Advertisement

Behavior Genetics

, Volume 46, Issue 6, pp 754–762 | Cite as

The Unique Evolutionary Signature of Genes Associated with Autism Spectrum Disorder

  • Erez Tsur
  • Michael Friger
  • Idan Menashe
Original Research

Abstract

Autism spectrum disorder (ASD) is a common heritable neurodevelopmental disorder, which is characterized by communication and social deficits that reduce the reproductive fitness of individuals with the disorder. Here, we studied the genomic characteristics of 651 ASD genes in a whole-exome sequencing dataset, to search for traces of the evolutionary forces that helped maintain ASD in the human population. We show that ASD genes are ~65 longer and ~20 % less variable than non-ASD genes. The mutational shortage in ASD genes was particularly eminent when considering only deleterious genetic variations, which is a hallmark of negative selection. We further show that these genomic characteristics are unique to ASD genes, as compared with brain-specific genes or with genes of other diseases. Our findings suggest that ASD genes have evolved under complex evolutionary forces, which have left a unique signature that can be used to identify new candidate ASD genes.

Keywords

Autism spectrum disorder (ASD) Evolution Exome Negative selection 

Notes

Acknowledgments

The authors are thankful to Dr. Ram Gal for the editing of the manuscript and his useful comments.

Compliance with Ethical Standards

Conflict of Interest

Mr. Erez Tsur declares that he has no conflict of interest. Prof. Michael Friger declares that he has no conflict of interest. Dr. Idan Menashe declares that he has no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

10519_2016_9804_MOESM1_ESM.tif (124 kb)
Figure S1: Venn diagram of the genes associated with autism spectrum disorder 489 (ASD), schizophrenia, Alzheimer’s disease, and asthma (TIFF 124 kb)
10519_2016_9804_MOESM2_ESM.pdf (437 kb)
(PDF 436 kb)
10519_2016_9804_MOESM3_ESM.docx (39 kb)
(DOCX 39 kb)
10519_2016_9804_MOESM4_ESM.pdf (196 kb)
Supplementary material 4 (PDF 197 kb)
10519_2016_9804_MOESM5_ESM.pdf (208 kb)
Supplementary material 5 (PDF 208 kb)

