Function and Regulation of , a Gene Implicated in Autism and Human Evolution

English version České info

Nucleotide changes in the AUTS2 locus, some of which affect only noncoding regions, are associated with autism and other neurological disorders, including attention deficit hyperactivity disorder, epilepsy, dyslexia, motor delay, language delay, visual impairment, microcephaly, and alcohol consumption. In addition, AUTS2 contains the most significantly accelerated genomic region differentiating humans from Neanderthals, which is primarily composed of noncoding variants. However, the function and regulation of this gene remain largely unknown. To characterize auts2 function, we knocked it down in zebrafish, leading to a smaller head size, neuronal reduction, and decreased mobility. To characterize AUTS2 regulatory elements, we tested sequences for enhancer activity in zebrafish and mice. We identified 23 functional zebrafish enhancers, 10 of which were active in the brain. Our mouse enhancer assays characterized three mouse brain enhancers that overlap an ASD–associated deletion and four mouse enhancers that reside in regions implicated in human evolution, two of which are active in the brain. Combined, our results show that AUTS2 is important for neurodevelopment and expose candidate enhancer sequences in which nucleotide variation could lead to neurological disease and human-specific traits.

Vyšlo v časopise: Function and Regulation of , a Gene Implicated in Autism and Human Evolution. PLoS Genet 9(1): e32767. doi:10.1371/journal.pgen.1003221
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003221

Souhrn

Zdroje

1. BaioJ (2012) Prevalence of Autism Spectrum Disorders —⁠ Autism and Developmental Disabilities Monitoring Network , 14 Sites , United States , 2008. Centers for Disease Control and Prevention MMWR Surveillance Summaries 61.

2. PardoCa, EberhartCG (2007) The neurobiology of autism. Brain Pathol 17 : 434–447.

3. RischN, SpikerD, LotspeichL, NouriN, HindsD, et al. (1999) A Genomic Screen of Autism: Evidence for a Multilocus Etiology. Amer J Hum Genet 65 : 931.

4. SultanaR, YuC-E, YuJ, MunsonJ, ChenD, et al. (2002) Identification of a Novel Gene on Chromosome 7q11.2 Interrupted by a Translocation Breakpoint in a Pair of Autistic Twins. Genomics 80 : 129–134.

5. PintoD, PagnamentaAT, KleiL, AnneyR, MericoD, et al. (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466 : 368–372.

6. KalscheuerVM, FitzPatrickD, TommerupN, BuggeM, NiebuhrE, et al. (2007) Mutations in autism susceptibility candidate 2 (AUTS2) in patients with mental retardation. Hum Genet 121 : 501–509.

7. BakkalogluB, RoakBJO, LouviA, GuptaAR, AbelsonJF, et al. (2008) Molecular Cytogenetic Analysis and Resequencing of Contactin Associated Protein-Like 2 in Autism Spectrum Disorders. Amer J Hum Genet 165–173 doi:10.1016/j.ajhg.2007.09.017.

8. HuangX-L, ZouYS, Maher Ta, NewtonS, MilunskyJM (2010) A de novo balanced translocation breakpoint truncating the autism susceptibility candidate 2 (AUTS2) gene in a patient with autism. Am J Med Genet A 152A: 2112–2114.

9. GlessnerJT, WangK, CaiG, KorvatskaO, KimCE, et al. (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459 : 569–573.

10. Ben-DavidE, Granot-HershkovitzE, Monderer-RothkoffG, LererE, LeviS, et al. (2011) Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression. Hum Mol Genet 20 : 3632–3641.

11. GirirajanS, BrkanacZ, CoeBP, BakerC, VivesL, et al. (2011) Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes. PLoS Genet 7: e1002334 doi:10.1371/journal.pgen.1002334.

12. TalkowskiME, RosenfeldJA, BlumenthalI, PillalamarriV, ChiangC, et al. (2012) Sequencing Chromosomal Abnormalities Reveals Neurodevelopmental Loci that Confer Risk across Diagnostic Boundaries. Cell 149 : 525–537.

