Chromothripsis and Human Genetic Disease


Chromothripsis (CTH) is a newly discovered mutational mechanism, which in a single catastrophic event results in localised complex structural rearrangements confined to one or a few chromosomes. After an initial shattering or clustered fragmentation of a chromosomal region, the fragments join together in random order and orientation. During this process some of the generated fragments may be lost. It is not entirely clear which factors trigger the localised fragmentation; however, several mechanisms have been proposed, such as ionising radiation, aborted apoptosis, isolation of chromosome(s) in micronuclei, LINE1‐endonucleases, etc. CTH may disrupt multiple genes and/or regulatory regions. When it is incompatible with cell survival, the result should be apoptosis. However, if a cell escapes apoptosis, the extensive genomic rearrangements may have different phenotypic outcomes: cancer (somatic), congenital and developmental disorders (germline), neutral or even beneficial effects.

Key Concepts

  • Chromothripsis is a phenomenon where multiple localised double‐stranded DNA breaks result in complex genomic rearrangements.
  • Chromothripsis occurs within a single cell cycle.
  • Ionising radiation, aborted apoptosis, isolation of chromosome(s) in micronuclei and LINE1‐endonucleases are proposed to have a role in chromothripsis.
  • Chromothripsis in somatic cells may trigger cancer development.
  • Chromothripsis in the germline may result in congenital and developmental disorders.

Keywords: chromothripsis; clustered mutations; single‐step event; structural rearrangements; repair mechanisms; micronuclei; chromosome pulverisation; LINE‐1 endonuclease; cancer; congenital and developmental disorders

Figure 1. Schematic mechanism of chromothripsis. The first step of chromothripsis is the generation of clustered DNA (deoxyribonucleic acid) double‐strand breaks. Chromothripsis may involve one or few chromosomes, a chromosomal arm (both p and q arms) or an entire chromosome. This results in multiple fragments, which are stitched together in random order, and orientation by DNA repair machineries. During this process some of the fragments may be lost. The derivative chromosome(s) will contain complex structural rearrangements. By piecing together all the structural variants detected by paired‐end or mate‐pair sequencing, it should be possible to delineate the derivative chromosomes.
Figure 2. Proposed mechanisms for chromosome shattering. (a) Localised ionising irradiation within the nucleus may induce localised DNA double‐strand breaks, resulting in complex chromosomal alterations typical of chromothripsis. (b) Some stress factors may induce apoptosis (programmed cell death) triggering DNA fragmentation. However, if the damage is not too severe, abortion of apoptosis could occur, and incorrect repair of DNA fragments could lead to complex chromosomal rearrangements. (c) During cell division lagging chromosomes or fragments may be isolated within micronuclei, where they undergo defective DNA replication and repair, resulting in extensive DNA fragmentation. (d) LINE1‐endonuclease may cleave DNA on its target sites at multiple places owing to spatial organisation of the interphase DNA and occasionally facilitate insertion of retrotransposons at the breakpoints.
Figure 3. Schematic illustration of phenotypic consequences of chromothripsis.


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Further Reading

Chen JM, Férec C and Cooper DN (2012) Transient hypermutability, chromothripsis and replication‐based mechanisms in the generation of concurrent clustered mutations. Mutation Research 750 (1): 52–59.

Forment JV, Kaidi A and Jackson SP (2012) Chromothripsis and cancer: causes and consequences of chromosome shattering. Nature Reviews. Cancer 12 (10): 663–670.

Hart L and O'Driscoll M (2001) Causes and Consequences of Structural Genomic Alterations in the Human Genome (In: eLS). John Wiley & Sons, Ltd. DOI: 10.1002/9780470015902.a0024976.

Storchova Z and Kloosterman WP (2016) The genomic characteristics and cellular origin of chromothripsis. Current Opinion in Cell Biology 40: 106–113.

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Nazaryan‐Petersen, Lusine, and Tommerup, Niels(Sep 2016) Chromothripsis and Human Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024627]