Complex Genomic Rearrangements at the Locus Include Triplication and Quadruplication

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Genomic architecture, such as direct or inverted repeats, can facilitate structural variation (SV) of the human genome. SV can consist of deletion, duplication, or inversion of a genomic segment, or combinations thereof, the latter referred to as complex genomic rearrangements (CGR). CGR are defined as requiring two or more novel DNA breakpoint junctions. We described a CGR product at the MECP2 locus with an unusual pattern consisting of an inverted triplicated segment flanked by duplicated segments of the genome. This complex CGR is facilitated by inverted repeats in a process that mechanistically could occur by two template switches mediated by replicative DNA repair. We now investigate the PLP1 locus and demonstrate that 16/17 CGR independent events present with duplication—inverted triplication—duplication pattern facilitated by two inverted repeats, similar to events involving MECP2. We show that the same inverted repeats facilitating CGR formation are also responsible for an inversion polymorphism observed frequently in the normal population. Intriguingly, one CGR was found to have a quadruplication resulting in the presence of four copies of a genomic segment. Breakpoint studies suggest this quadruplication occurred in a manner consistent with rolling circle amplification as predicted by previously postulated models.

Vyšlo v časopise: Complex Genomic Rearrangements at the Locus Include Triplication and Quadruplication. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005050
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005050

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Zdroje

1. Carvalho CM, Ramocki MB, Pehlivan D, Franco LM, Gonzaga-Jauregui C, et al. (2011) Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nat Genet 43: 1074–1081. doi: 10.1038/ng.944 21964572

2. Dittwald P, Gambin T, Gonzaga-Jauregui C, Carvalho CM, Lupski JR, et al. (2013) Inverted low-copy repeats and genome instability—a genome-wide analysis. Hum Mutat 34: 210–220. doi: 10.1002/humu.22217 22965494

3. Zhou W, Zhang F, Chen X, Shen Y, Lupski JR, et al. (2013) Increased genome instability in human DNA segments with self-chains: homology-induced structural variations via replicative mechanisms. Hum Mol Genet 22: 2642–2651. doi: 10.1093/hmg/ddt113 23474816

4. Lakich D, Kazazian HH Jr., Antonarakis SE, Gitschier J (1993) Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Genet 5: 236–241. 8275087

5. Hermetz KE, Newman S, Conneely KN, Martin CL, Ballif BC, et al. (2014) Large inverted duplications in the human genome form via a fold-back mechanism. PLoS Genet 10: e1004139. doi: 10.1371/journal.pgen.1004139 24497845

6. Giorda R, Ciccone R, Gimelli G, Pramparo T, Beri S, et al. (2007) Two classes of low-copy repeats comediate a new recurrent rearrangement consisting of duplication at 8p23.1 and triplication at 8p23.2. Hum Mutat 28: 459–468. 17262805

7. Lange J, Skaletsky H, van Daalen SK, Embry SL, Korver CM, et al. (2009) Isodicentric Y chromosomes and sex disorders as byproducts of homologous recombination that maintains palindromes. Cell 138: 855–869. doi: 10.1016/j.cell.2009.07.042 19737515

8. Kidd JM, Cooper GM, Donahue WF, Hayden HS, Sampas N, et al. (2008) Mapping and sequencing of structural variation from eight human genomes. Nature 453: 56–64. doi: 10.1038/nature06862 18451855

9. Flores M, Morales L, Gonzaga-Jauregui C, Dominguez-Vidana R, Zepeda C, et al. (2007) Recurrent DNA inversion rearrangements in the human genome. Proc Natl Acad Sci U S A 104: 6099–6106. 17389356

10. Soler-Alfonso C, Carvalho CM, Ge J, Roney EK, Bader PI, et al. (2014) CHRNA7 triplication associated with cognitive impairment and neuropsychiatric phenotypes in a three-generation pedigree. Eur J Hum Genet.

