Genomics & Informatics

Korea Genome Organization (한국유전체학회)
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Structural Variation of Alu Element and Human Disease

  • Kim, Songmi (Department of Nanobiomedical Science, Dankook University) ;
  • Cho, Chun-Sung (Department of Neurosurgery, Dankook University College of Medicine) ;
  • Han, Kyudong (Department of Nanobiomedical Science, Dankook University) ;
  • Lee, Jungnam (Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida)
  • Received : 2016.06.09
  • Accepted : 2016.08.10
  • Published : 2016.09.30
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Abstract

Transposable elements are one of major sources to cause genomic instability through various mechanisms including de novo insertion, insertion-mediated genomic deletion, and recombination-associated genomic deletion. Among them is Alu element which is the most abundant element, composing ~10% of the human genome. The element emerged in the primate genome 65 million years ago and has since propagated successfully in the human and non-human primate genomes. Alu element is a non-autonomous retrotransposon and therefore retrotransposed using L1-enzyme machinery. The 'master gene' model has been generally accepted to explain Alu element amplification in primate genomes. According to the model, different subfamilies of Alu elements are created by mutations on the master gene and most Alu elements are amplified from the hyperactive master genes. Alu element is frequently involved in genomic rearrangements in the human genome due to its abundance and sequence identity between them. The genomic rearrangements caused by Alu elements could lead to genetic disorders such as hereditary disease, blood disorder, and neurological disorder. In fact, Alu elements are associated with approximately 0.1% of human genetic disorders. The first part of this review discusses mechanisms of Alu amplification and diversity among different Alu subfamilies. The second part discusses the particular role of Alu elements in generating genomic rearrangements as well as human genetic disorders.

