Synergistic Interactions between Orthologues of Genes Spanned by Human CNVs Support Multiple-Hit Models of Autism

English version České info

Autism spectrum disorders (ASDs), which are characterised by poor social interaction and repetitive behaviours, are in part caused by genetic variation. A number of genes that vary in copy number in ASD patients have been identified, many of which were known to function at the neuronal synapse. We theorised that in some cases the dosage change of multiple genes simultaneously, rather than singularly, may lead to faulty neuronal development, and contribute to ASD. To test this, we asked whether alterations in these candidate genes would cause neuronal synapse and sleep/rest changes using the fruit fly Drosophila, and validated this model using single-gene models. We considered the simultaneous change of pairs of genes that were jointly affected by a large human copy number variant (CNVs), which are structural changes in the genome. In three of four CNVs, mutations in subsets of genes synergistically interacted to cause neuronal changes comparable to the single gene candidates. We also observed that the changes in synapse size followed the direction of the human gene copy number change. Finally, we show that different interactions affect the development of the synapse through different mechanisms, allowing us to identify distinct molecular alterations that illuminate the etiological heterogeneity of ASD.

Vyšlo v časopise: Synergistic Interactions between Orthologues of Genes Spanned by Human CNVs Support Multiple-Hit Models of Autism. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1004998
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004998

Souhrn

Zdroje

1. Veenstra-Vanderweele J, Christian SL, Cook EH Jr. (2004) Autism as a paradigmatic complex genetic disorder. Annu Rev Genomics Hum Genet 5: 379–405. 15485354

2. Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, et al. (2014) The familial risk of autism. JAMA 311: 1770–1777. doi: 10.1001/jama.2014.4144 24794370

3. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, et al. (1995) Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 25: 63–77. 7792363

4. Kusenda M, Sebat J (2008) The role of rare structural variants in the genetics of autism spectrum disorders. Cytogenet Genome Res 123: 36–43. doi: 10.1159/000184690 19287137

5. Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, et al. (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466: 368–372. doi: 10.1038/nature09146 20531469

6. Moreno-De-Luca D, Sanders SJ, Willsey AJ, Mulle JG, Lowe JK, et al. (2013) Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts. Mol Psychiatry 18: 1090–1095. doi: 10.1038/mp.2012.138 23044707

7. Gilman SR, Iossifov I, Levy D, Ronemus M, Wigler M, et al. (2011) Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 70: 898–907. doi: 10.1016/j.neuron.2011.05.021 21658583

8. Gai X, Xie HM, Perin JC, Takahashi N, Murphy K, et al. (2012) Rare structural variation of synapse and neurotransmission genes in autism. Mol Psychiatry 17: 402–411. doi: 10.1038/mp.2011.10 21358714

9. Noh HJ, Ponting CP, Boulding HC, Meader S, Betancur C, et al. (2013) Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism. PLoS Genet 9: e1003523. doi: 10.1371/journal.pgen.1003523 23754953

10. Steinberg J, Webber C (2013) The roles of FMRP-regulated genes in autism spectrum disorder: single- and multiple-hit genetic etiologies. Am J Hum Genet 93: 825–839. doi: 10.1016/j.ajhg.2013.09.013 24207117

11. van Alphen B, van Swinderen B (2013) Drosophila strategies to study psychiatric disorders. Brain Res Bull 92: 1–11. doi: 10.1016/j.brainresbull.2011.09.007 21978945

12. Greenspan RJ (2009) Selection, gene interaction, and flexible gene networks. Cold Spring Harb Symp Quant Biol 74: 131–138. doi: 10.1101/sqb.2009.74.029 19903749

13. Mackay TF (2014) Epistasis and quantitative traits: using model organisms to study gene-gene interactions. Nat Rev Genet 15: 22–33. doi: 10.1038/nrg3627 24296533

14. Liebl FL, Werner KM, Sheng Q, Karr JE, McCabe BD, et al. (2006) Genome-wide P-element screen for Drosophila synaptogenesis mutants. J Neurobiol 66: 332–347. 16408305

15. Gatto CL, Broadie K (2011) Drosophila modeling of heritable neurodevelopmental disorders. Curr Opin Neurobiol 21: 834–841. doi: 10.1016/j.conb.2011.04.009 21596554

16. Lu Y, Wang F, Li Y, Ferris J, Lee JA, et al. (2009) The Drosophila homologue of the Angelman syndrome ubiquitin ligase regulates the formation of terminal dendritic branches. Hum Mol Genet 18: 454–462. doi: 10.1093/hmg/ddn373 18996915