11. Beri S, Bonaglia MC, Giorda R (2013) Low-copy repeats at the human VIPR2 gene predispose to recurrent and nonrecurrent rearrangements. Eur J Hum Genet 21: 757–761. doi: 10.1038/ejhg.2012.235 23073313

12. Ishmukhametova A, Chen JM, Bernard R, de Massy B, Baudat F, et al. (2013) Dissecting the structure and mechanism of a complex duplication-triplication rearrangement in the DMD gene. Hum Mutat 34: 1080–1084. doi: 10.1002/humu.22353 23649991

13. Shimojima K, Mano T, Kashiwagi M, Tanabe T, Sugawara M, et al. (2012) Pelizaeus-Merzbacher disease caused by a duplication-inverted triplication-duplication in chromosomal segments including the PLP1 region. Eur J Med Genet 55: 400–403. doi: 10.1016/j.ejmg.2012.02.013 22490426

14. Wolf NI, Sistermans EA, Cundall M, Hobson GM, Davis-Williams AP, et al. (2005) Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus-Merzbacher disease. Brain 128: 743–751. 15689360

15. Garbern J, Hobson G (2002) Prenatal diagnosis of Pelizaeus-Merzbacher disease. Prenat Diagn 22: 1033–1035. 12424770

16. Inoue K, Osaka H, Thurston VC, Clarke JT, Yoneyama A, et al. (2002) Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females. Am J Hum Genet 71: 838–853. 12297985

17. Inoue K, Osaka H, Imaizumi K, Nezu A, Takanashi J, et al. (1999) Proteolipid protein gene duplications causing Pelizaeus-Merzbacher disease: molecular mechanism and phenotypic manifestations. Ann Neurol 45: 624–632. 10319885

18. Lupski JR, de Oca-Luna RM, Slaugenhaupt S, Pentao L, Guzzetta V, et al. (1991) DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66: 219–232. 1677316

19. Liu P, Gelowani V, Zhang F, Drory VE, Ben-Shachar S, et al. (2014) Mechanism, Prevalence, and More Severe Neuropathy Phenotype of the Charcot-Marie-Tooth Type 1A Triplication. Am J Hum Genet 94: 462–469. doi: 10.1016/j.ajhg.2014.01.017 24530202

20. Carvalho CM, Pehlivan D, Ramocki MB, Fang P, Alleva B, et al. (2013) Replicative mechanisms for CNV formation are error prone. Nat Genet 45: 1319–1326. doi: 10.1038/ng.2768 24056715

21. Lee JA, Carvalho CM, Lupski JR (2007) A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131: 1235–1247. 18160035

22. Hastings PJ, Ira G, Lupski JR (2009) A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet 5: e1000327. doi: 10.1371/journal.pgen.1000327 19180184

23. Lee JA, Inoue K, Cheung SW, Shaw CA, Stankiewicz P, et al. (2006) Role of genomic architecture in PLP1 duplication causing Pelizaeus-Merzbacher disease. Hum Mol Genet 15: 2250–2265. 16774974

24. Woodward KJ, Cundall M, Sperle K, Sistermans EA, Ross M, et al. (2005) Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination. Am J Hum Genet 77: 966–987. 16380909

25. Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, et al. (2002) The human genome browser at UCSC. Genome Res 12: 996–1006. 12045153

26. Tuzun E, Sharp AJ, Bailey JA, Kaul R, Morrison VA, et al. (2005) Fine-scale structural variation of the human genome. Nat Genet 37: 727–732. 15895083

27. Small K, Iber J, Warren ST (1997) Emerin deletion reveals a common X-chromosome inversion mediated by inverted repeats. Nat Genet 16: 96–99. 9140403

28. Liu P, Lacaria M, Zhang F, Withers M, Hastings PJ, et al. (2011) Frequency of nonallelic homologous recombination is correlated with length of homology: evidence that ectopic synapsis precedes ectopic crossing-over. Am J Hum Genet 89: 580–588. doi: 10.1016/j.ajhg.2011.09.009 21981782

29. The 1000 Genomes Project Consortium, Abecasis GR, Altshuler D, Auton A, Brooks LD, et al. (2010) A map of human genome variation from population-scale sequencing. Nature 467: 1061–1073. doi: 10.1038/nature09534 20981092

30. Lee JA, Madrid RE, Sperle K, Ritterson CM, Hobson GM, et al. (2006) Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann Neurol 59: 398–403. 16374829

31. Mizuno K, Miyabe I, Schalbetter SA, Carr AM, Murray JM (2013) Recombination-restarted replication makes inverted chromosome fusions at inverted repeats. Nature 493: 246–249. doi: 10.1038/nature11676 23178809

