Origin-Dependent Inverted-Repeat Amplification: A Replication-Based Model for Generating Palindromic Amplicons

Brewer, Bonita J.; Payen, Célia; Raghuraman, M. K.; Dunham, Maitreya J.

doi:10.1371/journal.pgen.1002016

Cited by 58 publications

(84 citation statements)

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“…6,23 In all cases where the parental origin could be determined, the triplication was found to be composed of alleles from both homologs of one of the parents, consistent with a meiotic or pre-meiotic origin. We previously demonstrated the same arrangement in two larger nonrecurrent rearrangements and pointed out for the first time the presence of both duplicated and triplicated portions.…”

Section: Discussionmentioning

confidence: 93%

“…[26][27][28][29] One exchange between homologous chromatids would take place at the distal breakpoint region, the other at the proximal breakpoint region, between either sister chromatids or homologous chromosomes. Brewer et al 23 proposed a replicationbased mechanism, supported by yeast observations, involving the generation of a dimeric inverted circular intermediate. Unfortunately, the model fails to account for the constant presence of duplicated regions of variable, and sometimes fairly large, size in all rearrangements examined so far.…”

Section: Discussionmentioning

confidence: 98%

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Low-copy repeats at the human VIPR2 gene predispose to recurrent and nonrecurrent rearrangements

2012

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Submicroscopic structural variations, including deletions, duplications, inversions and more complex rearrangements, are widespread in normal human genomes. Inverted segmental duplications or highly identical low-copy repeat (LCR) sequences can mediate the formation of inversions and more complex structural rearrangements through non-allelic homologous recombination. In a patient with 7q36 inverted duplication/terminal deletion, we demonstrated the central role of a pair of short inverted LCRs in the vasoactive intestinal peptide receptor gene (VIPR2)-LCRs in generating the rearrangement. We also revealed a relatively common VIPR2-LCR-associated inversion polymorphism disrupting the gene in almost 1% of healthy subjects, and a small number of complex duplications/triplications. In genome-wide studies of several thousand patients, a significant association of rare microduplications with variable size, all involving VIPR2, with schizophrenia was recently described, suggesting that altered vasoactive intestinal peptide signaling is likely implicated in the pathogenesis of schizophrenia. Genetic testing for VIPR2-LCR-associated inversions should be performed on available cohorts of psychiatric patients to evaluate their potential pathogenic role.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 98%

Low-copy repeats at the human VIPR2 gene predispose to recurrent and nonrecurrent rearrangements

2012

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“…For example, growth of yeast cells in medium with low levels of phosphate result in duplication of the linked PHO3 and PHO5 genes (Hansche et al 1978), cells grown in limited glucose have duplications of the hexose transporter encoded by HXT6 (Brown et al 1998;Dunham et al 2002), and cells selected in medium with low sulfur concentrations amplified the SUL1 gene (Gresham et al 2008). Amplification of the HTA2-HTB2 histone genes has also been identified as a dosage compensation mechanism for the deletion of HTA1-HTB1 ( arm associated with a terminal deletion of another chromosome (Dunham et al 2002;Umezu et al 2002;Kim et al 2008;Vernon et al 2008;Hoang et al 2010;McCulley and Petes 2010; Kolodner 2011, 2012); (5) linear extrachromosomal plasmids with the amplified copies in inverted orientation (Dorsey et al 1992;Narayanan et al 2006); and, (6) interstitial triplications of a genomic segment containing an origin of replication flanked by short inverted repeats (Brewer et al 2011). Class 1 duplications can be generated by unequal crossovers ( Figure 1B) or by break-induced replication (BIR) in which a double-strand break (DSB) in one repeat is repaired using a nonallelic repeat on a sister chromatid or a homolog.…”

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confidence: 99%

“…The formation of the palindromic plasmid in one system reflected the processing of a small palindromic repeat located centromere proximal to the reporter gene (Narayanan et al 2006). Finally, class 6 inverted triplication events observed at the SUL1 locus have been proposed to occur through the extrusion of a circular DNA intermediate formed during replication, followed by reintegration into the genome via homologous recombination (Brewer et al 2011).In summary, there are a variety of mechanisms that produce and select for CNVs in S. cerevisiae. The relative importance of these mechanisms is dependent on the chromosome context (in particular, whether the reporter gene is flanked by repeats) and ploidy.…”

