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PMID: 22440479 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

Mechanisms for recurrent and complex human genomic rearrangements.

Current opinion in genetics & development ·Vol. 22 ·No. 3 ·2012-06-00 ·Pages 211-20

Liu P, Carvalho CM, Hastings PJ, Lupski JR

Abstract

During the last two decades, the importance of human genome copy number variation (CNV) in disease has become widely recognized. However, much is not understood about underlying mechanisms. We show how, although model organism research guides molecular understanding, important insights are gained from study of the wealth of information available in the clinic. We describe progress in explaining nonallelic homologous recombination (NAHR), a major cause of copy number change occurring when control of allelic recombination fails, highlight the growing importance of replicative mechanisms to explain complex events, and describe progress in understanding extreme chromosome reorganization (chromothripsis). Both nonhomologous end-joining and aberrant replication have significant roles in chromothripsis. As we study CNV, the processes underlying human genome evolution are revealed.

MeSH Terms
Alleles Chromosomes, Human/genetics,metabolism DNA/genetics,metabolism DNA Copy Number Variations DNA End-Joining Repair DNA Replication Gene Rearrangement Genetic Diseases, Inborn/genetics Genome, Human Genomic Instability Histone-Lysine N-Methyltransferase/genetics,metabolism Homologous Recombination Humans
Chemicals
DNA Histone-Lysine N-Methyltransferase PRDM9 protein, human
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Liu Pengfei
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Carvalho Claudia M B
Hastings P J
Lupski James R
References (76)
76 references, click to expand
  1. Replication stress induces genome-wide copy number changes in human cells that resemble polymorphic and pathogenic variants.
    Am J Hum Genet. 2009 Mar;84(3):339-50 PMID: 19232554
  2. The genomic complexity of primary human prostate cancer.
    Nature. 2011 Feb 10;470(7333):214-20 PMID: 21307934
  3. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders.
    Cell. 2007 Dec 28;131(7):1235-47 PMID: 18160035
  4. Mapping copy number variation by population-scale genome sequencing.
    Nature. 2011 Feb 3;470(7332):59-65 PMID: 21293372
  5. Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching.
    Hum Mol Genet. 2009 Jun 15;18(12):2188-203 PMID: 19324899
  6. Hypervariable 'minisatellite' regions in human DNA.
    Nature. 1985 Mar 7-13;314(6006):67-73 PMID: 3856104
  7. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A.
    Nat Genet. 1993 Nov;5(3):236-41 PMID: 8275087
  8. Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females.
    Am J Hum Genet. 2002 Oct;71(4):838-53 PMID: 12297985
  9. Prdm9 controls activation of mammalian recombination hotspots.
    Science. 2010 Feb 12;327(5967):835 PMID: 20044538
  10. Recombination and recombination-dependent DNA replication in bacteriophage T4.
    Annu Rev Genet. 1998;32:379-413 PMID: 9928485
  11. DPY19L2 deletion as a major cause of globozoospermia.
    Am J Hum Genet. 2011 Mar 11;88(3):344-50 PMID: 21397063
  12. Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit.
    Nat Genet. 1992 Dec;2(4):292-300 PMID: 1303282
  13. Complex landscapes of somatic rearrangement in human breast cancer genomes.
    Nature. 2009 Dec 24;462(7276):1005-10 PMID: 20033038
  14. Variants of the protein PRDM9 differentially regulate a set of human meiotic recombination hotspots highly active in African populations.
    Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12378-83 PMID: 21750151
  15. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing.
    Nat Genet. 2008 Jun;40(6):722-9 PMID: 18438408
  16. Mutation spectrum revealed by breakpoint sequencing of human germline CNVs.
    Nat Genet. 2010 May;42(5):385-91 PMID: 20364136
  17. Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome.
    Nat Genet. 1997 Oct;17(2):154-63 PMID: 9326934
  18. Origins and functional impact of copy number variation in the human genome.
    Nature. 2010 Apr 1;464(7289):704-12 PMID: 19812545
  19. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability.
    Nat Genet. 2006 Sep;38(9):1032-7 PMID: 16906163
  20. The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans.
    Nat Genet. 2009 Jul;41(7):849-53 PMID: 19543269
  21. Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes.
    Genome Res. 2011 Jan;21(1):33-46 PMID: 21205869