32. Zhang Y, Saini N, Sheng Z, Lobachev KS (2013) Genome-wide screen reveals replication pathway for quasi-palindrome fragility dependent on homologous recombination. PLoS Genet 9: e1003979. doi: 10.1371/journal.pgen.1003979 24339793

33. de Wind N, Dekker M, Claij N, Jansen L, van Klink Y, et al. (1999) HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions. Nat Genet 23: 359–362. 10545954

34. Boone PM, Yuan B, Campbell IM, Scull JC, Withers MA, et al. (2014) The Alu-Rich Genomic Architecture of SPAST Predisposes to Diverse and Functionally Distinct Disease-Associated CNV Alleles. Am J Hum Genet 95: 143–161. doi: 10.1016/j.ajhg.2014.06.014 25065914

35. Lindsay SJ, Khajavi M, Lupski JR, Hurles ME (2006) A chromosomal rearrangement hotspot can be identified from population genetic variation and is coincident with a hotspot for allelic recombination. Am J Hum Genet 79: 890–902. 17033965

36. Yu C, Bonaduce MJ, Klar AJ (2012) Remarkably high rate of DNA amplification promoted by the mating-type switching mechanism in Schizosaccharomyces pombe. Genetics 191: 285–289. doi: 10.1534/genetics.112.138727 22377633

37. McEachern MJ, Haber JE (2006) Break-induced replication and recombinational telomere elongation in yeast. Annu Rev Biochem 75: 111–135. 16756487

38. Andersson DI, Hughes D (2009) Gene amplification and adaptive evolution in bacteria. Annu Rev Genet 43: 167–195. doi: 10.1146/annurev-genet-102108-134805 19686082

39. Sudmant PH, Kitzman JO, Antonacci F, Alkan C, Malig M, et al. (2010) Diversity of human copy number variation and multicopy genes. Science 330: 641–646. doi: 10.1126/science.1197005 21030649

40. Rayssiguier C, Thaler DS, Radman M (1989) The barrier to recombination between Escherichia coli and Salmonella typhimurium is disrupted in mismatch-repair mutants. Nature 342: 396–401. 2555716

41. Deem A, Keszthelyi A, Blackgrove T, Vayl A, Coffey B, et al. (2011) Break-induced replication is highly inaccurate. PLoS Biol 9: e1000594. doi: 10.1371/journal.pbio.1000594 21347245

42. Saini N, Ramakrishnan S, Elango R, Ayyar S, Zhang Y, et al. (2013) Migrating bubble during break-induced replication drives conservative DNA synthesis. Nature 502: 389–392. doi: 10.1038/nature12584 24025772

43. Wilson MA, Kwon Y, Xu Y, Chung WH, Chi P, et al. (2013) Pif1 helicase and Poldelta promote recombination-coupled DNA synthesis via bubble migration. Nature 502: 393–396. doi: 10.1038/nature12585 24025768

44. Dittwald P, Gambin T, Szafranski P, Li J, Amato S, et al. (2013) NAHR-mediated copy-number variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits. Genome Res 23: 1395–1409. doi: 10.1101/gr.152454.112 23657883

45. Mizuno K, Lambert S, Baldacci G, Murray JM, Carr AM (2009) Nearby inverted repeats fuse to generate acentric and dicentric palindromic chromosomes by a replication template exchange mechanism. Genes Dev 23: 2876–2886. doi: 10.1101/gad.1863009 20008937

46. Watanabe T, Tanabe H, Horiuchi T (2011) Gene amplification system based on double rolling-circle replication as a model for oncogene-type amplification. Nucleic Acids Res 39: e106. doi: 10.1093/nar/gkr442 21653557

47. Windle BE, Wahl GM (1992) Molecular dissection of mammalian gene amplification: new mechanistic insights revealed by analyses of very early events. Mutat Res 276: 199–224. 1374515

48. The International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437: 1299–1320. 16255080

49. Kidd JM, Graves T, Newman TL, Fulton R, Hayden HS, et al. (2010) A human genome structural variation sequencing resource reveals insights into mutational mechanisms. Cell 143: 837–847. doi: 10.1016/j.cell.2010.10.027 21111241