← Back to Search
A Microhomology-Mediated Break-Induced Replication Model For The Origin Of Human Copy Number Variation
P. Hastings, G. Ira, J. Lupski
Published 2009 · Biology, Medicine
Download PDFAnalyze on Scholarcy
Chromosome structural changes with nonrecurrent endpoints associated with genomic disorders offer windows into the mechanism of origin of copy number variation (CNV). A recent report of nonrecurrent duplications associated with Pelizaeus-Merzbacher disease identified three distinctive characteristics. First, the majority of events can be seen to be complex, showing discontinuous duplications mixed with deletions, inverted duplications, and triplications. Second, junctions at endpoints show microhomology of 2–5 base pairs (bp). Third, endpoints occur near pre-existing low copy repeats (LCRs). Using these observations and evidence from DNA repair in other organisms, we derive a model of microhomology-mediated break-induced replication (MMBIR) for the origin of CNV and, ultimately, of LCRs. We propose that breakage of replication forks in stressed cells that are deficient in homologous recombination induces an aberrant repair process with features of break-induced replication (BIR). Under these circumstances, single-strand 3′ tails from broken replication forks will anneal with microhomology on any single-stranded DNA nearby, priming low-processivity polymerization with multiple template switches generating complex rearrangements, and eventual re-establishment of processive replication.
This paper references
Saccharomyces cerevisiae Sae2- and Tel1-Dependent Single-Strand DNA Formation at DNA Break Promotes Microhomology-Mediated End Joining
Kihoon Lee (2007)
Comparison of filler DNA at immune, nonimmune, and oncogenic rearrangements suggests multiple mechanisms of formation.
D. Roth (1989)
General stress response regulator RpoS in adaptive mutation and amplification in Escherichia coli.
M. Lombardo (2004)
Break-induced replication: What is it and what is it for?
B. Llorente (2008)
Decoding the fine-scale structure of a breast cancer genome and transcriptome.
S. Volik (2006)
Genome structural variation and sporadic disease traits
J. Lupski (2006)
Ability of Polymerase η and T7 DNA Polymerase to Bypass Bulge Structures*
V. Cannistraro (2007)
Rad51 Protein Controls Rad52-mediated DNA Annealing*
Y. Wu (2008)
Serial segmental duplications during primate evolution result in complex human genome architecture.
P. Stankiewicz (2004)
Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect
J. Lee (2006)
Uniparental disomy as a mechanism for human genetic disease.
J. Spence (1988)
Double-strand-break repair in Escherichia coli: physical evidence for a DNA replication mechanism in vivo
M Motamedi (1999)
Chromosomal rearrangements occur in S. cerevisiae rfa1 mutator mutants due to mutagenic lesions processed by double-strand-break repair.
C. Chen (1998)
Genome-wide detection of human copy number variations using high-density DNA oligonucleotide arrays.
D. Komura (2006)
Fine-scale structural variation of the human genome
E. Tuzun (2005)
"Break copy" duplication: a model for chromosome fragment formation in Saccharomyces cerevisiae.
D. Morrow (1997)
Short, direct repeats at the breakpoints of deletions of the retinoblastoma gene.
S. Canning (1989)
Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males
D. Gaudio (2006)
An evolution revolution provides further revelation
J. Lupski (2007)
High-frequency illegitimate integration of transfected DNA at preintegrated target sites in a mammalian genome.
R. V. Merrihew (1996)
Gene duplication and the adaptive evolution of a classic genetic switch
C. Hittinger (2007)
Instability of repetitive DNA sequences: The role of replication in multiple mechanisms
M. Bzymek (2001)
Regulation of DNA repair in hypoxic cancer cells
R. Bindra (2007)
A new role for hypoxia in tumor progression: induction of fragile site triggering genomic rearrangements and formation of complex DMs and HSRs.
A. Coquelle (1998)
Characterization of Potocki-Lupski syndrome
L B Potocki (2007)
On the formation of spontaneous deletions: The importance of short sequence homologies in the generation of large deletions
A. Albertini (1982)
Double complex mutations involving F8 and FUNDC2 caused by distinct break‐induced replication
C. Sheen (2007)
Multiple pathways of selected gene amplification during adaptive mutation
E. Kugelberg (2006)
Break-induced replication and recombinational telomere elongation in yeast.
M. Mceachern (2006)
Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution.
