectrum Disorders , 2012 .

[93]  S. Scherer,et al.  Detection and characterization of copy number variation in autism spectrum disorder. , 2012, Methods in molecular biology.

[94]  L. Feuk Genomic structural variants : methods and protocols , 2012 .

[95]  A. Percy,et al.  Rett Syndrome Exploring the Autism Link , 2011 .

[96]  Andrew P. Feinberg,et al.  Genome-scale approaches to the epigenetics of common human disease , 2009, Virchows Archiv.

[97]  G. B. Schaefer,et al.  Genetics evaluation for the etiologic diagnosis of autism spectrum disorders , 2008, Genetics in Medicine.

[98]  A. Midei,et al.  General Summary , 2004, Molecular Psychiatry.

[99]  J. LaSalle,et al.  Elevated methyl-CpG-binding protein 2 expression is acquired during postnatal human brain development and is correlated with alternative polyadenylation , 2002, Journal of Molecular Medicine.

[100]  M. Meaney,et al.  Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. , 2001, Annual review of neuroscience.