The enrichment of breakpoints in late-replicating chromatin provides novel insights into chromoanagenesis mechanisms

Chatron, Nicolas; Giannuzzi, Giuliana; Rollat‐Farnier, Pierre‐Antoine; Diguet, Flavie; Porcu, Eleonora; Yammine, Tony; Uguen, Kévin; Bellil, Zohra-Lydia; Zillhardt, Julia Lauer; Sorlin, Arthur; Ader, Flavie; Afenjar, Alexandra; Andrieux, Joris; Bardel, Claire; Calpena, Eduardo; Chantot‐Bastaraud, Sandra; Callier, Patrick; Chelloug, Nora; Chopin, Emilie; Cordier, Marie‐Pierre; Dubourg, Christèle; Faivre, Laurence; Girard, Françoise; Heide, Solveig; Herenger, Yvan; Jaillard, Sylvie; Keren, Boris; Knight, Samantha Jl; Lespinasse, James; Lohmann, Laurence; Marle, Nathalie; Maroofian, Reza; Masurel‐Paulet, Alice; Mathieu‐Dramard, Michèle; Métay, Corinne; Pagnamenta, Alistair T.; Portnoı̈, Marie-France; Prieur, Fabienne; Rio, Marlène; Siffroi, Jean‐Pierre; Valence, Stéphanie; Taylor, Jenny C.; Wilkie, Andrew; Edery, Patrick; Reymond, Alexandre; Sanlaville, Damien; Schluth-Bolard, Caroline

doi:10.1101/2020.07.17.206771

Cited by 3 publications

(3 citation statements)

References 58 publications

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“…This patient had five segments of chromosome 1 inserted into chromosome 17q24.3, which is hypothesised to disrupt a TAD close to KCNJ2/SOX9. The rearrangement was confirmed by nanopore long-read genome sequencing and has been classified as an example of chromoanasynthesis [99] revealing a new mechanism for this rare craniofacial phenotype.…”

Section: Table 1 Structural Variants Found In the Oxclinwgs Cohortmentioning

confidence: 88%

Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

Pagnamenta,

Camps,

Giacopuzzi

et al. 2023

Genome Med

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Background Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25–30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. Methods We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. Results Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. Conclusions Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.

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Section: Table 1 Structural Variants Found In the Oxclinwgs Cohortmentioning

confidence: 88%

Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

Pagnamenta,

Camps,

Giacopuzzi

et al. 2023

Genome Med

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“…Work in preprint suggests that premature condensation of the late replication regions in micronucleus leads to either replication forks collapse (and creat DSBs) or stall (will initiate MMBIR events), so that both chromothripsis and chromoanasynthesis can be observed in micronucleated chromosomes. 93 Third, chromothripsis in chromatin bridges is frequently accompanied by kataegis (Table 1)…”

Section: Mutational Landscapes Within the Micronucleated Chromosomementioning

confidence: 99%

“…Second, it has found that copy numbers are increased at multiple loci in the micronucleated chromosomes, 24,38 suggesting chromoanasynthesis (Table 1) occurs downstream of micronucleation. Work in preprint suggests that premature condensation of the late replication regions in micronucleus leads to either replication forks collapse (and creat DSBs) or stall (will initiate MMBIR events), so that both chromothripsis and chromoanasynthesis can be observed in micronucleated chromosomes 93 . Third, chromothripsis in chromatin bridges is frequently accompanied by kataegis (Table 1).…”

Section: Mutational Landscapes Within the Micronucleated Chromosomes:mentioning

confidence: 99%

Small but strong: Mutational and functional landscapes of micronuclei in cancer genomes

Guo

Dai

et al. 2020

Intl Journal of Cancer

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Micronuclei, small spatially-separated, nucleus-like structures, are a common feature of human cancer cells. There are considerable heterogeneities in the sources, structures and genetic activities of micronuclei. Accumulating evidence suggests that micronuclei and main nuclei represent separate entities with respect to DNA replication, DNA damage sensing and repairing capacity because micronuclei are not monitored by the same checkpoints nor covered by the same nuclear envelope as the main nuclei. Thus, micronuclei are spatially restricted "mutation factories." Several large-scale DNA sequencing and bioinformatics studies over the last few years have revealed that most micronuclei display a mutational signature of chromothripsis immediately after their generation and the underlying molecular mechanisms have been dissected extensively. Clonal expansion of the micronucleated cells is contextdependent and is associated with chromothripsis and several other mutational signatures including extrachromosomal circular DNA, kataegis and chromoanasynthesis. These results suggest what was once thought to be merely a passive indicator of chromosomal instability is now being recognized as a strong mutator phenotype that may drive intratumoral genetic heterogeneity. Herein, we revisit the actionable determinants that contribute to the bursts of mutagenesis in micronuclei and present the growing number of evidence which suggests that micronuclei have distinct shortand long-term mutational and functional effects to cancer genomes. We also pose challenges for studying the long-term effects of micronucleation in the upcoming years.

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Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes

et al. 2022

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Structural variants are a common cause of disease and contribute to a large extent to inter-individual variability, but their detection and interpretation remain a challenge. Here, we investigate 11 individuals with complex genomic rearrangements including germline chromothripsis by combining short- and long-read genome sequencing (GS) with Hi-C. Large-scale genomic rearrangements are identified in Hi-C interaction maps, allowing for an independent assessment of breakpoint calls derived from the GS methods, resulting in >300 genomic junctions. Based on a comprehensive breakpoint detection and Hi-C, we achieve a reconstruction of whole rearranged chromosomes. Integrating information on the three-dimensional organization of chromatin, we observe that breakpoints occur more frequently than expected in lamina-associated domains (LADs) and that a majority reshuffle topologically associating domains (TADs). By applying phased RNA-seq, we observe an enrichment of genes showing allelic imbalanced expression (AIG) within 100 kb around the breakpoints. Interestingly, the AIGs hit by a breakpoint (19/22) display both up- and downregulation, thereby suggesting different mechanisms at play, such as gene disruption and rearrangements of regulatory information. However, the majority of interpretable genes located 200 kb around a breakpoint do not show significant expression changes. Thus, there is an overall robustness in the genome towards large-scale chromosome rearrangements.

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The enrichment of breakpoints in late-replicating chromatin provides novel insights into chromoanagenesis mechanisms

Cited by 3 publications

References 58 publications

Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

Small but strong: Mutational and functional landscapes of micronuclei in cancer genomes

Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes

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