G. Bignell (2007)
Evolution by Gene Duplication
Dr. Susumu Ohno (1970)
The hypoxic tumour microenvironment and metastatic progression
P. Subarsky (2004)
A DNA Replication Mechanism for Generating Nonrecurrent Rearrangements Associated with Genomic Disorders
J. Lee (2007)
Genomic Rearrangements and Gene Copy-Number Alterations as a Cause of Nervous System Disorders
J. Lee (2006)
Human DNA polymerase eta promotes DNA synthesis from strand invasion intermediates of homologous recombination.
M. McIlwraith (2005)
Adaptive reversion of a frameshift mutation in Escherichia coli.
J. Cairns (1991)
Large-Scale Copy Number Polymorphism in the Human Genome
J. Sebat (2004)
On the Mechanism of Gene Amplification Induced under Stress in Escherichia coli
A. Slack (2006)
Repression of RAD51 gene expression by E2F4/p130 complexes in hypoxia
R. Bindra (2007)
Template Switching: From Replication Fork Repair to Genome Rearrangements
D. Branzei (2007)
Segmental Duplications Arise from Pol32-Dependent Repair of Broken Forks through Two Alternative Replication-Based Mechanisms
Celia Payen (2008)
Molecular analysis of the non-recurrent genomic duplications causing Pelizaeus-Merzbacher disease and its allelic disorder paraplegia type 2
J A Lee (2006)
Multiple pathways cooperate in the suppression of genome instability in Saccharomyces cerevisiae
K. Myung (2001)
Genomic Disorders: Molecular Mechanisms for Rearrangements and Conveyed Phenotypes
J. Lupski (2005)
A comprehensive analysis of common copy-number variations in the human genome.
K. K. Wong (2007)
Accurate and reliable high-throughput detection of copy number variation in the human genome.
H. Fiegler (2006)
Control of Translocations between Highly Diverged Genes by Sgs1, the Saccharomyces cerevisiae Homolog of the Bloom'sSyndrome Protein
K. Schmidt (2006)
Mitotic stability of yeast chromosomes: A colony color assay that measures nondisjunction and chromosome loss
P. Hieter (1985)
Paired-End Mapping Reveals Extensive Structural Variation in the Human Genome
J. Korbel (2007)
Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair.
M. Bauters (2008)
Removal of nonhomologous DNA ends in double-strand break recombination: the role of the yeast ultraviolet repair gene RAD1.
J. Fishman-Lobell (1992)
Primate segmental duplications: crucibles of evolution, diversity and disease
J. Bailey (2006)
Global variation in copy number in the human genome
R. Redon (2006)
DNA double strand break repair in human bladder cancer is error prone and involves microhomology-associated end-joining.
J. Bentley (2004)
Crossing over between regions of limited homology in Escherichia coli. RecA-dependent and RecA-independent pathways.
S. Lovett (2002)
Inverted DNA Repeats Channel Repair of Distant Double-Strand Breaks into Chromatid Fusions and Chromosomal Rearrangements
K. Vanhulle (2007)
Non-recurrent 17p11.2 deletions are generated by homologous and non-homologous mechanisms
C. Shaw (2004)
Spontaneous DNA breakage in single living cells of Escherichia coli
S. Rosenberg (2007)
Human meiotic recombination products revealed by sequencing a hotspot for homologous strand exchange in multiple HNPP deletion patients.
L. Reiter (1998)
Characterization of genomic breakpoints in MLL and CBP in leukemia patients with t(11;16)
Y. Zhang (2004)
Gross genomic rearrangements involving deletions in the CFTR gene: characterization of six new events from a large cohort of hitherto unidentified cystic fibrosis chromosomes and meta-analysis of the underlying mechanisms
C. Férec (2006)
Template switching during break-induced replication
C. E. Smith (2007)
Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits.
J. Lupski (1998)
Evolution by gene duplication. Berlin, New York: SpringerVerlag
S Ohno (1970)
[Structural variation in the human genome].
Y. He (2009)
Pairedend mapping reveals extensive structural variation in the human
JO Korbel (2007)
Double-strand-break repair recombination in Escherichia coli: physical evidence for a DNA replication mechanism in vivo.
M. R. Motamedi (1999)
Break-induced replication and telomerase-independent telomere maintenance require Pol32
John R. Lydeard (2007)
Role of genomic architecture in PLP1 duplication causing Pelizaeus-Merzbacher disease.
