When the micronucleus is re-incorporated into the nucleus during mitosis, the DSBs undergo repair through NHEJ, where chromosome segments are randomly stitched back together, lost, or become double minutes. All rights reserved.Ĭharacteristics of Chromothripsis, Chromoplexy, and Chromoanasynthesis-Derived SVs (A) A chromosome in a micronucleus can undergo massive DNA damage and result in multiple double-strand breaks (DSBs, depicted with dashed black lines). We highlight future applications of routine screening of complex and balanced SVs in the clinic, as these represent a potential and often neglected genetic disease source, a true 'iceberg under water.'Ĭopyright © 2019 American Society of Human Genetics. This review focuses on congenital chromoanagenesis, mechanisms leading to occurrence of these complex rearrangements, and their impact on chromosome organization and genome function.

Such observations advocate for a deeper study of the polymorphic and pathogenic properties of complex germline SVs, many of which go undetected by traditional clinical molecular and cytogenetic methods. While chromothripsis and chromoplexy have been shown to be key signatures of cancer, chromoanagenesis has been detected in numerous cases of developmental disease and phenotypically normal individuals. Chromothripsis, chromoplexy, and chromoanasynthesis, collectively referred to as chromoanagenesis, are three major mechanisms that explain the occurrence of complex germline and somatic SVs. At the nucleotide level, structural variants (SVs) have been shown to frequently harbor additional breakpoints and copy-number imbalances, a complexity predicted to emerge wholly as a single-cell division event.

Structural variation, composed of balanced and unbalanced genomic rearrangements, is an important contributor to human genetic diversity with prominent roles in somatic and congenital disease.

Iceberg underwater