Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development

Autoři: Tanzeen Yusuff aff001;  Matthew Jensen aff001;  Sneha Yennawar aff001;  Lucilla Pizzo aff001;  Siddharth Karthikeyan aff001;  Dagny J. Gould aff001;  Avik Sarker aff001;  Erika Gedvilaite aff001;  Yurika Matsui aff001;  Janani Iyer aff001;  Zhi-Chun Lai aff001;  Santhosh Girirajan aff001
Působiště autorů: Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, United States of America aff001;  Department of Biology, Pennsylvania State University, University Park, Pennsylvania, United States of America aff002;  Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania, United States of America aff003
Vyšlo v časopise: Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008792
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008792


While rare pathogenic copy-number variants (CNVs) are associated with both neuronal and non-neuronal phenotypes, functional studies evaluating these regions have focused on the molecular basis of neuronal defects. We report a systematic functional analysis of non-neuronal defects for homologs of 59 genes within ten pathogenic CNVs and 20 neurodevelopmental genes in Drosophila melanogaster. Using wing-specific knockdown of 136 RNA interference lines, we identified qualitative and quantitative phenotypes in 72/79 homologs, including 21 lines with severe wing defects and six lines with lethality. In fact, we found that 10/31 homologs of CNV genes also showed complete or partial lethality at larval or pupal stages with ubiquitous knockdown. Comparisons between eye and wing-specific knockdown of 37/45 homologs showed both neuronal and non-neuronal defects, but with no correlation in the severity of defects. We further observed disruptions in cell proliferation and apoptosis in larval wing discs for 23/27 homologs, and altered Wnt, Hedgehog and Notch signaling for 9/14 homologs, including AATF/Aatf, PPP4C/Pp4-19C, and KIF11/Klp61F. These findings were further supported by tissue-specific differences in expression patterns of human CNV genes, as well as connectivity of CNV genes to signaling pathway genes in brain, heart and kidney-specific networks. Our findings suggest that multiple genes within each CNV differentially affect both global and tissue-specific developmental processes within conserved pathways, and that their roles are not restricted to neuronal functions.

Klíčová slova:

Apoptosis – Drosophila melanogaster – Eyes – Genetic networks – Hedgehog signaling – Notch signaling – Phenotypes – RNA interference


1. Girirajan S, Campbell CD, Eichler EE. Human Copy Number Variation and Complex Genetic Disease. Annu Rev Genet. 2011;45: 203–226. doi: 10.1146/annurev-genet-102209-163544 21854229

2. Malhotra D, Sebat J. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell. 2012;148: 1223–1241. doi: 10.1016/j.cell.2012.02.039 22424231

3. Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, et al. A copy number variation morbidity map of developmental delay. Nat Genet. 2011;43: 838–846. doi: 10.1038/ng.909 21841781

4. Zhang F, Gu W, Hurles ME, Lupski JR. Copy Number Variation in Human Health, Disease, and Evolution. Annu Rev Genomics Hum Genet. 2009;10: 451–481. doi: 10.1146/annurev.genom.9.081307.164217 19715442

5. Greenway SC, Pereira AC, Lin JC, Depalma SR, Israel SJ, Mesquita SM, et al. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat Genet. 2009;41: 931–935. doi: 10.1038/ng.415 19597493

6. Glessner JT, Bick AG, Ito K et al. Increased Frequency of De Novo Copy Number Variations in Congenital Heart Disease by Integrative Analysis of SNP Array and Exome Sequence Data. Circ Res. 2014;115: 884–896. doi: 10.1161/CIRCRESAHA.115.304458 25205790

7. Sanna-Cherchi S, Kiryluk K, Burgess KE, Bodria M, Sampson MG, Hadley D, et al. Copy-number disorders are a common cause of congenital kidney malformations. Am J Hum Genet. 2012;91: 987–997. doi: 10.1016/j.ajhg.2012.10.007 23159250

8. Zahnleiter D, Uebe S, Ekici AB, Hoyer J, Wiesener A, Wieczorek D, et al. Rare copy number variants are a common cause of short stature. PLoS Genet. 2013;9: e1003365. doi: 10.1371/journal.pgen.1003365 23516380

9. Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009;84: 524–533. doi: 10.1016/j.ajhg.2009.03.010 19344873

10. Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008;359: 1685–99. doi: 10.1056/NEJMoa0805384 18784092

11. Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T, et al. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet. 2008;40: 1466–1471. doi: 10.1038/ng.279 19029900

12. Christiansen J, Dyck JD, Elyas BG, Lilley M, Bamforth JS, Hicks M, et al. Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease. Circ Res. 2004;94: 1429–35. doi: 10.1161/01.RES.0000130528.72330.5c 15117819

13. Pober BR. Williams-Beuren syndrome. N Engl J Med. 2010;362: 239–52. doi: 10.1056/NEJMra0903074 20089974

14. Horev G, Ellegood J, Lerch JP, Son Y-EE, Muthuswamy L, Vogel H, et al. Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism. Proc Natl Acad Sci. 2011;108: 17076–17081. doi: 10.1073/pnas.1114042108 21969575

15. Pucilowska J, Vithayathil J, Tavares EJ, Kelly C, Karlo JC, Landreth GE. The 16p11.2 Deletion Mouse Model of Autism Exhibits Altered Cortical Progenitor Proliferation and Brain Cytoarchitecture Linked to the ERK MAPK Pathway. J Neurosci. 2015;35: 3190–3200. doi: 10.1523/JNEUROSCI.4864-13.2015 25698753

16. Portmann T, Yang M, Mao R, Panagiotakos G, Ellegood J, Dolen G, et al. Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome. Cell Rep. 2014;7: 1077–1092. doi: 10.1016/j.celrep.2014.03.036 24794428

17. Rutkowski TP, Purcell RH, Pollak RM, Grewenow SM, Gafford GM, Malone T, et al. Behavioral changes and growth deficits in a CRISPR engineered mouse model of the schizophrenia-associated 3q29 deletion. Mol Psychiatry. 2019. doi: 10.1038/s41380-019-0413-5 30976085

18. Baba M, Yokoyama K, Seiriki K, Naka Y, Matsumura K, Kondo M, et al. Psychiatric-disorder-related behavioral phenotypes and cortical hyperactivity in a mouse model of 3q29 deletion syndrome. Neuropsychopharmacology. 2019;44: 2125–2135. doi: 10.1038/s41386-019-0441-5 31216562

19. Arbogast T, Ouagazzal A-M, Chevalier C, Kopanitsa M, Afinowi N, Migliavacca E, et al. Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes. PLOS Genet. 2016;12: e1005709. doi: 10.1371/journal.pgen.1005709 26872257

20. Haller M, Au J, O’Neill M, Lamb DJ. 16p11.2 transcription factor MAZ is a dosage-sensitive regulator of genitourinary development. Proc Natl Acad Sci. 2018;115: 201716092. doi: 10.1073/pnas.1716092115 29432158

21. Yadav S, Oses-Prieto JA, Peters CJ, Zhou J, Pleasure SJ, Burlingame AL, et al. TAOK2 Kinase Mediates PSD95 Stability and Dendritic Spine Maturation through Septin7 Phosphorylation. Neuron. 2017;93: 379–393. doi: 10.1016/j.neuron.2016.12.006 28065648

22. Richter M, Murtaza N, Scharrenberg R, White SH, Johanns O, Walker S, et al. Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling. Mol Psychiatry. 2019;24: 1329–1350. doi: 10.1038/s41380-018-0025-5 29467497

23. Golzio C, Willer J, Talkowski ME, Oh EC, Taniguchi Y, Jacquemont S, et al. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature. 2012;485: 363–367. doi: 10.1038/nature11091 22596160

24. Escamilla CO, Filonova I, Walker AK, Xuan ZX, Holehonnur R, Espinosa F, et al. Kctd13 deletion reduces synaptic transmission via increased RhoA. Nature. 2017;551: 227–231. doi: 10.1038/nature24470 29088697

25. Ip JPK, Nagakura I, Petravicz J, Li K, Wiemer EAC, Sur M. Major vault protein, a candidate gene in 16p11.2 microdeletion syndrome, is required for the homeostatic regulation of visual cortical plasticity. J Neurosci. 2018;38: 2017–2034. doi: 10.1523/JNEUROSCI.2034-17.2018 29540554