13. NagamaniSCS, ErezA, Ben-ZeevB, FrydmanM, WinterS, et al. (2012) Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders. Eur J Hum Genet 1–4.

14. EliaJ, GaiX, XieHM, PerinJC, GeigerE, et al. (2010) Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol Psychiatry 15 : 637–646.

15. MeffordHC, MuhleH, OstertagP, Von SpiczakS, BuysseK, et al. (2010) Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet 6: e1000962 doi:10.1371/journal.pgen.1000962.

16. SchumannG, CoinLJ, LourdusamyA, CharoenP, BergerKH, et al. (2011) Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proc Natl Acad Sci U S A 108 : 7119–7124.

17. GreenRE, KrauseJ, BriggsAW, MaricicT, StenzelU, et al. (2010) A draft sequence of the Neandertal genome. Science 328 : 710–722.

18. PollardKS, SalamaSR, KingB, KernAD, DreszerT, et al. (2006) Forces shaping the fastest evolving regions in the human genome. PLoS Genet 2: e168 doi:10.1371/journal.pgen.0020168.

19. PrabhakarS, NoonanJP, PääboS, RubinEM (2006) Accelerated evolution of conserved noncoding sequences in humans. Science 314 : 786.

20. ZhangYE, LandbackP, VibranovskiMD, LongM (2011) Accelerated Recruitment of New Brain Development Genes into the Human Genome. PLoS Biol 9: e1001179 doi:10.1371/journal.pbio.1001179.

21. ViselA, ThallerC, EicheleG (2004) GenePaint.org: an atlas of gene expression patterns in the mouse embryo. Nucleic Acids Res 32: D552–6.

22. BedogniF, HodgeRD, NelsonBR, Frederick Ea, ShibaN, et al. (2010) Autism susceptibility candidate 2 (Auts2) encodes a nuclear protein expressed in developing brain regions implicated in autism neuropathology. Gene Expr Patterns 10 : 9–15.

23. BedogniF, HodgeRD, ElsenGE, NelsonBR, Daza R aM, et al. (2010) Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex. Proc Natl Acad Sci U S A 107 : 13129–13134.

24. HevnerRF, ShiL, JusticeN, HsuehY, ShengM, et al. (2001) Tbr1 regulates differentiation of the preplate and layer 6. Neuron 29 : 353–366.

25. FatemiSH, SnowAV, StaryJM, Araghi-NiknamM, ReutimanTJ, et al. (2005) Reelin signaling is impaired in autism. Biol Psychiatry 57 : 777–787.

26. TropepeV, SiveHL (2003) Can zebrafish be used as a model to study the neurodevelopmental causes of autism? Genes Brain Behav 268–281 doi:10.1046/j.1601-183X.2003.00038.x.

27. ParkHC, KimCH, BaeYK, YeoSY, KimSH, et al. (2000) Analysis of upstream elements in the HuC promoter leads to the establishment of transgenic zebrafish with fluorescent neurons. Dev Biol 227 : 279–293.

28. EvanG, LittlewoodT (1998) A Matter of Life and Cell Death. Science 281 : 1317–1322.

29. AlenziFQB (2004) Links between apoptosis, proliferation and the cell cycle. Br J Biomed Sci 61 : 99–102.

30. Flanagan-SteetH, Fox Ma, MeyerD, SanesJR (2005) Neuromuscular synapses can form in vivo by incorporation of initially aneural postsynaptic specializations. Development 132 : 4471–4481.

31. GordonLR, GribbleKD, SyrettCM, GranatoM (2012) Initiation of synapse formation by Wnt-induced MuSK endocytosis. Development 139 : 1023–1033.

32. ViselA, BlowMJ, LiZ, ZhangT, AkiyamaJa, et al. (2009) ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457 : 854–858.