References

  1. Abrahams BS, Arking DE, Campbell DB, Mefford HC, Morrow EM, Weiss LA, Menashe I, Wadkins T, Banerjee-Basu S, Packer A (2013) SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs). Mol Autism 4(1):36PubMedPubMedCentralCrossRefGoogle Scholar
  2. Adzhubei I, Jordan DM, Sunyaev SR (2013) Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet Chapter 7:20Google Scholar
  3. Akey JM (2009) Constructing genomic maps of positive selection in humans: where do we go from here? Genome Res 19(5):711–722PubMedPubMedCentralCrossRefGoogle Scholar
  4. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th Edition (DSM-V). American Psychiatric Publishing, ArlingtonCrossRefGoogle Scholar
  5. Basu SN, Kollu R, Banerjee-Basu S (2009) AutDB: a gene reference resource for autism research. Nucleic Acids Res 37:D832–D836PubMedCrossRefGoogle Scholar
  6. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE (2007) Systematic meta-analyses of alzheimer disease genetic association studies: the AlzGene database. Nat Genet 39(1):17–23PubMedCrossRefGoogle Scholar
  7. Brown GR, Hem V, Katz KS, Ovetsky M, Wallin C, Ermolaeva O, Tolstoy I, Tatusova T, Pruitt KD, Maglott DR, Murphy TD (2014) Gene: a gene-centered information resource at NCBI. Nucleic Acids Res 43:36–42CrossRefGoogle Scholar
  8. Chaste P, Leboyer M (2012) Autism risk factors: genes, environment, and gene-environment interactions. Dialogues Clin Neurosci 14(3):281–292PubMedPubMedCentralGoogle Scholar
  9. Christensen DL, Baio J, Braun KV, Bilder D, Charles J, Constantino JN, Daniels J, Durkin MS, Fitzgerald RT, Kurzius-Spencer M, Lee LC, Pettygrove S, Robinson C, Schulz E, Wells C, Wingate MS, Zahorodny W, Yeargin-Allsopp M (2016) Prevalence and characteristics of autism spectrum disorder among children aged 8 Years—autism and developmental disabilities monitoring network, 11 sites, United States 2012. MMWR Surveill Summ 65(3):1–23PubMedCrossRefGoogle Scholar
  10. Connolly JJ, Hakonarson H (2014) Etiology of autism spectrum disorder: a genomics perspective. Curr Psychiatry rep 16(11):501PubMedCrossRefGoogle Scholar
  11. Corominas R, Yang X, Lin GN, Kang S, Shen Y, Ghamsari L, Broly M, Rodriguez M, Tam S, Trigg SA, Fan C, Yi S, Tasan M, Lemmens I, Kuang X, Zhao N, Malhotra D, Michaelson JJ, Vacic V, Calderwood MA, Roth FP, Tavernier J, Horvath S, Salehi-Ashtiani K, Korkin D, Sebat J, Hill DE, Hao T, Vidal M, Iakoucheva LM (2014) Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism. Nat Commun 5:3650Google Scholar
  12. da Huang W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4(1):44–57CrossRefGoogle Scholar
  13. Davidovitch M, Hemo B, Manning-Courtney P, Fombonne E (2013) Prevalence and incidence of autism spectrum disorder in an Israeli population. J Autism Dev Disord 43(4):785–793PubMedCrossRefGoogle Scholar
  14. de la Torre-Ubieta L, Won H, Stein JL, Geschwind DH (2016) Advancing the understanding of autism disease mechanisms through genetics. Nat Med 22(4):345–361PubMedCrossRefPubMedCentralGoogle Scholar
  15. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimaki T, Lin CF, Ma’ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnstrom K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Ruther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, Study DDD, Consortium UK, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD, Homozygosity mapping 428 collaborative for A (2014) Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515(7526):209–215PubMedPubMedCentralCrossRefGoogle Scholar
  16. Devlin B, Scherer SW (2012) Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev 22(3):229–237PubMedCrossRefGoogle Scholar
  17. Elsabbagh M, Divan G, Koh YJ, Kim YS, Kauchali S, Marcin C, Montiel-Nava C, Patel V, Paula CS, Wang C, Yasamy MT, Fombonne E (2012) Global prevalence of autism and other pervasive developmental disorders. Autism Res 5(3):160–179PubMedPubMedCentralCrossRefGoogle Scholar
