Absence of Heterozygosity Due to Template Switching during Replicative Rearrangements

Carvalho, Claudia M.B.; Pfundt, Rolph; King, Dan; Lindsay, Sarah; Zuccherato, Luciana W.; Macville, Merryn; Liu, Pengfei; Johnson, Diana; Stankiewicz, Paweł; Brown, Chester; Shaw, Chad A.; Hurles, Matthew E.; Ira, Grzegorz; Hastings, P. J.; Brunner, Han G.; Lupski, James R.

doi:10.1016/j.ajhg.2015.01.021

Cited by 48 publications

(84 citation statements)

References 35 publications

(39 reference statements)

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“…Recently, terminal regions of absence of heterozygosity were detected distal of some triplications. Extended absence of heterozygosity adjacent to triplications is likely due to MMBIR template switching between homologous chromosomes, which leads to regional uniparental disomy at end of the chromosome [70]. …”

Section: Complex Chromosome Rearrangementmentioning

confidence: 99%

Human Structural Variation: Mechanisms of Chromosome Rearrangements

2015

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Chromosome structural variation (SV) is a normal part of variation in the human genome, but some classes of SV can cause neurodevelopmental disorders. Analysis of the DNA sequence at SV breakpoints can reveal mutational mechanisms and risk factors for chromosome rearrangement. Large-scale SV breakpoint studies have become possible recently owing to advances in next-generation sequencing (NGS) including whole-genome sequencing (WGS). These findings have shed light on complex forms of SV such as triplications, inverted duplications, insertional translocations, and chromothripsis. Sequence-level breakpoint data resolve SV structure and determine how genes are disrupted, fused, and/or misregulated by breakpoints. Recent improvements in breakpoint sequencing have also revealed non-allelic homologous recombination (NAHR) between paralogous long interspersed nuclear element (LINE) or human endogenous retrovirus (HERV) repeats as a cause of deletions, duplications, and translocations. This review covers the genomic organization of simple and complex constitutional SVs, as well as the molecular mechanisms of their formation.

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Section: Complex Chromosome Rearrangementmentioning

confidence: 99%

Human Structural Variation: Mechanisms of Chromosome Rearrangements

2015

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“…Recently, several cases of 'borderline CCRs' consisting of duplications and triplications associated with segments of copy-number-neutral loss of heterozygosity have been reported [Carvalho et al, 2015]. Detailed analyses suggest that these have resulted from a postzygotic MMBIR-like process involving template switches between sister chromatids [Carvalho et al, 2015].…”

Section: Molecular Mechanisms: Fork Stalling and Template Switching mentioning

confidence: 99%

“…Detailed analyses suggest that these have resulted from a postzygotic MMBIR-like process involving template switches between sister chromatids [Carvalho et al, 2015].…”

Section: Molecular Mechanisms: Fork Stalling and Template Switching mentioning

confidence: 99%

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Poot

Haaf

2015

Mol Syndromol

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Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM, BLM, WRN, ATR, MRE11, NBS1, and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed - these mechanisms will predominantly affect gene expression - or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C(JMJD2C) as a novel candidate gene for mental retardation.

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“…For example, CNVs and SNVs can be generated concomitantly 10 , and SNVs created during mutagenic repair can potentially affect the function of genes that do not map within the CNV. Also, CNVs can be followed by extended regions of absence of heterozygosity (AOH) 11,12 . If the AOH that is generated from template switching between homologues versus sister chromatids occurs at an imprinted locus, disease can result.…”

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confidence: 99%

Mechanisms underlying structural variant formation in genomic disorders

2016

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With the recent burst of technological developments in genomics, and the clinical implementation of genome-wide assays, our understanding of the molecular basis of genomic disorders, specifically the contribution of structural variation to disease burden, is evolving quickly. Ongoing studies have revealed a ubiquitous role for genome architecture in the formation of structural variants at a given locus, both in DNA recombination-based processes and in replication-based processes. These reports showcase the influence of repeat sequences on genomic stability and structural variant complexity and also highlight the tremendous plasticity and dynamic nature of our genome in evolution, health and disease susceptibility.

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Absence of Heterozygosity Due to Template Switching during Replicative Rearrangements

Cited by 48 publications

References 35 publications

Human Structural Variation: Mechanisms of Chromosome Rearrangements

Human Structural Variation: Mechanisms of Chromosome Rearrangements

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Mechanisms underlying structural variant formation in genomic disorders

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