26. Dickinson ME, Flenniken AM, Ji X, Teboul L, Wong MD, White JK, et al. High-throughput discovery of novel developmental phenotypes. Nature. 2016;537: 508–514. doi: 10.1038/nature19356 27626380

27. Wangler MF, Yamamoto S, Bellen HJ. Fruit flies in biomedical research. Genetics. 2015;199: 639–653. doi: 10.1534/genetics.114.171785 25624315

28. Chien S. Homophila: human disease gene cognates in Drosophila. Nucleic Acids Res. 2002;30: 149–151. doi: 10.1093/nar/30.1.149 11752278

29. Reiter LT, Potocki L, Chien S, Gribskov M, Bier E. A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome Res. 2001;11: 1114–1125. doi: 10.1101/gr.169101 11381037

30. Iyer J, Singh MD, Jensen M, Patel P, Pizzo L, Huber E, et al. Pervasive genetic interactions modulate neurodevelopmental defects of the autism-associated 16p11.2 deletion in Drosophila melanogaster. Nat Commun. 2018;9: 2548. doi: 10.1038/s41467-018-04882-6 29959322

31. Singh MD, Jensen M, Lasser M, Huber E, Yusuff T, Pizzo L, et al. NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models. PLOS Genet. 2020;16: e1008590. doi: 10.1371/journal.pgen.1008590 32053595

32. Molnar C, Resnik-Docampo M, F. M, Martin M, F. C, de Celis JF. Signalling Pathways in Development and Human Disease: A Drosophila Wing Perspective. Human Genetic Diseases. InTech; 2011. doi: 10.5772/23858

33. Dworkin I, Gibson G. Epidermal growth factor receptor and transforming growth factor-β signaling contributes to variation for wing shape in Drosophila melanogaster. Genetics. 2006;173: 1417–1431. doi: 10.1534/genetics.105.053868 16648592

34. Testa ND, Dworkin I. The sex-limited effects of mutations in the EGFR and TGF-β signaling pathways on shape and size sexual dimorphism and allometry in the Drosophila wing. Dev Genes Evol. 2016;226: 159–171. doi: 10.1007/s00427-016-0534-7 27038022

35. Yan SJ, Gu Y, Li WX, Fleming RJ. Multiple signaling pathways and a selector protein sequentially regulate Drosophila wing development. Development. 2004;131: 285–298. doi: 10.1242/dev.00934 14701680

36. Strigini M, Cohen SM. A Hedgehog activity gradient contributes to AP axial patterning of the Drosophila wing. Development. 1997;124: 4697–4705. 9409685

37. Diaz de la Loza MC, Thompson BJ. Forces shaping the Drosophila wing. Mech Dev. 2017;144: 23–32. doi: 10.1016/j.mod.2016.10.003 27784612

38. Bier E. Drosophila, the golden bug, emerges as a tool for human genetics. Nat Rev Genet. 2005;6: 9–23. doi: 10.1038/nrg1503 15630418

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

40. Yamamoto S, Jaiswal M, Charng WL, Gambin T, Karaca E, Mirzaa G, et al. A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases. Cell. 2014;159: 200–214. doi: 10.1016/j.cell.2014.09.002 25259927

41. Kochinke K, Zweier C, Nijhof B, Fenckova M, Cizek P, Honti F, et al. Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules. Am J Hum Genet. 2016;98: 149–164. doi: 10.1016/j.ajhg.2015.11.024 26748517

42. Hu Y, Flockhart I, Vinayagam A, Bergwitz C, Berger B, Perrimon N, et al. An integrative approach to ortholog prediction for disease-focused and other functional studies. BMC Bioinformatics. 2011;12: 357. doi: 10.1186/1471-2105-12-357 21880147

43. Capdevila J, Guerrero I. Targeted expression of the signaling molecule decapentaplegic induces pattern duplications and growth alterations in Drosophila wings. EMBO J. 1994;13: 4459–4468. doi: 10.1002/j.1460-2075.1994.tb06768.x 7925288

44. Lindström R, Lindholm P, Palgi M, Saarma M, Heino TI. In vivo screening reveals interactions between Drosophila Manf and genes involved in the mitochondria and the ubiquinone synthesis pathway. BMC Genet. 2017;18: 52. doi: 10.1186/s12863-017-0509-3 28578657

