Large Inverted Duplications in the Human Genome Form via a Fold-Back Mechanism

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Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. For half of the rearrangements in our study, we sequenced at least one breakpoint junction. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted sequences are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a “fold-back” intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the fold-back loop. This process can lead to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes.

Vyšlo v časopise: Large Inverted Duplications in the Human Genome Form via a Fold-Back Mechanism. PLoS Genet 10(1): e32767. doi:10.1371/journal.pgen.1004139
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004139

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1. WeleberRG, VermaRS, KimberlingWJ, FiegerHGJr, lubsHA (1976) Duplication-deficiency of the short arm of chromosome 8 following artificial insemination. Annales de genetique 19: 241–247.

2. ZuffardiO, BonagliaM, CicconeR, GiordaR (2009) Inverted duplications deletions: underdiagnosed rearrangements?? Clinical genetics 75: 505–513.

3. Rudd MK (2011) Structural variation in subtelomeres. In: Feuk L, editor. Genomic Structural Variants: Methods and Protocols. New York: Springer Science+Business Media, LLC.

4. BallifBC, YuW, ShawCA, KashorkCD, ShafferLG (2003) Monosomy 1p36 breakpoint junctions suggest pre-meiotic breakage-fusion-bridge cycles are involved in generating terminal deletions. Hum Mol Genet 12: 2153–2165.

5. BonagliaMC, GiordaR, MassagliA, GalluzziR, CicconeR, et al. (2009) A familial inverted duplication/deletion of 2p25.1–25.3 provides new clues on the genesis of inverted duplications. European journal of human genetics : EJHG 17: 179–186.

6. RoweLR, LeeJY, RectorL, KaminskyEB, BrothmanAR, et al. (2009) U-type exchange is the most frequent mechanism for inverted duplication with terminal deletion rearrangements. J Med Genet 46: 694–702.

7. YuS, GrafWD (2010) Telomere capture as a frequent mechanism for stabilization of the terminal chromosomal deletion associated with inverted duplication. Cytogenetic and genome research 129: 265–274.

8. Vera-CarbonellA, Lopez-ExpositoI, BafalliuJA, Ballesta-MartinezM, GloverG, et al. (2010) Molecular characterization of a new patient with a non-recurrent inv dup del 2q and review of the mechanisms for this rearrangement. American journal of medical genetics Part A 152A: 2670–2680.

9. TanakaH, CaoY, BergstromDA, KooperbergC, TapscottSJ, et al. (2007) Intrastrand annealing leads to the formation of a large DNA palindrome and determines the boundaries of genomic amplification in human cancer. Mol Cell Biol 27: 1993–2002.

10. StephensPJ, McBrideDJ, LinML, VarelaI, PleasanceED, et al. (2009) Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462: 1005–1010.

11. CampbellPJ, YachidaS, MudieLJ, StephensPJ, PleasanceED, et al. (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467: 1109–1113.

12. StephensPJ, GreenmanCD, FuB, YangF, BignellGR, et al. (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144: 27–40.

13. GuenthoerJ, DiedeSJ, TanakaH, ChaiX, HsuL, et al. (2012) Assessment of palindromes as platforms for DNA amplification in breast cancer. Genome research 22: 232–245.

14. OuelletteM, HettemaE, WustD, Fase-FowlerF, BorstP (1991) Direct and inverted DNA repeats associated with P-glycoprotein gene amplification in drug resistant Leishmania. The EMBO journal 10: 1009–1016.

15. ButlerDK, YasudaLE, YaoMC (1995) An intramolecular recombination mechanism for the formation of the rRNA gene palindrome of Tetrahymena thermophila. Molecular and cellular biology 15: 7117–7126.

16. QinZ, CohenSN (2000) Long palindromes formed in Streptomyces by nonrecombinational intra-strand annealing. Genes & development 14: 1789–1796.

17. LinCT, LinWH, LyuYL, Whang-PengJ (2001) Inverted repeats as genetic elements for promoting DNA inverted duplication: implications in gene amplification. Nucleic Acids Research 29: 3529–3538.

18. RattrayAJ, ShaferBK, NeelamB, StrathernJN (2005) A mechanism of palindromic gene amplification in Saccharomyces cerevisiae. Genes Dev 19: 1390–1399.

19. AdmireA, ShanksL, DanzlN, WangM, WeierU, et al. (2006) Cycles of chromosome instability are associated with a fragile site and are increased by defects in DNA replication and checkpoint controls in yeast. Genes & development 20: 159–173.

20. NarayananV, MieczkowskiPA, KimHM, PetesTD, LobachevKS (2006) The pattern of gene amplification is determined by the chromosomal location of hairpin-capped breaks. Cell 125: 1283–1296.

21. LowdenMR, FlibotteS, MoermanDG, AhmedS (2011) DNA synthesis generates terminal duplications that seal end-to-end chromosome fusions. Science 332: 468–471.