Keywords

References

  1. Cordaux R, Batzer MA. The impact of retrotransposons on human genome evolution. Nat Rev Genet 2009;10:691-703. https://doi.org/10.1038/nrg2640
  2. Batzer MA, Deininger PL. Alu repeats and human genomic diversity. Nat Rev Genet 2002;3:370-379. https://doi.org/10.1038/nrg798
  3. Deininger P. Alu elements: know the SINEs. Genome Biol 2011;12:236. https://doi.org/10.1186/gb-2011-12-12-236
  4. Deininger PL, Batzer MA, Hutchison CA 3rd, Edgell MH. Master genes in mammalian repetitive DNA amplification. Trends Genet 1992;8:307-311. https://doi.org/10.1016/0168-9525(92)90262-3
  5. Han K, Xing J, Wang H, Hedges DJ, Garber RK, Cordaux R, et al. Under the genomic radar: the stealth model of Alu amplification. Genome Res 2005;15:655-664. https://doi.org/10.1101/gr.3492605
  6. Shen MR, Batzer MA, Deininger PL. Evolution of the master Alu gene(s). J Mol Evol 1991;33:311-320. https://doi.org/10.1007/BF02102862
  7. Ayarpadikannan S, Kim HS. The impact of transposable elements in genome evolution and genetic instability and their implications in various diseases. Genomics Inform 2014;12:98-104. https://doi.org/10.5808/GI.2014.12.3.98
  8. Ayarpadikannan S, Lee HE, Han K, Kim HS. Transposable element-driven transcript diversification and its relevance to genetic disorders. Gene 2015;558:187-194. https://doi.org/10.1016/j.gene.2015.01.039
  9. Belancio VP, Hedges DJ, Deininger P. Mammalian non-LTR retrotransposons: for better or worse, in sickness and in health. Genome Res 2008;18:343-358. https://doi.org/10.1101/gr.5558208
  10. Deininger PL, Batzer MA. Alu repeats and human disease. Mol Genet Metab 1999;67:183-193. https://doi.org/10.1006/mgme.1999.2864
  11. Hancks DC, Kazazian HH Jr. Active human retrotransposons: variation and disease. Curr Opin Genet Dev 2012;22:191-203. https://doi.org/10.1016/j.gde.2012.02.006
  12. Xing J, Zhang Y, Han K, Salem AH, Sen SK, Huff CD, et al. Mobile elements create structural variation: analysis of a complete human genome. Genome Res 2009;19:1516-1526. https://doi.org/10.1101/gr.091827.109
  13. Cordaux R, Hedges DJ, Batzer MA. Retrotransposition of Alu elements: how many sources? Trends Genet 2004;20:464-467. https://doi.org/10.1016/j.tig.2004.07.012
  14. Kim YJ, Lee J, Han K. Transposable elements: no more 'Junk DNA'. Genomics Inform 2012;10:226-233. https://doi.org/10.5808/GI.2012.10.4.226
  15. Mills RE, Bennett EA, Iskow RC, Luttig CT, Tsui C, Pittard WS, et al. Recently mobilized transposons in the human and chimpanzee genomes. Am J Hum Genet 2006;78:671-679. https://doi.org/10.1086/501028
  16. Baskaev KK, Buzdin AA. Evolutionary recent insertions of mobile elements and their contribution to the structure of human genome. Zh Obshch Biol 2012;73:3-20.
  17. Sorek R, Ast G, Graur D. Alu-containing exons are alternatively spliced. Genome Res 2002;12:1060-1067. https://doi.org/10.1101/gr.229302
  18. Mitchell GA, Labuda D, Fontaine G, Saudubray JM, Bonnefont JP, Lyonnet S, et al. Splice-mediated insertion of an Alu sequence inactivates ornithine delta-aminotransferase: a role for Alu elements in human mutation. Proc Natl Acad Sci U S A 1991;88:815-819. https://doi.org/10.1073/pnas.88.3.815
  19. Lev-Maor G, Sorek R, Levanon EY, Paz N, Eisenberg E, Ast G. RNA-editing-mediated exon evolution. Genome Biol 2007;8:R29. https://doi.org/10.1186/gb-2007-8-2-r29
  20. Athanasiadis A, Rich A, Maas S. Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol 2004;2:e391. https://doi.org/10.1371/journal.pbio.0020391
  21. Bass BL. RNA editing by adenosine deaminases that act on RNA. Annu Rev Biochem 2002;71:817-846. https://doi.org/10.1146/annurev.biochem.71.110601.135501
  22. Bazak L, Haviv A, Barak M, Jacob-Hirsch J, Deng P, Zhang R, et al. A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes. Genome Res 2014;24:365-376. https://doi.org/10.1101/gr.164749.113
  23. Kim DD, Kim TT, Walsh T, Kobayashi Y, Matise TC, Buyske S, et al. Widespread RNA editing of embedded Alu elements in the human transcriptome. Genome Res 2004;14:1719-1725. https://doi.org/10.1101/gr.2855504
  24. Ganguly A, Dunbar T, Chen P, Godmilow L, Ganguly T. Exon skipping caused by an intronic insertion of a young Alu Yb9 element leads to severe hemophilia A. Hum Genet 2003;113:348-352. https://doi.org/10.1007/s00439-003-0986-5
  25. Beaudoing E, Freier S, Wyatt JR, Claverie JM, Gautheret D. Patterns of variant polyadenylation signal usage in human genes. Genome Res 2000;10:1001-1010. https://doi.org/10.1101/gr.10.7.1001
  26. Lopez F, Granjeaud S, Ara T, Ghattas B, Gautheret D. The disparate nature of “intergenic” polyadenylation sites. RNA 2006;12:1794-1801. https://doi.org/10.1261/rna.136206
  27. Chen C, Ara T, Gautheret D. Using Alu elements as polyadenylation sites: a case of retroposon exaptation. Mol Biol Evol 2009;26:327-334. https://doi.org/10.1093/molbev/msn249
  28. Roy-Engel AM, El-Sawy M, Farooq L, Odom GL, Perepelitsa-Belancio V, Bruch H, et al. Human retroelements may introduce intragenic polyadenylation signals. Cytogenet Genome Res 2005;110:365-371. https://doi.org/10.1159/000084968
  29. Bai M, Janicic N, Trivedi S, Quinn SJ, Cole DE, Brown EM, et al. Markedly reduced activity of mutant calcium-sensing receptor with an inserted Alu element from a kindred with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. J Clin Invest 1997;99:1917-1925. https://doi.org/10.1172/JCI119359
