Loss of subtelomeric sequence associated with a terminal inversion duplication of the short arm of chromosome 4

Cotter, Philip D.; Kaffe, Sara; Li, Lei; Gershin, Irina F.; Hirschhorn, Kurt

doi:10.1002/1096-8628(20010722)102:1<76::aid-ajmg1389>3.0.co;2-4

Cited by 43 publications

(37 citation statements)

References 33 publications

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“…Six of our inverted duplications arose on chromosome 18q and were part of the Heard study, two inverted duplications arose on chromosome 2q, and one occurred on chromosome 5p. Other studies have described maternal and paternal origins of inverted duplications [4], [8], [60], [61], [62], [63], [64], [65]. These data argue against a parent-of-origin bias for inverted duplications overall.…”

Section: Discussionmentioning

confidence: 89%

Large Inverted Duplications in the Human Genome Form via a Fold-Back Mechanism

et al. 2014

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Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. For half of the rearrangements in our study, we sequenced at least one breakpoint junction. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted sequences are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a “fold-back” intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the fold-back loop. This process can lead to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes.

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Section: Discussionmentioning

confidence: 89%

Large Inverted Duplications in the Human Genome Form via a Fold-Back Mechanism

et al. 2014

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“…A similar sensitivity to DSBs near telomeres in human germ line cells would also explain the high degree of variability in subtelomeric regions in humans, which have been attributed to a high frequency of translocations [95]. In addition, the sensitivity of telomeric regions to DSBs could explain the prevalence of human genetic diseases resulting from terminal deletions and inversions at the ends of chromosomes that are associated with translocations [96]–[100]. Further studies in the mechanism of sensitivity of telomeric regions to DSBs should therefore provide valuable insights into the mechanisms of human disease.…”

Section: Discussionmentioning

confidence: 96%

The Role of ATM in the Deficiency in Nonhomologous End-Joining near Telomeres in a Human Cancer Cell Line

et al. 2013

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Telomeres distinguish chromosome ends from double-strand breaks (DSBs) and prevent chromosome fusion. However, telomeres can also interfere with DNA repair, as shown by a deficiency in nonhomologous end joining (NHEJ) and an increase in large deletions at telomeric DSBs. The sensitivity of telomeric regions to DSBs is important in the cellular response to ionizing radiation and oncogene-induced replication stress, either by preventing cell division in normal cells, or by promoting chromosome instability in cancer cells. We have previously proposed that the telomeric protein TRF2 causes the sensitivity of telomeric regions to DSBs, either through its inhibition of ATM, or by promoting the processing of DSBs as though they are telomeres, which is independent of ATM. Our current study addresses the mechanism responsible for the deficiency in repair of DSBs near telomeres by combining assays for large deletions, NHEJ, small deletions, and gross chromosome rearrangements (GCRs) to compare the types of events resulting from DSBs at interstitial and telomeric DSBs. Our results confirm the sensitivity of telomeric regions to DSBs by demonstrating that the frequency of GCRs is greatly increased at DSBs near telomeres and that the role of ATM in DSB repair is very different at interstitial and telomeric DSBs. Unlike at interstitial DSBs, a deficiency in ATM decreases NHEJ and small deletions at telomeric DSBs, while it increases large deletions. These results strongly suggest that ATM is functional near telomeres and is involved in end protection at telomeric DSBs, but is not required for the extensive resection at telomeric DSBs. The results support our model in which the deficiency in DSB repair near telomeres is a result of ATM-independent processing of DSBs as though they are telomeres, leading to extensive resection, telomere loss, and GCRs involving alternative NHEJ.

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“…17 An alternative mechanism may consist of a two-chromatid break, followed by a U-type reunion of the broken ends producing a dicentric intermediate chromosome that is rescued by subsequent random breakage and telomere healing. 21 Such an event, occurring during paternal meiosis, 22 may be underlying our case, as the abnormal chromosome is of paternal origin. Our patient highlights the complexity of clinical phenotypes in patients with chromosomal aberrations.…”

Section: Discussionmentioning

confidence: 99%