  22. Isodicentric Y chromosomes and sex disorders as byproducts of homologous recombination that maintains palindromes.
    Cell. 2009 Sep 4;138(5):855-69 PMID: 19737515
  23. Identification of uncommon recurrent Potocki-Lupski syndrome-associated duplications and the distribution of rearrangement types and mechanisms in PTLS.
    Am J Hum Genet. 2010 Mar 12;86(3):462-70 PMID: 20188345
  24. Homology requirement for efficient gene conversion between duplicated chromosomal sequences in mammalian cells.
    Genetics. 1987 Jan;115(1):161-7 PMID: 3557108
  25. DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes.
    Nat Biotechnol. 2011 Nov 20;29(12):1103-8 PMID: 22101487
  26. Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions.
    J Med Genet. 2011 Dec;48(12):840-50 PMID: 21984752
  27. Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination.
    Science. 2010 Feb 12;327(5967):876-9 PMID: 20044541
  28. Hydroxyurea induces de novo copy number variants in human cells.
    Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17360-5 PMID: 21987784
  29. Recent segmental duplications in the human genome.
    Science. 2002 Aug 9;297(5583):1003-7 PMID: 12169732
  30. Deletion of VCX-A due to NAHR plays a major role in the occurrence of mental retardation in patients with X-linked ichthyosis.
    Hum Mol Genet. 2005 Jul 1;14(13):1795-803 PMID: 15888481
  31. Substrate length requirements for efficient mitotic recombination in Saccharomyces cerevisiae.
    Mol Cell Biol. 1993 Jul;13(7):3937-50 PMID: 8321201
  32. Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome.
    Nat Genet. 2011 Oct 02;43(11):1074-81 PMID: 21964572
  33. Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline.
    Hum Mol Genet. 2011 May 15;20(10):1916-24 PMID: 21349919
  34. A microhomology-mediated break-induced replication model for the origin of human copy number variation.
    PLoS Genet. 2009 Jan;5(1):e1000327 PMID: 19180184
  35. High order chromatin architecture shapes the landscape of chromosomal alterations in cancer.
    Nat Biotechnol. 2011 Nov 20;29(12):1109-13 PMID: 22101486
  36. Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination.
    Am J Hum Genet. 2005 Dec;77(6):966-87 PMID: 16380909
  37. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits.
    Trends Genet. 1998 Oct;14(10):417-22 PMID: 9820031
  38. Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability.
    Am J Hum Genet. 2010 Jun 11;86(6):892-903 PMID: 20493460
  39. The breakpoint region of the most common isochromosome, i(17q), in human neoplasia is characterized by a complex genomic architecture with large, palindromic, low-copy repeats.
    Am J Hum Genet. 2004 Jan;74(1):1-10 PMID: 14666446
  40. On the mechanism of gene amplification induced under stress in Escherichia coli.
    PLoS Genet. 2006 Apr;2(4):e48 PMID: 16604155
  41. A chromosomal rearrangement hotspot can be identified from population genetic variation and is coincident with a hotspot for allelic recombination.
    Am J Hum Genet. 2006 Nov;79(5):890-902 PMID: 17033965
  42. Two long homologous retroviral sequence blocks in proximal Yq11 cause AZFa microdeletions as a result of intrachromosomal recombination events.
    Hum Mol Genet. 2000 Oct 12;9(17):2563-72 PMID: 11030762
  43. Frequency of nonallelic homologous recombination is correlated with length of homology: evidence that ectopic synapsis precedes ectopic crossing-over.
    Am J Hum Genet. 2011 Oct 7;89(4):580-8 PMID: 21981782
  44. Evolution in health and medicine Sackler colloquium: Genomic disorders: a window into human gene and genome evolution.
    Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1765-71 PMID: 20080665
  45. Segmental duplications arise from Pol32-dependent repair of broken forks through two alternative replication-based mechanisms.
    PLoS Genet. 2008 Sep 05;4(9):e1000175 PMID: 18773114
  46. Genome architecture, rearrangements and genomic disorders.
    Trends Genet. 2002 Feb;18(2):74-82 PMID: 11818139
  47. Break-induced replication is highly inaccurate.
    PLoS Biol. 2011 Feb 15;9(2):e1000594 PMID: 21347245
  48. Genomic disorders ten years on.
    Genome Med. 2009 Apr 24;1(4):42 PMID: 19439022
  49. Break-induced replication and telomerase-independent telomere maintenance require Pol32.
    Nature. 2007 Aug 16;448(7155):820-3 PMID: 17671506
  50. Massive genomic rearrangement acquired in a single catastrophic event during cancer development.
    Cell. 2011 Jan 7;144(1):27-40 PMID: 21215367
