Experimental Induction of Genome Chaos

Ye, Christine J.; Heng, Henry H.Q.

doi:10.1007/978-1-4939-7780-2_21

Cited by 14 publications

(18 citation statements)

References 56 publications

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“…Indeed, the finding that in case 3 the breakpoint junction 7a(+)_6b(+) was present in mother's blood but not in her saliva indicated that the (three) massively broken chromosomes underwent a series of postzygotic repairs resulting in small differences of the same chromothriptic event in the different tissues. This observation parallels what has been documented in cancer cells where massive genome reorganization, whichever the related mechanisms and clinical outcome, indeed requires evolutionary selection processes to pick up winning genomes that may be different in the different tissues (Behjati et al, 2017;Ye, Liu, & Heng, 2018).…”

Section: Chromothripsis: Constitutional Versus Mosaics Eventssupporting

confidence: 79%

Insertional translocation involving an additional nonchromothriptic chromosome in constitutional chromothripsis: Rule or exception?

Kurtas

Xumerle

Giussani

et al. 2018

Molec Gen & Gen Med

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Background Chromothripsis, which is the local massive shattering of one or more chromosomes and their reassembly in a disordered array with frequent loss of some fragments, has been mainly reported in association with abnormal phenotypes. We report three unrelated healthy persons, two of which parenting a child with some degree of intellectual disability, carrying a chromothripsis involving respectively one, two, and three chromosomes, which was detected only after whole‐genome sequencing. Unexpectedly, in all three cases a fragment from one of the chromothripsed chromosomes resulted to be inserted within a nonchromothripsed one. Methods Conventional cytogenetic techniques, paired‐end whole‐genome sequencing, polymerase chain reaction, and Sanger sequencing were used to characterize complex rearrangements, copy‐number variations, and breakpoint sequences in all three families. Results In two families, one parent was carrier of a balanced chromothripsis causing in the index case a deletion and a noncontiguous duplication at 3q in case 1, and a t(6;14) translocation associated with interstitial 14q deletion in case 2. In the third family, an unbalanced chromothripsis involving chromosomes 6, 7, and 15 was inherited to the proband by the mosaic parent. In all three parents, the chromothripsis was concurrent with an insertional translocation of a portion of one of the chromothriptic chromosomes within a further chromosome that was not involved in the chromothripsis event. Conclusion Our findings show that (a) both simple and complex unbalanced rearrangements may result by the recombination of a cryptic parental balanced chromothripsis and that (b) insertional translocations are the spy of more complex rearrangements and not simply a three‐breakpoint event.

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Section: Chromothripsis: Constitutional Versus Mosaics Eventssupporting

confidence: 79%

Insertional translocation involving an additional nonchromothriptic chromosome in constitutional chromothripsis: Rule or exception?

Kurtas

Xumerle

Giussani

et al. 2018

Molec Gen & Gen Med

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“…The identification of chromoanagenesis phenomenon in both cancers and congenital disorders provides a new perception of how genomes can be rapidly altered. Despite a high incidence of cell death during the process, the formation of chaotic genomes could represent a powerful survival strategy for the genome when under crisis, and chromoanagenesis-mediated events could constitute inherent mechanisms for maintaining genome stability and integrity [128, 129].…”

Section: Resultsmentioning

confidence: 99%

Chromoanagenesis: cataclysms behind complex chromosomal rearrangements

Pellestor

2019

Mol Cytogenet

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BackgroundDuring the last decade, genome sequencing projects in cancer genomes as well as in patients with congenital diseases and healthy individuals have led to the identification of new types of massive chromosomal rearrangements arising during single chaotic cellular events. These unanticipated catastrophic phenomenon are termed chromothripsis, chromoanasynthesis and chromoplexis., and are grouped under the name of “chromoanagenesis”.ResultsFor each process, several specific features have been described, allowing each phenomenon to be distinguished from each other and to understand its mechanism of formation and to better understand its aetiology. Thus, chromothripsis derives from chromosome shattering followed by the random restitching of chromosomal fragments with low copy-number change whereas chromoanasynthesis results from erroneous DNA replication of a chromosome through serial fork stalling and template switching with variable copy-number gains, and chromoplexy refers to the occurrence of multiple inter-and intra-chromosomal translocations and deletions with little or no copy-number alterations in prostate cancer. Cumulating data and experimental models have shown that chromothripsis and chromoanasynthesis may essentially result from lagging chromosome encapsulated in micronuclei or telomere attrition and end-to-end telomere fusion.ConclusionThe concept of chromanagenesis has provided new insight into the aetiology of complex structural rearrangements, the connection between defective cell cycle progression and genomic instability, and the complexity of cancer evolution. Increasing reported chromoanagenesis events suggest that these chaotic mechanisms are probably much more frequent than anticipated.

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“…Despite the observation that chromothripsis has been experimentally induced with micronuclei [91], we should not consider micronuclei to be the main causative factor for chromothripsis. In contrast, the high level of stress represents a major and common factor which can trigger genome chaos (both locally, reflected as chromothripsis; and the entire genome, reflected as a massive chaotic genome) [11,15]. Based on the cytogenetic analysis of experimentally induced genome chaos, chromothripsis accounts for 10% of all induced chaotic genomes.…”

Section: New Challenges and Opportunities For Micronuclei Researchmentioning

confidence: 99%

Micronuclei and Genome Chaos: Changing the System Inheritance

Sharpe

Alemara

et al. 2019

Genes

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105

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Micronuclei research has regained its popularity due to the realization that genome chaos, a rapid and massive genome re-organization under stress, represents a major common mechanism for punctuated cancer evolution. The molecular link between micronuclei and chromothripsis (one subtype of genome chaos which has a selection advantage due to the limited local scales of chromosome re-organization), has recently become a hot topic, especially since the link between micronuclei and immune activation has been identified. Many diverse molecular mechanisms have been illustrated to explain the causative relationship between micronuclei and genome chaos. However, the newly revealed complexity also causes confusion regarding the common mechanisms of micronuclei and their impact on genomic systems. To make sense of these diverse and even conflicting observations, the genome theory is applied in order to explain a stress mediated common mechanism of the generation of micronuclei and their contribution to somatic evolution by altering the original set of information and system inheritance in which cellular selection functions. To achieve this goal, a history and a current new trend of micronuclei research is briefly reviewed, followed by a review of arising key issues essential in advancing the field, including the re-classification of micronuclei and how to unify diverse molecular characterizations. The mechanistic understanding of micronuclei and their biological function is re-examined based on the genome theory. Specifically, such analyses propose that micronuclei represent an effective way in changing the system inheritance by altering the coding of chromosomes, which belongs to the common evolutionary mechanism of cellular adaptation and its trade-off. Further studies of the role of micronuclei in disease need to be focused on the behavior of the adaptive system rather than specific molecular mechanisms that generate micronuclei. This new model can clarify issues important to stress induced micronuclei and genome instability, the formation and maintenance of genomic information, and cellular evolution essential in many common and complex diseases such as cancer.

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Experimental Induction of Genome Chaos

Cited by 14 publications

References 56 publications

Insertional translocation involving an additional nonchromothriptic chromosome in constitutional chromothripsis: Rule or exception?

Insertional translocation involving an additional nonchromothriptic chromosome in constitutional chromothripsis: Rule or exception?

Chromoanagenesis: cataclysms behind complex chromosomal rearrangements

Micronuclei and Genome Chaos: Changing the System Inheritance

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