17. Pan L, Zhang YQ, Woodruff E, Broadie K (2004) The Drosophila fragile X gene negatively regulates neuronal elaboration and synaptic differentiation. Curr Biol 14: 1863–1870. 15498496

18. Zweier C, de Jong EK, Zweier M, Orrico A, Ousager LB, et al. (2009) CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am J Hum Genet 85: 655–666. doi: 10.1016/j.ajhg.2009.10.004 19896112

19. Oortveld MA, Keerthikumar S, Oti M, Nijhof B, Fernandes AC, et al. (2013) Human intellectual disability genes form conserved functional modules in Drosophila. PLoS Genet 9: e1003911. doi: 10.1371/journal.pgen.1003911 24204314

20. Morales J, Hiesinger PR, Schroeder AJ, Kume K, Verstreken P, et al. (2002) Drosophila fragile X protein, DFXR, regulates neuronal morphology and function in the brain. Neuron 34: 961–972. 12086643

21. Wu Y, Bolduc FV, Bell K, Tully T, Fang Y, et al. (2008) A Drosophila model for Angelman syndrome. Proc Natl Acad Sci U S A 105: 12399–12404. doi: 10.1073/pnas.0805291105 18701717

22. Glickman G (2010) Circadian rhythms and sleep in children with autism. Neurosci Biobehav Rev 34: 755–768. doi: 10.1016/j.neubiorev.2009.11.017 19963005

23. Bourgeron T (2007) The possible interplay of synaptic and clock genes in autism spectrum disorders. Cold Spring Harb Symp Quant Biol 72: 645–654. doi: 10.1101/sqb.2007.72.020 18419324

24. Stavropoulos N, Young MW (2011) insomniac and Cullin-3 regulate sleep and wakefulness in Drosophila. Neuron 72: 964–976. doi: 10.1016/j.neuron.2011.12.003 22196332

25. O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, et al. (2012) Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485: 246–250. doi: 10.1038/nature10989 22495309

26. Grima B, Dognon A, Lamouroux A, Chelot E, Rouyer F (2012) CULLIN-3 controls TIMELESS oscillations in the Drosophila circadian clock. PLoS Biol 10: e1001367. doi: 10.1371/journal.pbio.1001367 22879814

27. Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, et al. (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82: 477–488. doi: 10.1016/j.ajhg.2007.12.009 18252227

28. Levy D, Ronemus M, Yamrom B, Lee YH, Leotta A, et al. (2011) Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70: 886–897. doi: 10.1016/j.neuron.2011.05.015 21658582

29. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, et al. (2011) Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70: 863–885. doi: 10.1016/j.neuron.2011.05.002 21658581

30. Knight D, Xie W, Boulianne GL (2011) Neurexins and neuroligins: recent insights from invertebrates. Mol Neurobiol 44: 426–440. doi: 10.1007/s12035-011-8213-1 22037798

31. Bottos A, Rissone A, Bussolino F, Arese M (2011) Neurexins and neuroligins: synapses look out of the nervous system. Cell Mol Life Sci 68: 2655–2666. doi: 10.1007/s00018-011-0664-z 21394644

32. Tessier CR, Broadie K (2012) Molecular and genetic analysis of the Drosophila model of fragile X syndrome. Results Probl Cell Differ 54: 119–156. doi: 10.1007/978-3-642-21649-7_7 22009350

33. Cortesi F, Giannotti F, Ivanenko A, Johnson K (2010) Sleep in children with autistic spectrum disorder. Sleep Med 11: 659–664. doi: 10.1016/j.sleep.2010.01.010 20605110

34. Sun M, Liu L, Zeng X, Xu M, Fang M, et al. (2009) Genetic interaction between Neurexin and CAKI/CMG is important for synaptic function in Drosophila neuromuscular junction. Neurosci Res 64: 362–371. doi: 10.1016/j.neures.2009.04.009 19379781

35. Myster SH, Cavallo R, Anderson CT, Fox DT, Peifer M (2003) Drosophila p120catenin plays a supporting role in cell adhesion but is not an essential adherens junction component. J Cell Biol 160: 433–449. 12551951

36. Albin SD, Davis GW (2004) Coordinating structural and functional synapse development: postsynaptic p21-activated kinase independently specifies glutamate receptor abundance and postsynaptic morphology. J Neurosci 24: 6871–6879. 15295021

37. Harden N, Lee J, Loh HY, Ong YM, Tan I, et al. (1996) A Drosophila homolog of the Rac- and Cdc42-activated serine/threonine kinase PAK is a potential focal adhesion and focal complex protein that colocalizes with dynamic actin structures. Mol Cell Biol 16: 1896–1908. 8628256

