![]() ![]() As such, the BPJs will cluster within genes, and may involve multiple co-transcribed genes. Chromoplexy is believed to occur due to aberrant binding of transcription factors (Haffner et al. In contrast to BFB cycles, chromothripsis is a single event of localized scattering of one or a few ( 2), and is generally a copy number neutral event (Pellestor 2019). CCRs formed through BFB cycles may also be recognized based on the characteristic, non-random orientation of the DNA fragments involved, and various algorithms are described for such purposes (Kinsella and Bafna 2012). Since the resulting chromatids have lost the telomere, they may fuse and be torn apart the next cell cycle, allowing for continuous cycles of breakage, fusion and bridging (McClintock 1941).ĬCRs formed through BFB cycles are, therefore, mainly terminal rearrangements, they include duplications, deletions as well as copy number neutral fragments (Zakov and Bafna 2015). During anaphase, these fused chromatids will be torn apart, resulting in rearranged chromatids that are lacking the telomere. Chromatids carrying dysfunctional telomeres may undergo rearrangements and fuse with other chromatids. ![]() 2013).īFB cycles may be initiated through telomeric dysfunction. CCRs arise through a multitude of events, including breakage-fusion-bridge (BFB) cycles (McClintock 1941), chromoanasynthesis (Liu et al. 2019), and such CCRs are known to cause a variety of disorders, including intellectual disability and dysmorphism (Eisfeldt et al. However, a growing number of CCRs are reported also in the germline (Collins et al. The vast majority of CCRs are reported in cancers, and most of the current knowledge on CCRs originate from such studies (Collins et al. Through in-depth statistical assessment, it was found that the CCRs most likely was formed through an event resembling chromoplexy-a catastrophic event caused by erroneous transcription factor binding.Ĭomplex chromosomal rearrangements (CCRs) are structural variants (SVs) consisting of multiple adjacent breakpoint junctions (BPJs). We also show that a hybrid sequencing approach is necessary for the correct characterization of complex CCRs. In summary, we report a new maximum number of BPJs (137) in germline chromoanagenesis. In addition, we find that the DNA fragments are unevenly and non-randomly distributed across the derivative chromosomes indicating a multistep process of scattering and re-joining of DNA fragments. We also performed a statistical assessment of the positioning of the breakpoints, revealing a significant enrichment of BPJ-affecting genes (96 intragenic BPJs, 26 genes, p < 0.0001), indicating that the CCRs formed during active transcription of these genes. We identified 137 BPJs, which to our knowledge is the highest number of reported breakpoint junctions in germline chromoanagenesis. The results were validated using multiple cytogenetic methods, including fluorescence in situ hybridization, spectral karyotyping, and Sanger sequencing. We characterized the CCRs using a hybrid-sequencing approach, combining short-read sequencing, nanopore sequencing, and optical mapping. Here, we report a healthy female carrying two de novo CCRs involving chromosomes 4, 19, 21 and X and chromosomes 7 and 11, respectively, with a total of 137 breakpoint junctions (BPJs). Germline chromoanagenesis is rare and the majority of reported cases are associated with an affected phenotype. Chromoanagenesis is a genomic event responsible for the formation of complex structural chromosomal rearrangements (CCRs). ![]()
0 Comments
Leave a Reply. |