  51. Copy number gain at Xp22.31 includes complex duplication rearrangements and recurrent triplications.
    Hum Mol Genet. 2011 May 15;20(10):1975-88 PMID: 21355048
  52. A molecular throttle: the recombination hotspot chi controls DNA translocation by the RecBCD helicase.
    Cell. 2003 Sep 5;114(5):647-54 PMID: 13678587
  53. FoSTeS, MMBIR and NAHR at the human proximal Xp region and the mechanisms of human Xq isochromosome formation.
    Hum Mol Genet. 2011 May 15;20(10):1925-36 PMID: 21349920
  54. A human genome structural variation sequencing resource reveals insights into mutational mechanisms.
    Cell. 2010 Nov 24;143(5):837-47 PMID: 21111241
  55. Double-strand break repair in the absence of RAD51 in yeast: a possible role for break-induced DNA replication.
    Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7131-6 PMID: 8692957
  56. Development and validation of a CGH microarray for clinical cytogenetic diagnosis.
    Genet Med. 2005 Jul-Aug;7(6):422-32 PMID: 16024975
  57. Increased LIS1 expression affects human and mouse brain development.
    Nat Genet. 2009 Feb;41(2):168-77 PMID: 19136950
  58. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome.
    Nat Genet. 2006 Sep;38(9):1038-42 PMID: 16906162
  59. A common sequence motif associated with recombination hot spots and genome instability in humans.
    Nat Genet. 2008 Sep;40(9):1124-9 PMID: 19165926
  60. Germline rates of de novo meiotic deletions and duplications causing several genomic disorders.
    Nat Genet. 2008 Jan;40(1):90-5 PMID: 18059269
  61. New insights into the biological basis of genomic disorders.
    Nat Genet. 2006 Dec;38(12):1363-4 PMID: 17133221
  62. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements.
    Cell. 2011 Sep 16;146(6):889-903 PMID: 21925314
  63. Template switching during break-induced replication.
    Nature. 2007 May 3;447(7140):102-5 PMID: 17410126
  64. Hotspots of homologous recombination in the human genome: not all homologous sequences are equal.
    Genome Biol. 2004;5(10):242 PMID: 15461806
  65. Targeted genomic microarray analysis for identification of chromosome abnormalities in 1500 consecutive clinical cases.
    J Pediatr. 2006 Jul;149(1):98-102 PMID: 16860135
  66. "Break copy" duplication: a model for chromosome fragment formation in Saccharomyces cerevisiae.
    Genetics. 1997 Oct;147(2):371-82 PMID: 9335579
  67. PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice.
    Science. 2010 Feb 12;327(5967):836-40 PMID: 20044539
  68. THE BAR "GENE" A DUPLICATION.
    Science. 1936 Feb 28;83(2148):210-1 PMID: 17796454
  69. Genomic rearrangements in inherited disease and cancer.
    Semin Cancer Biol. 2010 Aug;20(4):222-33 PMID: 20541013
  70. DNA breaks and chromosome pulverization from errors in mitosis.
    Nature. 2012 Jan 18;482(7383):53-8 PMID: 22258507
  71. BLM ortholog, Sgs1, prevents aberrant crossing-over by suppressing formation of multichromatid joint molecules.
    Cell. 2007 Jul 27;130(2):259-72 PMID: 17662941
  72. PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans.
    Nat Genet. 2010 Oct;42(10):859-63 PMID: 20818382
  73. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations.
    Cell. 2012 Jan 20;148(1-2):59-71 PMID: 22265402
  74. Rare pathogenic microdeletions and tandem duplications are microhomology-mediated and stimulated by local genomic architecture.
    Hum Mol Genet. 2009 Oct 1;18(19):3579-93 PMID: 19578123
  75. Global variation in copy number in the human genome.
    Nature. 2006 Nov 23;444(7118):444-54 PMID: 17122850
  76. Conservation of hotspots for recombination in low-copy repeats associated with the NF1 microdeletion.
    Nat Genet. 2006 Dec;38(12):1419-23 PMID: 17115058
Article Info
Journal
Current opinion in genetics & development
Abbr.
Curr Opin Genet Dev
ISSN
1879-0380
DOI
10.1016/j.gde.2012.02.012
Published
2012-06-00
Epub
2012-00-20
Pages
211-20
Language
English
Region
England
NLM ID
9111375
PMCID
PMC3378805
Subset
IM
Grants
NINDS NIH HHS · R01NS058529 · United States
NCRR NIH HHS · M01 RR000188 · United States
NINDS NIH HHS · R01 NS058529-04 · United States
NICHD NIH HHS · P30 HD024064 · United States
NCRR NIH HHS · M01 RR000188-47 · United States
NICHD NIH HHS · P30HD024064 · United States
NCRR NIH HHS · M01RR00188 · United States
NICHD NIH HHS · P30 HD024064-21S2 · United States
NINDS NIH HHS · R01 NS058529 · United States
External Links
PubMed source DOI: 10.1016/j.gde.2012.02.012 PMC Full Text View journal details
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