  18. Hartl DL, Clark AG (2006) Principles of Population Genetics. Sinauer Associates, IncGoogle Scholar
  19. Huguet G, Ey E, Bourgeron T (2013) The genetic landscapes of autism spectrum disorders. Annu Rev Genomics Hum Genet 14:191–213PubMedCrossRefGoogle Scholar
  20. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell JC, Darnell RB, Mardis ER, Wilson RK, Schatz MC, McCombie WR, Wigler M (2012) De novo gene disruptions in children on the autistic spectrum. Neuron 74(2):285–299PubMedPubMedCentralCrossRefGoogle Scholar
  21. Iossifov I, Levy D, Allen J, Ye K, Ronemus M, Lee YH, Yamrom B, Wigler M (2015) Low load for disruptive mutations in autism genes and their biased transmission. Proc Natl Acad Sci USA 112(41):E5600–E5607PubMedPubMedCentralCrossRefGoogle Scholar
  22. Jia P, Sun J, Guo AY, Zhao Z (2010) SZGR: a comprehensive schizophrenia gene resource. Mol Psychiatry 15(5):453–462PubMedPubMedCentralCrossRefGoogle Scholar
  23. Keller MC, Miller G (2006) Resolving the paradox of common, harmful, heritable mental disorders: which evolutionary genetic models work best? Behav Brain Sci 29(4):385–404PubMedGoogle Scholar
  24. King IF, Yandava CN, Mabb AM, Hsiao JS, Huang HS, Pearson BL, Calabrese JM, Starmer J, Parker JS, Magnuson T, Chamberlain SJ, Philpot BD, Zylka MJ (2013) Topoisomerases facilitate transcription of long genes linked to autism. Nature 501(7465):58–62PubMedPubMedCentralCrossRefGoogle Scholar
  25. Krumm N, Turner TN, Baker C, Vives L, Mohajeri K, Witherspoon K, Raja A, Coe BP, Stessman HA, He ZX, Leal SM, Bernier R, Eichler EE (2015) Excess of rare, inherited truncating mutations in autism. Nat Genet 47(6):582–588PubMedPubMedCentralCrossRefGoogle Scholar
  26. Lord C (2011) Epidemiology: how common is autism? Nature 474(7350):166–168PubMedCrossRefGoogle Scholar
  27. Lynn DJ, Winsor GL, Chan C, Richard N, Laird MR, Barsky A, Gardy JL, Roche FM, Chan TH, Shah N, Lo R, Naseer M, Que J, Yau M, Acab M, Tulpan D, Whiteside MD, Chikatamarla A, Mah B, Munzner T, Hokamp K, Hancock RE, Brinkman FS (2008) InnateDB: facilitating systems-level analyses of the mammalian innate immune response. Mol Syst Biol 4(1):218PubMedPubMedCentralGoogle Scholar
  28. Maenner MJ, Rice CE, Arneson CL, Cunniff C, Schieve LA, Carpenter LA, Van Naarden Braun K, Kirby RS, Bakian AV, Durkin MS (2014) Potential impact of DSM-5 criteria on autism spectrum disorder prevalence estimates. JAMA psychiatry 71(3):292–300PubMedPubMedCentralCrossRefGoogle Scholar
  29. McEvoy BP, Powell JE, Goddard ME, Visscher PM (2011) Human population dispersal “Out of Africa” estimated from linkage disequilibrium and allele frequencies of SNPs. Genome Res 21(6):821–829PubMedPubMedCentralCrossRefGoogle Scholar
  30. Muers M (2012) Human genetics: fruits of exome sequencing for autism. Nat Rev Genet 13(6):377PubMedCrossRefGoogle Scholar
  31. Myers RA, Casals F, Gauthier J, Hamdan FF, Keebler J, Boyko AR, Bustamante CD, Piton AM, Spiegelman D, Henrion E, Zilversmit M, Hussin J, Quinlan J, Yang Y, Lafreniere RG, Griffing AR, Stone EA, Rouleau GA, Awadalla P (2011) A population genetic approach to mapping neurological disorder genes using deep resequencing. PLoS Genet 7(2):e1001318PubMedPubMedCentralCrossRefGoogle Scholar
  32. Ouwenga RL, Dougherty J (2015) Fmrp targets or not: long, highly brain-expressed genes tend to be implicated in autism and brain disorders. Mol Autism 6(1):16PubMedPubMedCentralCrossRefGoogle Scholar
  33. Petrovski S, Wang Q, Heinzen EL, Allen AS, Goldstein DB (2013) Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet 9(8):e1003709PubMedPubMedCentralCrossRefGoogle Scholar
  34. Platt A, Novembre J (2012) A new era of human population genetics. Genome Biol 13(12):182PubMedPubMedCentralCrossRefGoogle Scholar
  35. Ploeger A, Galis F (2011) Evolutionary approaches to autism—an overview and integration. Mcgill J Med 13(2):38PubMedPubMedCentralGoogle Scholar