33. LiQ, RitterD, YangN, DongZ, LiH, et al. (2010) A systematic approach to identify functional motifs within vertebrate developmental enhancers. Dev Biol 337 : 484–495.

34. ViselA, MinovitskyS, DubchakI, Pennacchio La (2007) VISTA Enhancer Browser–a database of tissue-specific human enhancers. Nucleic Acids Res 35: D88–92.

35. LucianoM, HansellNK, LahtiJ, DaviesG, MedlandSE (2012) UKPMC Funders Group Whole genome association scan for genetic polymorphisms influencing information processing speed. Biol Psychol 86 : 193–202 doi:10.1016/j.biopsycho.2010.11.008.Whole.

36. FullwoodMJ, LiuMH, PanYF, LiuJ, HanX, et al. (2010) NIH Public Access. Nature 462 : 58–64 doi:10.1038/nature08497.An.

37. Lieberman-AidenE, Van BerkumNL, WilliamsL, ImakaevM, RagoczyT, et al. (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326 : 289–293.

38. NavratilovaP, FredmanD, Hawkins Ta, TurnerK, LenhardB, et al. (2009) Systematic human/zebrafish comparative identification of cis-regulatory activity around vertebrate developmental transcription factor genes. Dev Biol 327 : 526–540.

39. McgaugheyDM, VintonRM, HuynhJ, Al-saifA, BeerMA, et al. (2008) Metrics of sequence constraint overlook regulatory sequences in an exhaustive analysis at phox2b. Genome Res 18 : 252–260 doi:10.1101/gr.6929408.1.

40. FisherS, GriceEa, VintonRM, BesslingSL, McCallionAS (2006) Conservation of RET regulatory function from human to zebrafish without sequence similarity. Science 312 : 276–279.

41. Poot M, Smagt JJ Van Der, Brilstra EH, Bourgeron T (2011) Disentangling the Myriad Genomics of Complex Disorders , Specifically Focusing on Autism , Epilepsy, and Schizophrenia. Cytogenet Genome Res. doi:10.1159/000334064.

42. WhiteRM, SessaA, BurkeC, BowmanT, LeBlancJ, et al. (2008) Transparent adult zebrafish as a tool for in vivo transplantation analysis. Cell stem cell 2 : 183–189.

43. ThisseB, HeyerV, LuxA, AlunniV, DegraveA, et al. (2004) Spatial and temporal expression of the zebrafish genome by large-scale in situ hybridization screening. Methods Cell Biol 77 : 505–519.

44. Naseviciusa, EkkerSC (2000) Effective targeted gene “knockdown” in zebrafish. Nat Genet 26 : 216–220.

45. HolderN, HillJ (1991) Retinoic acid modifies development of the midbrain-hindbrain border and affects cranial ganglion formation in zebrafish embryos. Development (Cambridge, England) 113 : 1159–1170.

46. Westerfield M (2007) The Zebrafish Book. 5th ed. Eugene, Oregon: University of Oregon Press.

47. Pennacchio La, AhituvN, MosesAM, PrabhakarS, Nobrega Ma, et al. (2006) In vivo enhancer analysis of human conserved non-coding sequences. Nature 444 : 499–502.

48. Nusslein-Volhard C and RD(2002) Zebrafish. Oxford: Oxford University Press.

49. KawakamiK (2005) Transposon tools and methods in zebrafish. Dev Dyn 234 : 244–254 Av.

50. KotharyR, ClapoffS, BrownA, CampbellR (1988) PA& RJ (1988) A transgene containing lacZ inserted into the dystonia locus is expressed in neural tube. Nature 335 : 435–437.

51. Nagy A., Gertsenstein M., Vintersten K BR (2003) Manipulating the Mouse Embryo: A Laboratory Manual (Third Edition). Cold Spring Harbor: Cold Spring Harbor Laboratory Press.

52. PruittKD, TatusovaT, MaglottDR (2005) NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res 33: D501–4.