The Unique Evolutionary Signature of Genes Associated with Autism Spectrum Disorder

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.

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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):36

    PubMed  PubMed Central  Article  Google Scholar 

  2. Adzhubei I, Jordan DM, Sunyaev SR (2013) Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet Chapter 7:20

    Google Scholar 

  3. Akey JM (2009) Constructing genomic maps of positive selection in humans: where do we go from here? Genome Res 19(5):711–722

    PubMed  PubMed Central  Article  Google Scholar 

  4. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th Edition (DSM-V). American Psychiatric Publishing, Arlington

    Google Scholar 

  5. Basu SN, Kollu R, Banerjee-Basu S (2009) AutDB: a gene reference resource for autism research. Nucleic Acids Res 37:D832–D836

    PubMed  Article  Google 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):17–23

    PubMed  Article  Google 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 43:36–42

    Article  Google Scholar 

  8. Chaste P, Leboyer M (2012) Autism risk factors: genes, environment, and gene-environment interactions. Dialogues Clin Neurosci 14(3):281–292

    PubMed  PubMed Central  Google 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):1–23

    PubMed  Article  Google Scholar 

  10. Connolly JJ, Hakonarson H (2014) Etiology of autism spectrum disorder: a genomics perspective. Curr Psychiatry rep 16(11):501

    PubMed  Article  Google 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 5:3650

  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):44–57

    Article  Google 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):785–793

    PubMed  Article  Google 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):345–361

    PubMed  Article  PubMed Central  Google 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):209–215

    PubMed  PubMed Central  Article  Google Scholar 

  16. Devlin B, Scherer SW (2012) Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev 22(3):229–237

    PubMed  Article  Google 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):160–179

    PubMed  PubMed Central  Article  Google Scholar 

  18. Hartl DL, Clark AG (2006) Principles of Population Genetics. Sinauer Associates, Inc

  19. Huguet G, Ey E, Bourgeron T (2013) The genetic landscapes of autism spectrum disorders. Annu Rev Genomics Hum Genet 14:191–213

    PubMed  Article  Google 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):285–299

    PubMed  PubMed Central  Article  Google 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–E5607

    PubMed  PubMed Central  Article  Google Scholar 

  22. Jia P, Sun J, Guo AY, Zhao Z (2010) SZGR: a comprehensive schizophrenia gene resource. Mol Psychiatry 15(5):453–462

    PubMed  PubMed Central  Article  Google 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):385–404

    PubMed  Google 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):58–62

    PubMed  PubMed Central  Article  Google 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):582–588

    PubMed  PubMed Central  Article  Google Scholar 

  26. Lord C (2011) Epidemiology: how common is autism? Nature 474(7350):166–168

    PubMed  Article  Google 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):218

    PubMed  PubMed Central  Google 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):292–300

    PubMed  PubMed Central  Article  Google 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):821–829

    PubMed  PubMed Central  Article  Google Scholar 

  30. Muers M (2012) Human genetics: fruits of exome sequencing for autism. Nat Rev Genet 13(6):377

    PubMed  Article  Google 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):e1001318

    PubMed  PubMed Central  Article  Google 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):16

    PubMed  PubMed Central  Article  Google 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):e1003709

    PubMed  PubMed Central  Article  Google Scholar 

  34. Platt A, Novembre J (2012) A new era of human population genetics. Genome Biol 13(12):182

    PubMed  PubMed Central  Article  Google Scholar 

  35. Ploeger A, Galis F (2011) Evolutionary approaches to autism—an overview and integration. Mcgill J Med 13(2):38

    PubMed  PubMed Central  Google 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):85–90

    PubMed  Article  Google 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):319–327

    PubMed  Article  Google 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):22–30

    PubMed  Article  Google 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 10:909–916

    Article  Google 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):944–950

    PubMed  PubMed Central  Article  Google 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):1215–1233

    PubMed  PubMed Central  Article  Google Scholar 

  42. Shohat S, Shifman S (2014) Bias towards large genes in autism. Nature 512(7512):E1–E2

    PubMed  Article  Google Scholar 

  43. Tajima F (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123(3):585–595

    PubMed  PubMed Central  Google 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):e003219

    PubMed  PubMed Central  Article  Google 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):64–69

    PubMed  PubMed Central  Article  Google 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):9–18

    PubMed  Article  Google 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 5:53

    Article  Google 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):742–747

    PubMed  Article  Google Scholar 

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Acknowledgments

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

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Correspondence to Idan Menashe.

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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.

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Tsur, E., Friger, M. & Menashe, I. The Unique Evolutionary Signature of Genes Associated with Autism Spectrum Disorder. Behav Genet 46, 754–762 (2016). https://doi.org/10.1007/s10519-016-9804-4

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Keywords

  • Autism spectrum disorder (ASD)
  • Evolution
  • Exome
  • Negative selection