45. Nielsen J, Fejgin K, Sotty F, Nielsen V, Mørk A, Christoffersen CT, et al. A mouse model of the schizophrenia-associated 1q21.1 microdeletion syndrome exhibits altered mesolimbic dopamine transmission. Transl Psychiatry. 2017;7: 1261. doi: 10.1038/s41398-017-0011-8 29187755

46. Huang H, Potter CJ, Tao W, Li DM, Brogiolo W, Hafen E, et al. PTEN affects cell size, cell proliferation and apoptosis during Drosophila eye development. Development. 1999;126: 5365–5372. doi: 10.5167/uzh-627 10556061

47. Toyo-oka K, Mori D, Yano Y, Shiota M, Iwao H, Goto H, et al. Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation. J Cell Biol. 2008;180: 1133–1147. doi: 10.1083/jcb.200705148 18347064

48. Ohsugi M, Adachi K, Horai R, Kakuta S, Sudo K, Kotaki H, et al. Kid-Mediated Chromosome Compaction Ensures Proper Nuclear Envelope Formation. Cell. 2008;132: 771–782. doi: 10.1016/j.cell.2008.01.029 18329364

49. Kumar JP. Building an ommatidium one cell at a time. Dev Dyn. 2012;241: 136–149. doi: 10.1002/dvdy.23707 22174084

50. Nériec N, Desplan C. From the Eye to the Brain. Development of the Drosophila Visual System. Curr Top Dev Biol. 2016;116: 247–271. doi: 10.1016/bs.ctdb.2015.11.032 26970623

51. Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J, Hutton M, et al. Tauopathy in Drosophila: Neurodegeneration without neurofibrillary tangles. Science. 2001;293: 711–714. doi: 10.1126/science.1062382 11408621

52. Cukier HN, Perez AM, Collins AL, Zhou Z, Zoghbi HY, Botas J. Genetic modifiers of MeCP2 function in Drosophila. PLoS Genet. 2008;4: e1000179. doi: 10.1371/journal.pgen.1000179 18773074

53. Bilen J, Bonini NM. Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila. PLoS Genet. 2007;3: 1950–1964. doi: 10.1371/journal.pgen.0030177 17953484

54. Iyer J, Wang Q, Le T, Pizzo L, Grönke S, Ambegaokar SS, et al. Quantitative assessment of eye phenotypes for functional genetic studies using Drosophila melanogaster. G3 Genes, Genomes, Genet. 2016;6: 1427–1437. doi: 10.1534/g3.116.027060 26994292

55. Rosenberg MJ, Agarwala R, Bouffard G, Davis J, Fiermonte G, Hilliard MS, et al. Mutant deoxynucleotide carrier is associated with congenital microcephaly. Nat Genet. 2002;32: 175–179. doi: 10.1038/ng948 12185364

56. Chintapalli VR, Wang J, Dow JAT. Using FlyAtlas to identify better Drosophila melanogaster models of human disease. Nat Genet. 2007;39: 715–720. doi: 10.1038/ng2049 17534367

57. Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001;68: 1327–1332. doi: 10.1086/320609 11359211

58. Ardlie KG, DeLuca DS, Segrè AV., Sullivan TJ, Young TR, Gelfand ET, et al. The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans. Science. 2015;348: 648–660. doi: 10.1126/science.1262110 25954001

59. Ernst C. Proliferation and Differentiation Deficits are a Major Convergence Point for Neurodevelopmental Disorders. Trends Neurosci. 2016;39: 290–299. doi: 10.1016/j.tins.2016.03.001 27032601

60. Marchetto MC, Belinson H, Tian Y, Freitas BC, Fu C, Vadodaria KC, et al. Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol Psychiatry. 2017;22: 820–835. doi: 10.1038/mp.2016.95 27378147

61. Wei H, Alberts I, Li X. The apoptotic perspective of autism. Int J Dev Neurosci. 2014;36: 13–18. doi: 10.1016/j.ijdevneu.2014.04.004 24798024

62. Hartl TA, Scott MP. Wing tips: The wing disc as a platform for studying Hedgehog signaling. Methods. 2014;68: 199–206. doi: 10.1016/j.ymeth.2014.02.002 24556557