  36. Ploeger A, van der Maas HL, Raijmakers ME, Galis F (2009) Why did the savant syndrome not spread in the population? A psychiatric example of a developmental constraint. Psychiatry Res 166(1):85–90PubMedCrossRefGoogle Scholar
  37. Posserud M, Lundervold AJ, Lie SA, Gillberg C (2010) The prevalence of autism spectrum disorders: impact of diagnostic instrument and non-response bias. Soc Psychiatry Psychiatr Epidemiol 45(3):319–327PubMedCrossRefGoogle Scholar
  38. Power RA, Kyaga S, Uher R, MacCabe JH, Langstrom N, Landen M, McGuffin P, Lewis CM, Lichtenstein P, Svensson AC (2013) Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings. JAMA Psychiatry 70(1):22–30PubMedCrossRefGoogle Scholar
  39. Richards C, Jones C, Groves L, Moss J, Oliver C (2015) Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis. Lancet Psychiatry 10:909–916CrossRefGoogle Scholar
  40. Samocha KE, Robinson EB, Sanders SJ, Stevens C, Sabo A, McGrath LM, Kosmicki JA, Rehnstrom K, Mallick S, Kirby A, Wall DP, MacArthur DG, Gabriel SB, DePristo M, Purcell SM, Palotie A, Boerwinkle E, Buxbaum JD, Cook EH Jr, Gibbs RA, Schellenberg GD, Sutcliffe JS, Devlin B, Roeder K, Neale BM, Daly MJ (2014) A framework for the interpretation of de novo mutation in human disease. Nat Genet 46(9):944–950PubMedPubMedCentralCrossRefGoogle Scholar
  41. Sanders SJ, He X, Willsey AJ, Ercan-Sencicek AG, Samocha KE, Cicek AE, Murtha MT, Bal VH, Bishop SL, Dong S, Goldberg AP, Jinlu C, Keaney JF 3rd, Klei L, Mandell JD, Moreno-De-Luca D, Poultney CS, Robinson EB, Smith L, Solli-Nowlan T, Su MY, Teran NA, Walker MF, Werling DM, Beaudet AL, Cantor RM, Fombonne E, Geschwind DH, Grice DE, Lord C, Lowe JK, Mane SM, Martin DM, Morrow EM, Talkowski ME, Sutcliffe JS, Walsh CA, Yu TW, Ledbetter DH, Martin CL, Cook EH, Buxbaum JD, Daly MJ, Devlin B, Roeder K, State MW (2015) Insights into autism spectrum disorder genomic architecture and biology from 71 risk Loci. Neuron 87(6):1215–1233PubMedPubMedCentralCrossRefGoogle Scholar
  42. Shohat S, Shifman S (2014) Bias towards large genes in autism. Nature 512(7512):E1–E2PubMedCrossRefGoogle Scholar
  43. Tajima F (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123(3):585–595PubMedPubMedCentralGoogle Scholar
  44. Taylor B, Jick H, Maclaughlin D (2013) Prevalence and incidence rates of autism in the UK: time trend from 2004–2010 in children aged 8 years. BMJ Open 3(10):e003219PubMedPubMedCentralCrossRefGoogle Scholar
  45. Tennessen JA, Bigham AW, O’Connor TD, Fu W, Kenny EE, Gravel S, McGee S, Do R, Liu X, Jun G, Kang HM, Jordan D, Leal SM, Gabriel S, Rieder MJ, Abecasis G, Altshuler D, Nickerson DA, Boerwinkle E, Sunyaev S, Bustamante CD, Bamshad MJ, Akey JM, Broad GO, Seattle GO, Project NES (2012) Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 337(6090):64–69PubMedPubMedCentralCrossRefGoogle Scholar
  46. Thorisson GA, Muilu J, Brookes AJ (2009) Genotype-phenotype databases: challenges and solutions for the post-genomic era. Nat Rev Genet 10(1):9–18PubMedCrossRefGoogle Scholar
  47. Tordjman S, Somogyi E, Coulon N, Kermarrec S, Cohen D, Bronsard G, Bonnot O, Weismann-Arcache C, Botbol M, Lauth B, Ginchat V, Roubertoux P, Barburoth M, Kovess V, Geoffray MM, Xavier J (2014) Gene x environment interactions in autism spectrum disorders: role of epigenetic mechanisms. Front in Psychiatry 5:53CrossRefGoogle Scholar
  48. Uddin M, Tammimies K, Pellecchia G, Alipanahi B, Hu P, Wang Z, Pinto D, Lau L, Nalpathamkalam T, Marshall CR, Blencowe BJ, Frey BJ, Merico D, Yuen RK, Scherer SW (2014) Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder. Nat Genet 46(7):742–747PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Public Health, Faculty of Health SciencesBen-Gurion University of the NegevBeershebaIsrael
  2. 2.Zlotowski Center for NeuroscienceBen-Gurion University of the NegevBeershebaIsrael

Personalised recommendations