Causes and Consequences of Structural Genomic Alterations in the Human Genome


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.

Keywords: DNA; copy number variation; genome stability; genomic disorders; cancer

Figure 1.

LCRs and their relationship to recurrent and nonrecurrent CNVs in the human genome. (a) LCRs can occur in various orientations: directly orientated, inverted or in a more complex context. LCRs are depicted by grey boxes with the arrows indicating their orientation. (b) Schematic representation of recurrent genomic rearrangements. Recurrent rearrangements have the same‐sized deletion/duplication and typically share breakpoints which map within LCRs. (c) Nonrecurrent rearrangements have differing breakpoints but share a SRO. Sometimes, LCRs are present within the vicinity of the breakpoint.

Figure 2.

NAHR between LCRs can result in genomic rearrangement. Schematic representation of reciprocal duplications and deletions mediated by interchromosomal (a) and intrachromatid (b–d) NAHR using pairs in direct (a–c) or inverted orientation (d). Chromosomes are shown in black with the centromere depicted by the grey box. Orientations of the LCRs are indicated by the direction of the arrows. Interchromosomal and interchromatid NAHR between directly orientated LCRs results in deletion and duplication (a and b), whereas intrachromatid results only in deletion (c and d). Intrachromatid NAHR between LCRs in opposing orientation can result in inversion (d).

Figure 3.

NAHR can have complex consequences for gene function. NAHR not only results in deletion and duplication but can also impact on gene function through gene interruption, gene fusions, unmasking a recessive allele (asterix) and/or reveal recessive alleles which result in positional effects on the functions of distal genes.

Figure 4.

The FoSTeS and MMBIR mechanisms of CCR formation. (a) FoSTeS: The lagging strand of replication Fork 1 (green) stalls and disengages. The exposed 3′ end may then invade a proximal replication fork that shares microhomology (Fork 2, shown in red), thus causing deletion/duplication/inversion/translocation depending on position of the other replication fork. Repeated FoSTeS events further add to the complexity of the rearrangement. For example, if Fork 1 (green) stalls and disengages again, the strand derived from Fork 1, which now also contains material derived from Fork 2 (red), template switches into another distinct fork (Fork 3, shown in blue). When synthesis resumes on Fork 1, the extra material derived from Forks 2 and 3 contributes to the rearrangement. (b) MMBIR: Replication fork collapse can occur when the fork encounters a nicked template (green). This results in one‐sided DSB. This DSB is recessed from the 5′ end, generating a 3′ tail. This single‐stranded DNA can then initiate template switch into a proximal replication fork (blue) sharing microhomology.

Figure 5.

The BFB cycle. Centromeres are depicted by grey circles and telomeres by a blue block. A DSB occurs in a chromosome leading to loss of its telomere. Following replication, both sister chromatids lacking telomeres undergo end–end fusion forming a dicentric chromosome. During anaphase, the two centromeres of the dicentric are pulled towards the two opposite spindle poles and the chromosome is broken in a random fashion. The chromosome once again has an unprotected end lacking a telomere and thus a cycle is established.



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Hart, Lesley, and O'Driscoll, Mark(Sep 2013) Causes and Consequences of Structural Genomic Alterations in the Human Genome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024976]