63. de Celis JF, García-Bellido A. Roles of the Notch gene in Drosophila wing morphogenesis. Mech Dev. 1994;46: 109–122. doi: 10.1016/0925-4773(94)90080-9 7918096

64. Raftery LA, Umulis DM. Regulation of BMP activity and range in Drosophila wing development. Curr Opin Cell Biol. 2012;24: 158–65. doi: 10.1016/j.ceb.2011.11.004 22152945

65. Diaz-Benjumea FJ, Cohen SM. Serrate signals through Notch to establish a Wingless-dependent organizer at the dorsal/ventral compartment boundary of the Drosophila wing. Development. 1995;121: 4215–4225. 8575321

66. Becam I, Milán M. A permissive role of Notch in maintaining the DV affinity boundary of the Drosophila wing. Dev Biol. 2008;322: 190–8. doi: 10.1016/j.ydbio.2008.07.028 18703041

67. Zecca M, Basler K, Struhl G. Sequential organizing activities of engrailed, hedgehog and decapentaplegic in the Drosophila wing. Development. 1995;121: 2265–2278. doi: 10.5167/uzh-1053 7671794

68. Tabata T, Kornberg TB. Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell. 1994;76: 89–102. doi: 10.1016/0092-8674(94)90175-9 8287482

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

70. Hahn H, Wicking C, Zaphiropoulos PG, Gailani MR, Shanley S, Chidambaram A, et al. Mutations of the human homolog of drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85: 841–851. doi: 10.1016/s0092-8674(00)81268-4 8681379

71. Johnson RL, Rothman AL, Xie J, Goodrich LV., Bare JW, Bonifas JM, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272: 1668–1671. doi: 10.1126/science.272.5268.1668 8658145

72. Swarup S, Pradhan-Sundd T, Verheyen EM. Genome-wide identification of phospho-regulators of Wnt signaling in Drosophila. Dev. 2015;142: 1502–1515. doi: 10.1242/dev.116715 25852200

73. Six EM, Ndiaye D, Sauer G, Laâbi Y, Athman R, Cumano A, et al. The Notch ligand Delta1 recruits Dlg1 at cell-cell contacts and regulates cell migration. J Biol Chem. 2004;279: 55818–55826. doi: 10.1074/jbc.M408022200 15485825

74. Greene CS, Krishnan A, Wong AK, Ricciotti E, Zelaya RA, Himmelstein DS, et al. Understanding multicellular function and disease with human tissue-specific networks. Nat Genet. 2015;47: 569–576. doi: 10.1038/ng.3259 25915600

75. Bult CJ, Blake JA, Smith CL, Kadin JA, Richardson JE, Mouse Genome Database Group. Mouse Genome Database (MGD) 2019. Nucleic Acids Res. 2019;47: D801–D806. doi: 10.1093/nar/gky1056 30407599

76. Zhou W, Zhang L, Guoxiang X, Mojsilovic-Petrovic J, Takamaya K, Sattler R, et al. GluR1 controls dendrite growth through its binding partner, SAP97. J Neurosci. 2008;28: 10220–10233. doi: 10.1523/JNEUROSCI.3434-08.2008 18842882

77. Iizuka-Kogo A, Ishidao T, Akiyama T, Senda T. Abnormal development of urogenital organs in Dlgh1-deficient mice. Development. 2007;134: 1799–1807. doi: 10.1242/dev.02830 17435047

78. Mahoney ZX, Sammut B, Xavier RJ, Cunningham J, Go G, Brim KL, et al. Discs-large homolog 1 regulates smooth muscle orientation in the mouse ureter. Proc Natl Acad Sci U S A. 2006;103: 19872–19877. doi: 10.1073/pnas.0609326103 17172448

79. Caruana G, Bernstein A. Craniofacial dysmorphogenesis including cleft palate in mice with an insertional mutation in the discs large gene. Mol Cell Biol. 2001;21: 1475–83. doi: 10.1128/MCB.21.5.1475-1483.2001 11238884

80. Chapman DL, Papaioannou VE. Three neural tubes in mouse embryos with mutations in the T-box gene Tbx6. Nature. 1998;391: 695–697. doi: 10.1038/35624 9490412

81. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: Tool for the unification of biology. Nat Genet. 2000;25: 25–29. doi: 10.1038/75556 10802651