22. McClintockB (1939) The Behavior in Successive Nuclear Divisions of a Chromosome Broken at Meiosis. Proceedings of the National Academy of Sciences of the United States of America 25: 405–416.

23. FloridiaG, PiantanidaM, MinelliA, DellavecchiaC, BonagliaC, et al. (1996) The same molecular mechanism at the maternal meiosis I produces mono- and dicentric 8p duplications. American journal of human genetics 58: 785–796.

24. GiglioS, BromanKW, MatsumotoN, CalvariV, GimelliG, et al. (2001) Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am J Hum Genet 68: 874–883.

25. PramparoT, GiglioS, GregatoG, de GregoriM, PatricelliMG, et al. (2004) Inverted duplications: how many of them are mosaic? European journal of human genetics : EJHG 12: 713–717.

26. DanielA, St HeapsL, SylvesterD, DiazS, PetersG (2008) Two mosaic terminal inverted duplications arising post-zygotically: Evidence for possible formation of neo-telomeres. Cell & chromosome 7: 1.

27. VannesteE, VoetT, Le CaignecC, AmpeM, KoningsP, et al. (2009) Chromosome instability is common in human cleavage-stage embryos. Nat Med 15: 577–583.

28. VoetT, VannesteE, Van der AaN, MelotteC, JackmaertS, et al. (2011) Breakage-fusion-bridge cycles leading to inv dup del occur in human cleavage stage embryos. Human mutation 32: 783–793.

29. LuoY, HermetzKE, JacksonJM, MulleJG, DoddA, et al. (2011) Diverse mutational mechanisms cause pathogenic subtelomeric rearrangements. Human molecular genetics 20: 3769–3778.

30. ArltMF, MulleJG, SchaibleyVM, RaglandRL, DurkinSG, et al. (2009) Replication stress induces genome-wide copy number changes in human cells that resemble polymorphic and pathogenic variants. Am J Hum Genet 84: 339–350.

31. OkunoY, HahnPJ, GilbertDM (2004) Structure of a palindromic amplicon junction implicates microhomology-mediated end joining as a mechanism of sister chromatid fusion during gene amplification. Nucleic acids research 32: 749–756.

32. Nick McElhinnySA, HavenerJM, Garcia-DiazM, JuarezR, BebenekK, et al. (2005) A gradient of template dependence defines distinct biological roles for family X polymerases in nonhomologous end joining. Molecular cell 19: 357–366.

33. SimsekD, JasinM (2010) Alternative end-joining is suppressed by the canonical NHEJ component Xrcc4-ligase IV during chromosomal translocation formation. Nature structural & molecular biology 17: 410–416.

34. KentWJ (2002) BLAT–the BLAST-like alignment tool. Genome Res 12: 656–664.

35. Hazkani-CovoE, ZellerRM, MartinW (2010) Molecular poltergeists: mitochondrial DNA copies (numts) in sequenced nuclear genomes. PLoS genetics 6: e1000834.

36. Willett-BrozickJE, SavulSA, RicheyLE, BaysalBE (2001) Germ line insertion of mtDNA at the breakpoint junction of a reciprocal constitutional translocation. Human genetics 109: 216–223.

37. Hazkani-CovoE, CovoS (2008) Numt-mediated double-strand break repair mitigates deletions during primate genome evolution. PLoS genetics 4: e1000237.

38. YuAM, McVeyM (2010) Synthesis-dependent microhomology-mediated end joining accounts for multiple types of repair junctions. Nucleic acids research 38: 5706–5717.

39. RossiE, RiegelM, MessaJ, GimelliS, MaraschioP, et al. (2008) Duplications in addition to terminal deletions are present in a proportion of ring chromosomes: clues to the mechanisms of formation. Journal of medical genetics 45: 147–154.

40. MurmannAE, ConradDF, MashekH, CurtisCA, NicolaeRI, et al. (2009) Inverted duplications on acentric markers: mechanism of formation. Human molecular genetics 18: 2241–2256.

41. GuilhermeRS, MeloniVF, KimCA, PellegrinoR, TakenoSS, et al. (2011) Mechanisms of ring chromosome formation, ring instability and clinical consequences. BMC medical genetics 12: 171.

42. FlintJ, CraddockCF, VillegasA, BentleyDP, WilliamsHJ, et al. (1994) Healing of broken human chromosomes by the addition of telomeric repeats. Am J Hum Genet 55: 505–512.

43. YatsenkoSA, BrundageEK, RoneyEK, CheungSW, ChinaultAC, et al. (2009) Molecular mechanisms for subtelomeric rearrangements associated with the 9q34.3 microdeletion syndrome. Hum Mol Genet 18: 1924–1936.

44. RichardsonC, JasinM (2000) Frequent chromosomal translocations induced by DNA double-strand breaks. Nature 405: 697–700.

45. MizunoK, MiyabeI, SchalbetterSA, CarrAM, MurrayJM (2013) Recombination-restarted replication makes inverted chromosome fusions at inverted repeats. Nature 493: 246–249.

