Chromosome segregation errors generate a diverse spectrum of simple and complex genomic rearrangements

Abstract

Cancer genomes are frequently characterized by numerical and structural chromosomal abnormalities. Here we integrated a centromere-specific inactivation approach with selection for a conditionally essential gene, a strategy termed ‘CEN-SELECT’, to systematically interrogate the structural landscape of missegregated chromosomes. We show that single-chromosome missegregation into a micronucleus can directly trigger a broad spectrum of genomic rearrangement types. Cytogenetic profiling revealed that missegregated chromosomes exhibit 120-fold higher susceptibility to developing seven major categories of structural aberrations, including translocations, insertions, deletions, and complex reassembly through chromothripsis coupled to classical non-homologous end joining. Whole-genome sequencing of clonally propagated rearrangements identified random patterns of clustered breakpoints with copy-number alterations resulting in interspersed gene deletions and extrachromosomal DNA amplification events. We conclude that individual chromosome segregation errors during mitotic cell division are sufficient to drive extensive structural variations that recapitulate genomic features commonly associated with human disease.

Established and Novel Mechanisms Leading to de novo Genomic Rearrangements in the Human Germline

“…It is possible that several micronuclei concurrently developed in a testicular germ cell and created both simple and catastrophic rearrangements. Consistent with this, Ly et al [2019] reported that chromosomal missegregation during mitosis can induce various genomic rearrangements including chromothripsis and amplifications. Alternatively, a hitherto unrecognized mechanism may have produced the transient genomic crisis in our case.…”

Mechanisms Generating Cancer Genome Complexity From A Single Cell Division Error

“…In addition to the above described mutational events, we found that chromosome bridge formation predisposes to micronucleation, which could then initiate another round of chromothripsis downstream of bridge breakage (14, 17, 76). We attribute the high rate at which bridge chromosomes mis-segregate in the second mitosis to depletion of CENP-A nucleosomes, which provide the epigenetic specification of centromere identity (77, 78).…”

Enhancer hijacking determines intra- and extrachromosomal circularMYCNamplicon architecture in neuroblastoma

“…many individual circular DNA molecules (extrachromosomal DNA, ecDNA, alias double minute chromosomes, dmin) 1 . EcDNA can arise during genome reshuffling events like chromothripsis and are subsequently amplified 2,3 . This partially explains why such circular DNAs can consist of several coding and non-coding distant parts of one or more chromosomes 4 .…”