82. Carbon S, Douglass E, Dunn N, Good B, Harris NL, Lewis SE, et al. The Gene Ontology Resource: 20 years and still GOing strong. Nucleic Acids Res. 2019;47: D330–D338. doi: 10.1093/nar/gky1055 30395331

83. Pabis M, Neufeld N, Shav-Tal Y, Neugebauer KM. Binding properties and dynamic localization of an alternative isoform of the cap-binding complex subunit CBP20. Nucleus. 2010;1: 412–421. doi: 10.4161/nucl.1.5.12839 21326824

84. Di Padova M, Bruno T, De Nicola F, Iezzi S, D’Angelo C, Gallo R, et al. Che-1 arrests human colon carcinoma cell proliferation by displacing HDAC1 from the p21WAF1/CIP1 promoter. J Biol Chem. 2003;278: 36496–504. doi: 10.1074/jbc.M306694200 12847090

85. Bruno T, De Angelis R, De Nicola F, Barbato C, Di Padova M, Corbi N, et al. Che-1 affects cell growth by interfering with the recruitment of HDAC1 by Rb. Cancer Cell. 2002;2: 387–399. doi: 10.1016/S1535-6108(02)00182-4

86. Page G, Lödige I, Kögel D, Scheidtmann KH. AATF, a novel transcription factor that interacts with Dlk/ZIP kinase and interferes with apoptosis. FEBS Lett. 1999;462: 187–91. doi: 10.1016/s0014-5793(99)01529-x 10580117

87. Sumiyoshi E, Sugimoto A, Yamamoto M. Protein phosphatase 4 is required for centrosome maturation in mitosis and sperm meiosis in C. elegans. J Cell Sci. 2002;115: 1403–1410. 11896188

88. Jensen M, Girirajan S. An interaction-based model for neuropsychiatric features of copy-number variants. PLoS Genet. 2019;15: e1007879. doi: 10.1371/journal.pgen.1007879 30653500

89. Girirajan S, Rosenfeld JA, Coe BP, Parikh S, Friedman N, Goldstein A, et al. Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants. N Engl J Med. 2012;367: 1321–1331. doi: 10.1056/NEJMoa1200395 22970919

90. Coe BP, Girirajan S, Eichler EE. A genetic model for neurodevelopmental disease. Curr Opin Neurobiol. 2012;22: 829–836. doi: 10.1016/j.conb.2012.04.007 22560351

91. Nicholas AK, Swanson EA, Cox JJ, Karbani G, Malik S, Springell K, et al. The molecular landscape of ASPM mutations in primary microcephaly. J Med Genet. 2009;46: 249–253. doi: 10.1136/jmg.2008.062380 19028728

92. Lindsay EA, Vitelli F, Su H, Morishima M, Huynh T, Pramparo T, et al. Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature. 2001;410: 97–101. doi: 10.1038/35065105 11242049

93. Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet. 1997;15: 70–73. doi: 10.1038/ng0197-70 8988171

94. Brand AH, Perrimon N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development. 1993;118: 401–15. 8223268

95. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: An open-source platform for biological-image analysis. Nat Methods. 2012;9: 676–682. doi: 10.1038/nmeth.2019 22743772

96. Kanehisa M, Sato Y, Furumichi M, Morishima K, Tanabe M. New approach for understanding genome variations in KEGG. Nucleic Acids Res. 2019;47: D590–D595. doi: 10.1093/nar/gky962 30321428

97. Hagberg AA, Schult DA, Swart PJ. Exploring network structure, dynamics, and function using NetworkX. 7th Python in Science Conference (SciPy 2008). 2008. pp. 11–15.

98. Mi H, Huang X, Muruganujan A, Tang H, Mills C, Kang D, et al. PANTHER version 11: Expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements. Nucleic Acids Res. 2017;45: D183–D189. doi: 10.1093/nar/gkw1138 27899595

99. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13: 2498–2504. doi: 10.1101/gr.1239303 14597658

100. Köhler S, Carmody L, Vasilevsky N, Jacobsen JOB, Danis D, Gourdine JP, et al. Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources. Nucleic Acids Res. 2019;47: D1018–D1027. doi: 10.1093/nar/gky1105 30476213

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