Abstract
Both copy number variations (CNVs) and chromothripsis are phenomena that involve complex genomic rearrangements. Chromothripsis results in CNVs and other structural changes. CNVs are frequently observed in the human genome. Studies on CNVs have been increasing exponentially; the Database of Genomic Variants shows an increase in the number of data published on structural variations added to the database in the last 15 years. CNVs may be a result of replicative and non-replicative mechanisms, and are hypothesized to serve important roles in human health and disease. Chromothripsis is a phenomena of chromosomal rearrangement following chromosomal breaks at multiple locations and involves impaired DNA repair. In 2011, Stephens et al coined the term chromothripsis for this type of fragmenting event. Several proposed mechanisms have been suggested to underlie chromothripsis, such as p53 inactivation, micronuclei formation, abortive apoptosis and telomere fusions in telomere crisis. Chromothripsis gives rise to normal or abnormal phenotypes. In this review, constitutional chromothripsis, which may coexist with multiple de novo CNVs are described and discussed. This reviews aims to summarize recent advances in our understanding of CNVs and chromothripsis, and describe the effects of these phenomena on human health and birth defects.
Highlights
Both copy number variations (CNVs) and chro‐ mothripsis are phenomena that involve complex genomic rearrangements
NAHR‐ and nonhomol‐ ogous‐mediated CNVs are associated with different timings of DNA replication: Hotspots of NAHR‐mediated events were enriched in early‐replicating regions, whereas nonhomologous hotspots were enriched in late‐replicating regions [17]
Clustered CNVs detected by chromosomal microarray analysis (CMA) are frequently reported as constitutional chromothripsis [47]
Summary
Chromothripsis, chromoanasynthesis and chromoplexy are collectively termed chromoanagenesis (from the Greek chromo for chromosome and anagenesis for rebirth). One or even a small number of cells may not complete apoptosis and survive These surviving cells may incorrectly repair their DNA, giving rise to rearrangements characteristic of chromothripsis [30]. Formation of complex constitutional rearrangements involved in congenital defects, and suggested the possibility of consti‐ tutional chromothripsis [33]. It is possible that congenital chromothripsis rearrangements possess a similar architecture as simple reciprocal translocation, which, involves two breaks and subsequent formation of two derivative chromosomes [38]. The rearrangements observed by Kloosterman et al [34] were present on paternal chromosomes This finding highlights the vulnerability of sper‐ matogenesis to DNA damage and show that spermatogenesis is a critical stage in the genesis of congenital chromothripsis. These studies are important for the evaluation of patients with congenital diseases as well as in human health
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