38. Perrimon N (1988) The maternal effect of lethal(1)discs-large-1: a recessive oncogene of Drosophila melanogaster. Dev Biol 127: 392–407. 3132409

39. Jonas RK, Montojo CA, Bearden CE (2014) The 22q11.2 Deletion Syndrome as a Window into Complex Neuropsychiatric Disorders Over the Lifespan. Biol Psychiatry 75: 351–360. doi: 10.1016/j.biopsych.2013.07.019 23992925

40. Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing of primary microRNAs by the Microprocessor complex. Nature 432: 231–235. 15531879

41. Porsch M, Hofmeyer K, Bausenwein BS, Grimm S, Weber BH, et al. (1998) Isolation of a Drosophila T-box gene closely related to human TBX1. Gene 212: 237–248. 9611267

42. Chen YC, Lin YQ, Banerjee S, Venken K, Li J, et al. (2012) Drosophila neuroligin 2 is required presynaptically and postsynaptically for proper synaptic differentiation and synaptic transmission. J Neurosci 32: 16018–16030. doi: 10.1523/JNEUROSCI.1685-12.2012 23136438

43. Pan L, Broadie KS (2007) Drosophila fragile X mental retardation protein and metabotropic glutamate receptor A convergently regulate the synaptic ratio of ionotropic glutamate receptor subclasses. J Neurosci 27: 12378–12389. 17989302

44. Betancur C (2011) Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res 1380: 42–77. doi: 10.1016/j.brainres.2010.11.078 21129364

45. Klei L, Sanders SJ, Murtha MT, Hus V, Lowe JK, et al. (2012) Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism 3: 9. doi: 10.1186/2040-2392-3-9 23067556

46. Bernier R, Gerdts J, Munson J, Dawson G, Estes A (2012) Evidence for broader autism phenotype characteristics in parents from multiple-incidence autism families. Autism Res 5: 13–20. doi: 10.1002/aur.226 21905246

47. Stefansson H, Meyer-Lindenberg A, Steinberg S, Magnusdottir B, Morgen K, et al. (2014) CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 505: 361–366. doi: 10.1038/nature12818 24352232

48. MacDonald JR, Ziman R, Yuen RK, Feuk L, Scherer SW (2014) The Database of Genomic Variants: a curated collection of structural variation in the human genome. Nucleic Acids Res 42: D986–992. doi: 10.1093/nar/gkt958 24174537

49. Park H, Kim JI, Ju YS, Gokcumen O, Mills RE, et al. (2010) Discovery of common Asian copy number variants using integrated high-resolution array CGH and massively parallel DNA sequencing. Nat Genet 42: 400–405. doi: 10.1038/ng.555 20364138

50. McDonald-McGinn DM, Zackai EH (2008) Genetic counseling for the 22q11.2 deletion. Dev Disabil Res Rev 14: 69–74. doi: 10.1002/ddrr.10 18636638

51. Duffney LJ, Wei J, Cheng J, Liu W, Smith KR, et al. (2013) Shank3 Deficiency Induces NMDA Receptor Hypofunction via an Actin-Dependent Mechanism. J Neurosci 33: 15767–15778. doi: 10.1523/JNEUROSCI.1175-13.2013 24089484

52. Dolan BM, Duron SG, Campbell DA, Vollrath B, Shankaranarayana Rao BS, et al. (2013) Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486. Proc Natl Acad Sci U S A 110: 5671–5676. doi: 10.1073/pnas.1219383110 23509247

53. van der Bliek AM, Meyerowitz EM (1991) Dynamin-like protein encoded by the Drosophila shibire gene associated with vesicular traffic. Nature 351: 411–414. 1674590

54. Featherstone DE, Davis WS, Dubreuil RR, Broadie K (2001) Drosophila alpha- and beta-spectrin mutations disrupt presynaptic neurotransmitter release. J Neurosci 21: 4215–4224. 11404407

55. Melom JE, Littleton JT (2011) Synapse development in health and disease. Curr Opin Genet Dev 21: 256–261. doi: 10.1016/j.gde.2011.01.002 21277192

56. Pielage J, Bulat V, Zuchero JB, Fetter RD, Davis GW (2011) Hts/Adducin controls synaptic elaboration and elimination. Neuron 69: 1114–1131. doi: 10.1016/j.neuron.2011.02.007 21435557

57. Hagedorn EJ, Bayraktar JL, Kandachar VR, Bai T, Englert DM, et al. (2006) Drosophila melanogaster auxilin regulates the internalization of Delta to control activity of the Notch signaling pathway. J Cell Biol 173: 443–452. 16682530

58. Guan B, Hartmann B, Kho YH, Gorczyca M, Budnik V (1996) The Drosophila tumor suppressor gene, dlg, is involved in structural plasticity at a glutamatergic synapse. Curr Biol 6: 695–706. 8793296

