Chromothripsis: A New Mechanism for Rapid Karyotype Evolution

Abstract

Chromosomal rearrangements are generally thought to accumulate gradually over many generations. However, DNA sequencing of cancer and congenital disorders uncovered a new pattern in which multiple rearrangements arise all at once. The most striking example, chromothripsis, is characterized by tens or hundreds of rearrangements confined to a single chromosome or to local regions over a few chromosomes. Genomic analysis of chromothripsis and the search for its biological mechanism have led to new insights on how chromosome segregation errors can generate mutagenesis and changes to the karyotype. Here, we review the genomic features of chromothripsis and summarize recent progress on understanding its mechanism. This includes reviewing new work indicating that one mechanism to generate chromothripsis is through the physical isolation of chromosomes in abnormal nuclear structures (micronuclei). We also discuss connections revealed by recent genomic analysis of cancers between chromothripsis, chromosome bridges, and ring chromosomes.

MinION-based long-read sequencing and assembly extends the Caenorhabditis elegans reference genome

“…The long MinION reads provided context for the delineation of complex chromosomal rearrangements. MinION long reads offer the opportunity to identify genome rearrangements in tumors, including the highly complex chromothripsis events which can result in thousands of clustered localized chromosomal rearrangements (Leibowitz et al 2015).…”

The Role of Aneuploidy in Cancer Evolution

“…3A). Dicentric chromosomes were shown to be prone to extensive localized mutagenesis (kateagis, bearing a mutation signature characteristic of the APO-BEC family of cytidine deaminase enzymes) and chromothripsis (the random rearrangement of an entire chromosome or chromosome segment) (Stephens et al 2011;Leibowitz et al 2015;Maciejowski et al 2015). Chromosome bridges were found to be coated with RPA proteins, indicative of single-stranded (ssDNA) exposure (the substrate for APOBEC enzymes), and the bridge actively processed by an exonuclease (Maciejowski et al 2015).…”

Cancer cells that survive checkpoint adaptation contain micronuclei that harbor damaged DNA

“…37,38 It is proposed that micronuclei may have poorly functioning membrane, 39 which would affect the replication by a variety of means including DNA replication protein import and DNA organization. 40 In addition, if the DNA is damaged in the micronucleus, then DNA replication might be delayed, and if it is delayed to the point when the cell undergoes mitosis, DNA could be further damaged.…”

“…15 Our results also suggest that micronuclei are sources of continuous DNA damage, which may be caused by undergoing DNA replication at different times from that of the main nucleus. Micronuclei can undergo massive genomic change by the process of chromothripsis, 40 in which checkpoint adaptation might be a key step to start this process. Furthermore, chromothripsis is more likely to be identified in human cells that are mutated for p53.…”