J. Lee (2006)
Adaptive Amplification and Point Mutation Are Independent Mechanisms: Evidence for Various Stress-Inducible Mutation Mechanisms
P. Hastings (2004)
DNA strand annealing is promoted by the yeast Rad52 protein.
U. Mortensen (1996)
Birth of ‘Human-Specific’ Genes During Primate Evolution
J. Nahon (2004)
Dual roles for DNA polymerase eta in homologous DNA recombination and translesion DNA synthesis.
T. Kawamoto (2005)
Choreography of the DNA Damage Response Spatiotemporal Relationships among Checkpoint and Repair Proteins
M. Lisby (2004)
Effects of mutations of RAD50, RAD51, RAD52, and related genes on illegitimate recombination in Saccharomyces cerevisiae.
Y. Tsukamoto (1996)
Detection of large-scale variation in the human genome
A. Iafrate (2004)
P. Hastings (2007)
Telomere-Telomere Recombination Is an Efficient Bypass Pathway for Telomere Maintenance in Saccharomyces cerevisiae
S. Teng (1999)
Rag mutations reveal robust alternative end joining
B. Corneo (2007)
Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells.
R. Bindra (2004)
Adaptive Amplification An Inducible Chromosomal Instability Mechanism
P. Hastings (2000)
RAD51-Dependent Break-Induced Replication in Yeast
A. Davis (2004)
Genome architecture, rearrangements and genomic disorders.
P. Stankiewicz (2002)
Genomic DNA breakpoints in AML1/RUNX1 and ETO cluster with topoisomerase II DNA cleavage and DNase I hypersensitive sites in t(8;21) leukemia
Y. Zhang (2002)
Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells.
S. D. Young (1988)
Short-homology-independent illegitimate recombination in Escherichia coli: distinct mechanism from short-homology-dependent illegitimate recombination.
H. Shimizu (1997)
Evidence for Multiple Cycles of Strand Invasion During Repair of Double-Strand Gaps in Drosophila
M. McVey (2004)
Gene copy number variation spanning 60 million years of human and primate evolution.
L. Dumas (2007)
Gene Duplication: The Genomic Trade in Spare Parts
M. Hurles (2004)
Spontaneous Homologous Recombination Is Induced by Collapsed Replication Forks That Are Caused by Endogenous DNA Single-Strand Breaks
N. Saleh-Gohari (2005)
RAD50 and RAD51 define two pathways that collaborate to maintain telomeres in the absence of telomerase.
S. Le (1999)
Co-repression of mismatch repair gene expression by hypoxia in cancer cells: role of the Myc/Max network.
R. Bindra (2007)
Spontaneous DNA breakage in single living Escherichia coli cells
Jeanine M Pennington (2007)
Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype.
L. Potocki (2007)
Genome architecture catalyzes nonrecurrent chromosomal rearrangements.
P. Stankiewicz (2003)
Genetic studies of the lac repressor. VII. On the molecular nature of spontaneous hotspots in the lacI gene of Escherichia coli.
P. Farabaugh (1978)
Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females.
K. Inoue (2002)
Intrachromosomal serial replication slippage in trans gives rise to diverse genomic rearrangements involving inversions
J. Chen (2005)
Analysis of 22 deletion breakpoints in dystrophin intron 49
C. Nobile (2002)
Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells.
V. T. Mihaylova (2003)
Complex chromosome 17p rearrangements associated with low-copy repeats in two patients with congenital anomalies
L. Vissers (2007)
A switch from high-fidelity to error-prone DNA double-strand break repair underlies stress-induced mutation.
R. Ponder (2005)
A genome-wide survey of structural variation between human and chimpanzee.
T. Newman (2005)
Genome assembly comparison identifies structural variants in the human genome
R. Khaja (2006)
A novel assay for illegitimate recombination in Escherichia coli: stimulation of lambda bio transducing phage formation by ultra-violet light and its independence from RecA function.
H. Ikeda (1995)
Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles.
C. Bruder (2008)
Homology requirement for efficient gene conversion between duplicated chromosomal sequences in mammalian cells.
