No abstract

The revolutionary development and application of microarray‐based comparative genomic hybridisation (aCGH) technology within the past decade or so represents a profound and continuing fundamental contribution to the molecular dissection and characterisation of complex human disorders: disorders ranging from developmental pathologies including intellectual disability, schizophrenia and autism spectrum disorders to more common conditions such as cancer. A unifying underlying feature here is that these disorders are associated with complex structural rearrangements in chromosomes. aCGH technology application has also enabled the refinement of ‘old’ and identification of ‘new’ mechanisms to explain the origin of these complex chromosomal alterations. Interestingly, these structural variations can also incorporate genes whose products play fundamental roles in aspects of deoxyribonucleic acid repair, replication and recombination, thereby having an impact on genome‐wide stability and integrity. In this article, the mechanisms underlying complex structural chromosomal rearrangements are reviewed and their implications with respect to genome‐wide stability are discussed. Key Concepts: The locus‐specific frequency of CNVs are orders of magnitude higher than SNPs. CNVs are a significant contributor to human disease. CNVs can be recurrent or nonrecurrent. Nonallelic homologous recombination between low copy number repeats is a common mechanism of recurrent CNV. Nonhomologous end joining can underlie nonrecurrent CNVs. Complex Chromosomal Rearrangements (CCRs) are complex CNVs involving multiple contiguous changes in copy number. DNA replication based‐mechanisms have been invoked to explain CCRs. CNVs are fundamental contributors to cancer development and progression. CNVs incorporating genome instability pathway components can adversely impact on genome‐wide stability. Certain genomic disorders are characterised by impaired genome stability.