46. LeeJA, CarvalhoCM, LupskiJR (2007) A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131: 1235–1247.

47. ZhangF, KhajaviM, ConnollyAM, TowneCF, BatishSD, et al. (2009) The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nat Genet 41: 849–853.

48. HastingsPJ, IraG, LupskiJR (2009) A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS genetics 5: e1000327.

49. SobreiraNL, GnanakkanV, WalshM, MarosyB, WohlerE, et al. (2011) Characterization of complex chromosomal rearrangements by targeted capture and next-generation sequencing. Genome research 21: 1720–1727.

50. CarvalhoCM, RamockiMB, PehlivanD, FrancoLM, Gonzaga-JaureguiC, et al. (2011) Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nature genetics 43: 1074–1081.

51. ChiangC, JacobsenJC, ErnstC, HanscomC, HeilbutA, et al. (2012) Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration. Nature genetics 44: 390–S391, 390-397, S391.

52. AnkalaA, KohnJN, HegdeA, MekaA, EphremCL, et al. (2012) Aberrant firing of replication origins potentially explains intragenic nonrecurrent rearrangements within genes, including the human DMD gene. Genome research 22: 25–34.

53. BaldwinEL, LeeJY, BlakeDM, BunkeBP, AlexanderCR, et al. (2008) Enhanced detection of clinically relevant genomic imbalances using a targeted plus whole genome oligonucleotide microarray. Genet Med 10: 415–429.

54. PerryGH, Ben-DorA, TsalenkoA, SampasN, Rodriguez-RevengaL, et al. (2008) The fine-scale and complex architecture of human copy-number variation. Am J Hum Genet 82: 685–695.

55. ConradDF, BirdC, BlackburneB, LindsayS, MamanovaL, et al. (2010) Mutation spectrum revealed by breakpoint sequencing of human germline CNVs. Nat Genet 42: 385–391.

56. MillsRE, WalterK, StewartC, HandsakerRE, ChenK, et al. (2011) Mapping copy number variation by population-scale genome sequencing. Nature 470: 59–65.

57. ArltMF, WilsonTE, GloverTW (2012) Replication stress and mechanisms of CNV formation. Current opinion in genetics & development 22: 204–210.

58. TurnerDJ, MirettiM, RajanD, FieglerH, CarterNP, et al. (2008) Germline rates of de novo meiotic deletions and duplications causing several genomic disorders. Nat Genet 40: 90–95.

59. HeardPL, CarterEM, CrandallAC, SeboldC, HaleDE, et al. (2009) High resolution genomic analysis of 18q- using oligo-microarray comparative genomic hybridization (aCGH). Am J Med Genet A 149A: 1431–1437.

60. BonagliaMC, GiordaR, PoggiG, RaggiME, RossiE, et al. (2000) Inverted duplications are recurrent rearrangements always associated with a distal deletion: description of a new case involving 2q. Eur J Hum Genet 8: 597–603.

61. KotzotD, MartinezMJ, BagciG, BasaranS, BaumerA, et al. (2000) Parental origin and mechanisms of formation of cytogenetically recognisable de novo direct and inverted duplications. Journal of medical genetics 37: 281–286.

62. CotterPD, KaffeS, LiL, GershinIF, HirschhornK (2001) Loss of subtelomeric sequence associated with a terminal inversion duplication of the short arm of chromosome 4. Am J Med Genet 102: 76–80.

63. ChenCP, ChernSR, LinSP, LinCC, LiYC, et al. (2005) A paternally derived inverted duplication of distal 14q with a terminal 14q deletion. American journal of medical genetics Part A 139A: 146–150.

64. CuscoI, del CampoM, VilardellM, GonzalezE, GenerB, et al. (2008) Array-CGH in patients with Kabuki-like phenotype: identification of two patients with complex rearrangements including 2q37 deletions and no other recurrent aberration. BMC medical genetics 9: 27.

65. ManolakosE, SifakisS, SotiriouS, PeitsidisP, EleftheriadesM, et al. (2012) Prenatal detection of an inverted duplication deletion in the long arm of chromosome 1 in a fetus with increased nuchal translucency. Molecular cytogenetic analysis and review of the literature. Clinical dysmorphology 21: 101–105.

66. LiH, DurbinR (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25: 1754–1760.

67. LiH, HandsakerB, WysokerA, FennellT, RuanJ, et al. (2009) The Sequence Alignment/Map format and SAMtools. Bioinformatics 25: 2078–2079.

68. NgCK, CookeSL, HoweK, NewmanS, XianJ, et al. (2012) The role of tandem duplicator phenotype in tumour evolution in high-grade serous ovarian cancer. The Journal of pathology 226: 703–712.

69. RobinsonJT, ThorvaldsdottirH, WincklerW, GuttmanM, LanderES, et al. (2011) Integrative genomics viewer. Nature biotechnology 29: 24–26.