  30. Cole DE, Yun FH, Wong BY, Shuen AY, Booth RA, Scillitani A, et al. Calcium-sensing receptor mutations and denaturing high performance liquid chromatography. J Mol Endocrinol 2009;42:331-339.
  31. Janicic N, Pausova Z, Cole DE, Hendy GN. Insertion of an Alu sequence in the Ca(2+)-sensing receptor gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Am J Hum Genet 1995;56:880-886.
  32. Callinan PA, Wang J, Herke SW, Garber RK, Liang P, Batzer MA. Alu retrotransposition-mediated deletion. J Mol Biol 2005;348:791-800. https://doi.org/10.1016/j.jmb.2005.02.043
  33. Sen SK, Han K, Wang J, Lee J, Wang H, Callinan PA, et al. Human genomic deletions mediated by recombination between Alu elements. Am J Hum Genet 2006;79:41-53. https://doi.org/10.1086/504600
  34. Srikanta D, Sen SK, Huang CT, Conlin EM, Rhodes RM, Batzer MA. An alternative pathway for Alu retrotransposition suggests a role in DNA double-strand break repair. Genomics 2009;93:205-212. https://doi.org/10.1016/j.ygeno.2008.09.016
  35. Davis AJ, Chen DJ. DNA double strand break repair via non-homologous end-joining. Transl Cancer Res 2013;2:130-143.
  36. Weterings E, Chen DJ. The endless tale of non-homologous end-joining. Cell Res 2008;18:114-124. https://doi.org/10.1038/cr.2008.3
  37. Gu W, Zhang F, Lupski JR. Mechanisms for human genomic rearrangements. Pathogenetics 2008;1:4. https://doi.org/10.1186/1755-8417-1-4
  38. Purandare SM, Patel PI. Recombination hot spots and human disease. Genome Res 1997;7:773-786. https://doi.org/10.1101/gr.7.8.773
  39. Wu SJ, Hsieh TJ, Kuo MC, Tsai ML, Tsai KL, Chen CH, et al. Functional regulation of Alu element of human angiotensin-converting enzyme gene in neuron cells. Neurobiol Aging 2013;34:1921.e1-e7. https://doi.org/10.1016/j.neurobiolaging.2013.01.003
  40. Taskesen M, Collin GB, Evsikov AV, Guzel A, Ozgul RK, Marshall JD, et al. Novel Alu retrotransposon insertion leading to Alstrom syndrome. Hum Genet 2012;131:407-413. https://doi.org/10.1007/s00439-011-1083-9
  41. Kataoka M, Aimi Y, Yanagisawa R, Ono M, Oka A, Fukuda K, et al. Alu-mediated nonallelic homologous and nonhomologous recombination in the BMPR2 gene in heritable pulmonary arterial hypertension. Genet Med 2013;15:941-947. https://doi.org/10.1038/gim.2013.41
  42. Wada T, Matsuda Y, Muraoka M, Toma T, Takehara K, Fujimoto M, et al. Alu-mediated large deletion of the CDSN gene as a cause of peeling skin disease. Clin Genet 2014;86:383-386. https://doi.org/10.1111/cge.12294
  43. Nozu K, Iijima K, Ohtsuka Y, Fu XJ, Kaito H, Nakanishi K, et al. Alport syndrome caused by a COL4A5 deletion and exonization of an adjacent AluY. Mol Genet Genomic Med 2014;2:451-453. https://doi.org/10.1002/mgg3.89
  44. Flynn EK, Kamat A, Lach FP, Donovan FX, Kimble DC, Narisu N, et al. Comprehensive analysis of pathogenic deletion variants in Fanconi anemia genes. Hum Mutat 2014;35:1342-1353.
  45. Cozar M, Bembi B, Dominissini S, Zampieri S, Vilageliu L, Grinberg D, et al. Molecular characterization of a new deletion of the GBA1 gene due to an inter Alu recombination event. Mol Genet Metab 2011;102:226-228. https://doi.org/10.1016/j.ymgme.2010.10.004
  46. Aminoso C, Vallespin E, Fernandez L, Arrabal LF, Desviat LR, Perez B, et al. Identification of the first deletion-insertion involving the complete structure of GAA gene and part of CCDC40 gene mediated by an Alu element. Gene 2013;519:169-172. https://doi.org/10.1016/j.gene.2013.01.051
  47. Dobrovolny R, Nazarenko I, Kim J, Doheny D, Desnick RJ. Detection of large gene rearrangements in X-linked genes by dosage analysis: identification of novel $\alpha$-galactosidase A (GLA) deletions causing Fabry disease. Hum Mutat 2011;32:688-695. https://doi.org/10.1002/humu.21474
  48. Zhu M, Chen X, Zhang H, Xiao N, Zhu C, He Q, et al. AluYb8 insertion in the MUTYH gene and risk of early-onset breast and gastric cancers in the Chinese population. Asian Pac J Cancer Prev 2011;12:1451-1455.
  49. Choi BO, Kim NK, Park SW, Hyun YS, Jeon HJ, Hwang JH, et al. Inheritance of Charcot-Marie-Tooth disease 1A with rare nonrecurrent genomic rearrangement. Neurogenetics 2011;12:51-58. https://doi.org/10.1007/s10048-010-0272-3
  50. Bondurand N, Fouquet V, Baral V, Lecerf L, Loundon N, Goossens M, et al. Alu-mediated deletion of SOX10 regulatory elements in Waardenburg syndrome type 4. Eur J Hum Genet 2012;20:990-994. https://doi.org/10.1038/ejhg.2012.29
  51. Boone PM, Liu P, Zhang F, Carvalho CM, Towne CF, Batish SD, et al. Alu-specific microhomology-mediated deletion of the final exon of SPAST in three unrelated subjects with hereditary spastic paraplegia. Genet Med 2011;13:582-592. https://doi.org/10.1097/GIM.0b013e3182106775
  52. Conceicao Pereira M, Loureiro JL, Pinto-Basto J, Brandao E, Margarida Lopes A, Neves G, et al. Alu elements mediate large SPG11 gene rearrangements: further spatacsin mutations. Genet Med 2012;14:143-151. https://doi.org/10.1038/gim.2011.7
  53. Borun P, De Rosa M, Nedoszytko B, Walkowiak J, Plawski A. Specific Alu elements involved in a significant percentage of copy number variations of the STK11 gene in patients with Peutz-Jeghers syndrome. Fam Cancer 2015;14:455-461. https://doi.org/10.1007/s10689-015-9800-5
  54. Marshall JD, Hinman EG, Collin GB, Beck S, Cerqueira R, Maffei P, et al. Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alstrom syndrome. Hum Mutat 2007;28:1114-1123. https://doi.org/10.1002/humu.20577

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