R. Liskay (1987)
DNA Repair and Mutagenesis. Washington (DC): ASM Press. 1164 p. PLoS Genetics | www.plosgenetics.org 8 January 2009 | Volume 5 | Issue 1 | e1000327
EC Friedberg (2005)
Defective Break-Induced Replication Leads to Half-Crossovers in Saccharomyces cerevisiae
A. Deem (2008)
DNA Repair and Mutagenesis
E. Friedberg (2006)
Hypoxia-induced genetic instability—a calculated mechanism underlying tumor progression
L. Huang (2006)
Molecular processes of chromosome 9p21 deletions causing inactivation of the p16 tumor suppressor gene in human cancer: deduction from structural analysis of breakpoints for deletions.
T. Kohno (2006)
This paper is referenced by
Estudio de variantes estructurales del genoma humano asociadas a trastornos del neurodesarrollo
S. Villatoro (2016)
POL θ-MEDIATED END JOINING (TMEJ) OF TRANSPOSITION-INDUCED DOUBLE STRAND BREAKS IN C. ELEGANS GERM CELLS
Sophie F. Roerink (2014)
Analysen zum Entstehungsmechanismus von Typ-2 NF 1 Deletionen bei Patienten mit Neurofibromatose Typ
Christian Kubis (2012)
Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder
M. Poot (2009)
An investigation of genetic variation in complex disorders of the pituitary gland
E. Spadoni (2011)
What Limits the Efficiency of Double-Strand Break-Dependent Stress-Induced Mutation in Escherichia coli
Chandan Shee (2011)
chromosomal structural rearrangements characterizing interstitial deletions and duplications in the clinical practice
M. Riegel (2017)
The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway.
M. Lieber (2010)
Genomic disorders: A window into human gene and genome evolution
C. Carvalho (2010)
An evolving view of copy number variants
Stephanie Lauer (2019)
Chromosomal rearrangements in cancer
P. Hasty (2014)
In silico analysis highlights the copy number variation mechanism responsible for the historically reported VWF exon 42 deletion
A. Cartwright (2016)
Template Switching During Break-Induced Replication Is Promoted by the Mph1 Helicase in Saccharomyces cerevisiae
Anamarija Štafa (2014)
Identification of 15 novel partial SHOX deletions and 13 partial duplications, and a review of the literature reveals intron 3 to be a hotspot region
S. Benito-Sanz (2017)
The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy
D. Pehlivan (2016)
What is mutation? A chapter in the series: How microbes “jeopardize” the modern synthesis
D. Fitzgerald (2019)
The Diverse Effects of Complex Chromosome Rearrangements and Chromothripsis in Cancer Development.
Mirjam S de Pagter (2015)
Frequent Somatic Mutation in Adult Intestinal Stem Cells Drives Neoplasia and Genetic Mosaicism during Aging
Katarzyna Siudeja (2015)
Comparison of Constitutional and Replication Stress-Induced Genome Structural Variation by SNP Array and Mate-Pair Sequencing
M. Arlt (2011)
Protracted p53-independent stimulation of p21 fuels genomic instability by deregulating the replication licensing machinery
Panagiotis Galanos (2016)
Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability.
F. Zhang (2010)
Structural variation in the maize genome
K. Ying (2012)
DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes
S. De (2011)
Breakpoint mapping by next generation sequencing reveals causative gene disruption in patients carrying apparently balanced chromosome rearrangements with intellectual deficiency and/or congenital malformations
C. Schluth-Bolard (2013)
Aberrant firing of replication origins potentially explains intragenic nonrecurrent rearrangements within genes, including the human DMD gene.
A. Ankala (2012)
A MUTAGENIC REPAIR PATHWAY DEPENDENT ON POLYMERASE θ PROTECTS THE C. ELEGANS GENOME AGAINST LARGE CHROMOSOMAL DELETIONS
Sophie F. Roerink (2014)
Molecular and clinical characterization of patients with overlapping 10p deletions
A. Lindstrand (2010)
Chromosome 15q24 microdeletion syndrome
P. Magoulas (2012)
Origins and Breakpoint Analyses of Copy Number Variations: Up Close and Personal
E. V. Binsbergen (2011)
Breakpoint mapping at nucleotide resolution in X-autosome balanced translocations associated with clinical phenotypes
M. Moysés-Oliveira (2019)
Microdeletions including YWHAE in the Miller–Dieker syndrome region on chromosome 17p13.3 result in facial dysmorphisms, growth restriction, and cognitive impairment
S. C. Sreenath Nagamani (2009)
Intragenic DOK7 deletion detected by whole-genome sequencing in congenital myasthenic syndromes
Y. Azuma (2017)See more