Causes and Consequences of Structural Genomic Alterations in the Human Genome

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.

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

“…The eventual outcome of such a process would be a CCR. The molecular signature of such a FoSTeS-mediated CCR would be a set of closely interspersed joining points connecting multiple chromosomes or a set of interspersed duplications and triplications within a single chromosome, termed 'chromoanasynthesis' Hart and O'Driscoll, 2013;Plaisancié et al, 2014].…”

“…On the one hand, the joining of 2 open DNA strands is based upon the microhomology between the 2 participating stretches of DNA. On the other hand, small deletions will be generated at the joining points during the exonuclease-mediated resection step Hart and O'Driscoll, 2013]. The molecular signature of MMBIR will be the concomitant presence of microhomologies and small deletions at the joining points of the thus generated CCRs.…”

“…The third proposed mechanism for CCR-formation is the breakage-fusion-bridge cycle prompting NHEJ Hart and O'Driscoll, 2013]. DNA NHEJ is the predominant pathway of DSB repair, which involves heterodimers of Ku70 and Ku80, and DNA-dependent protein kinases, DNA-PKcs.…”

“…In a diploid genome, CNVs affecting the phenotype based on a change in dosage of a gene exert a dominant effect [Poot et al, 2011a;Hart and O'Driscoll, 2013]. Basically, changes in gene dosage may be phenotypically significant if the encoded protein interacts with other proteins [Veitia, 2010;Veitia and Birchler, 2010].…”

Chromothripsis after Stumbling through DNA Replication

“…Apparently, at least 3 distinct pathways of 'repair' of chromosome breaks exist. replication or during meiosis, or postzygotic rearrangements have been suggested [Hart and O'Driscoll, 2013;Robberecht et al, 2013;Pellestor et al, 2014;Poot and Haaf, 2015]. The most extreme form of SV is germline chromothripsis, i.e.…”