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confidence: 99%

“…arm associated with a terminal deletion of another chromosome (Dunham et al 2002;Umezu et al 2002;Kim et al 2008;Vernon et al 2008;Hoang et al 2010;McCulley and Petes 2010;Kolodner 2011, 2012); (5) linear extrachromosomal plasmids with the amplified copies in inverted orientation (Dorsey et al 1992;Narayanan et al 2006); and, (6) interstitial triplications of a genomic segment containing an origin of replication flanked by short inverted repeats (Brewer et al 2011).…”

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Gene Copy-Number Variation in Haploid and Diploid Strains of the Yeast Saccharomyces cerevisiae

et al. 2013

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The increasing ability to sequence and compare multiple individual genomes within a species has highlighted the fact that copy-number variation (CNV) is a substantial and underappreciated source of genetic diversity. Chromosome-scale mutations occur at rates orders of magnitude higher than base substitutions, yet our understanding of the mechanisms leading to CNVs has been lagging. We examined CNV in a region of chromosome 5 (chr5) in haploid and diploid strains of Saccharomyces cerevisiae. We optimized a CNV detection assay based on a reporter cassette containing the SFA1 and CUP1 genes that confer gene dosage-dependent tolerance to formaldehyde and copper, respectively. This optimized reporter allowed the selection of low-order gene amplification events, going from one copy to two copies in haploids and from two to three copies in diploids. In haploid strains, most events involved tandem segmental duplications mediated by nonallelic homologous recombination between flanking direct repeats, primarily Ty1 elements. In diploids, most events involved the formation of a recurrent nonreciprocal translocation between a chr5 Ty1 element and another Ty1 repeat on chr13. In addition to amplification events, a subset of clones displaying elevated resistance to formaldehyde had point mutations within the SFA1 coding sequence. These mutations were all dominant and are proposed to result in hyperactive forms of the formaldehyde dehydrogenase enzyme.A S a consequence of studies that utilize genomic microarrays and next-generation DNA sequencing, it has become clear that much of the natural genetic variation that exists between individuals is due to alterations in the number of copies of genes rather than differences in the nucleotide sequence (Girirajan et al. 2011;Veltman and Brunner 2012). It has been calculated that 8-25 kb of DNA are deleted or duplicated per generation in humans compared to about 100 bp of point mutations (Itsara et al. 2010). Although deletions and duplications vary in size from a few base pairs (for example, changes in the lengths of microsatellites) to many megabases (for example, changes in ploidy), Girirajan et al. (2011) define copy-number variants (CNVs) in humans as changes that vary in size between 50 bp and 1 Mb. While most CNV events have no obvious effect, a significant number are associated with human diseases including Charcot-Marie-Tooth syndrome, autosomal dominant leukodystrophy, Williams syndrome, several cancer predispositions, and autism-related and other neurodevelopmental disorders (Abrahams and Geschwind 2008;Girirajan et al. 2011;Krepischi et al. 2012;Malhotra and Sebat 2012;Sullivan et al. 2012). There is also strong evidence suggesting that CNVs played a significant role in human evolution (Iskow et al. 2012). Finally, multiple somatic CNV events are frequently observed in the altered karyotypes of cancer cells (Stratton et al. 2009).CNVs have also been widely observed in natural populations and have been studied in detail in model organisms. In the discussion below, w...

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An evolving view of copy number variants

Lauer

Gresham

2019

Curr Genet

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Origin-Dependent Inverted-Repeat Amplification: A Replication-Based Model for Generating Palindromic Amplicons

Cited by 58 publications

References 55 publications

Low-copy repeats at the human VIPR2 gene predispose to recurrent and nonrecurrent rearrangements

Low-copy repeats at the human VIPR2 gene predispose to recurrent and nonrecurrent rearrangements

Gene Copy-Number Variation in Haploid and Diploid Strains of the Yeast Saccharomyces cerevisiae

An evolving view of copy number variants

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