59. de Bivort BL, Guo HF, Zhong Y (2009) Notch signaling is required for activity-dependent synaptic plasticity at the Drosophila neuromuscular junction. J Neurogenet 23: 395–404. doi: 10.3109/01677060902878481 19863270

60. Sudhof TC (2008) Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455: 903–911. doi: 10.1038/nature07456 18923512

61. Chen K, Gracheva EO, Yu SC, Sheng Q, Richmond J, et al. (2010) Neurexin in embryonic Drosophila neuromuscular junctions. PLoS One 5: e11115. doi: 10.1371/journal.pone.0011115 20559439

62. Li J, Ashley J, Budnik V, Bhat MA (2007) Crucial role of Drosophila neurexin in proper active zone apposition to postsynaptic densities, synaptic growth, and synaptic transmission. Neuron 55: 741–755. 17785181

63. Delorme R, Ey E, Toro R, Leboyer M, Gillberg C, et al. (2013) Progress toward treatments for synaptic defects in autism. Nat Med 19: 685–694. doi: 10.1038/nm.3193 23744158

64. Wagh DA, Rasse TM, Asan E, Hofbauer A, Schwenkert I, et al. (2006) Bruchpilot, a protein with homology to ELKS/CAST, is required for structural integrity and function of synaptic active zones in Drosophila. Neuron 49: 833–844. 16543132

65. Hida Y, Ohtsuka T (2010) CAST and ELKS proteins: structural and functional determinants of the presynaptic active zone. J Biochem 148: 131–137. doi: 10.1093/jb/mvq065 20581014

66. Stork T, Thomas S, Rodrigues F, Silies M, Naffin E, et al. (2009) Drosophila Neurexin IV stabilizes neuron-glia interactions at the CNS midline by binding to Wrapper. Development 136: 1251–1261. doi: 10.1242/dev.032847 19261699

67. Reiff DF, Thiel PR, Schuster CM (2002) Differential regulation of active zone density during long-term strengthening of Drosophila neuromuscular junctions. J Neurosci 22: 9399–9409. 12417665

68. Gkogkas CG, Khoutorsky A, Ran I, Rampakakis E, Nevarko T, et al. (2013) Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493: 371–377. doi: 10.1038/nature11628 23172145

69. Penney J, Tsurudome K, Liao EH, Elazzouzi F, Livingstone M, et al. (2012) TOR is required for the retrograde regulation of synaptic homeostasis at the Drosophila neuromuscular junction. Neuron 74: 166–178. doi: 10.1016/j.neuron.2012.01.030 22500638

70. Im HI, Kenny PJ (2012) MicroRNAs in neuronal function and dysfunction. Trends Neurosci 35: 325–334. doi: 10.1016/j.tins.2012.01.004 22436491

71. Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, et al. (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146: 247–261. doi: 10.1016/j.cell.2011.06.013 21784246

72. Edbauer D, Neilson JR, Foster KA, Wang CF, Seeburg DP, et al. (2010) Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132. Neuron 65: 373–384. doi: 10.1016/j.neuron.2010.01.005 20159450

73. Schratt G (2009) microRNAs at the synapse. Nat Rev Neurosci 10: 842–849. doi: 10.1038/nrn2763 19888283

74. Karr J, Vagin V, Chen K, Ganesan S, Olenkina O, et al. (2009) Regulation of glutamate receptor subunit availability by microRNAs. J Cell Biol 185: 685–697. doi: 10.1083/jcb.200902062 19433455

75. Simon AF, Chou MT, Salazar ED, Nicholson T, Saini N, et al. (2012) A simple assay to study social behavior in Drosophila: measurement of social space within a group. Genes Brain Behav 11: 243–252. doi: 10.1111/j.1601-183X.2011.00740.x 22010812

76. Goodwin SF, O'Dell KM (2012) The best laid plans: analyzing courtship defects in Drosophila. Cold Spring Harb Protoc 2012: 1140–1145. doi: 10.1101/pdb.prot071647 23118354

77. O'Brien KP, Remm M, Sonnhammer EL (2005) Inparanoid: a comprehensive database of eukaryotic orthologs. Nucleic Acids Res 33: D476–480. 15608241

78. Reiter LT, Potocki L, Chien S, Gribskov M, Bier E (2001) A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome Res 11: 1114–1125. 11381037

79. Grice SJ, Liu JL (2011) Survival motor neuron protein regulates stem cell division, proliferation, and differentiation in Drosophila. PLoS Genet 7: e1002030. doi: 10.1371/journal.pgen.1002030 21490958