Genomic Rearrangements: Mutational Mechanisms


Genomic rearrangements involve gross alterations of chromosomes or large chromosomal regions and can take the form of deletions, duplications, insertions, inversions or translocations. The characterisation of a considerable number of rearrangement breakpoints has now been accomplished at the nucleotide sequence level, thereby providing an invaluable resource for the detailed study of the mutational mechanisms which underlie genomic recombination events. At least five categories of mutational mechanism are known to give rise to genomic rearrangements: (i) homologous recombination including nonallelic homologous recombination (NAHR), gene conversion, single strand annealing (SSA) and break‐induced replication (BIR); (ii) nonhomologous end joining (NHEJ); (iii) microhomology‐mediated replication‐dependent recombination (MMRDR); (iv) long interspersed element 1 (LINE‐1 or L1)‐mediated retrotransposition and (v) telomere healing. We compare and contrast the hallmark characteristics of the first three mutational mechanisms and discuss the recent developments with respect to the ratio of deletions to duplications in vivo.

Key Concepts:

  • Genomic rearrangements refer to changes in the genetic linkage relationship of discrete chromosomal fragments, involving deletions, duplications, insertions, inversions or translocations.

  • At least five categories of mutational mechanism can give rise to genomic rearrangements: homologous recombination, nonhomologous end joining (NHEJ), microhomology‐mediated replication‐dependent recombination (MMRDR), long interspersed element 1 (LINE‐1 or L1)‐mediated retrotransposition, and telomere healing.

  • Homologous recombination, one of the major pathways for the repair of double‐strand breaks, is mediated through sequences which exhibit considerable homology (generally >200 bp) that presumably serves to stabilise chromosomal mispairing.

  • Homologous recombination can be further subdivided into four pathways, namely, nonallelic homologous recombination (NAHR), gene conversion, break‐induced replication (BIR) and single‐strand annealing (SSA).

  • NHEJ involves simple ligation of any two broken DNA ends together. It is the most prominent DNA repair mechanism because it can occur at any time during the cell cycle and does not require a homologous sequence.

  • Replication‐based models such as serial replication slippage and microhomology‐mediated BIR have been increasingly used to account for the generation of gross genomic rearrangements.

  • The term ‘MMRDR’ was thought to best define the hallmark characteristics of the aforementioned replication‐based mutational mechanisms as compared with homologous recombination and NHEJ.

  • A deletion:duplication ratio of between 2 and 3 is likely to represent the best estimate of the relative occurrence of deletion and duplication copy number mutations in vivo.

Keywords: break‐induced replication; copy number variation; gene conversion; genomic rearrangements; NAHR; NHEJ; nonallelic homologous recombination; nonhomologous end joining; microhomology‐mediated replication‐dependent recombination; serial replication slippage

Figure 1.

Mutational models of homologous recombination. In the models of gene conversion, NAHR (nonallelic homologous recombination) and BIR (break‐induced replication), the invading strand invariably binds to a homologous sequence. In the model of SSA (single‐strand annealing), the black bars indicate the direct repeats that flank a DSB (double‐strand break). In the dissolution model of gene conversion, the two facing horizontal purple arrows indicate convergent branch migration. In the double HJ (Holliday junction) cleavage model of gene conversion, the four horizontal green arrows indicate the orientation of resolution. In the double HJ cleavage model of NAHR, the double HJs can be cleaved as indicated by the green arrows or by the red arrows. In the first pathway of BIR, the HJ is resolved as indicated by the facing horizontal green arrows. See text for details. D‐loop, displacement loop; RF, replication fork and SDSA, synthesis‐dependent strand annealing. Reproduced from Chen et al..

Figure 2.

Types of genomic rearrangements resulting from NAHR and BIR. Arrowed bars indicate duplicated sequences or low copy repeats and their relative orientations. The direction of BIR is indicated by a curved arrow. In BIR, the resulting rearranged chromosomes are within ovals. Reproduced from Chen et al..

Figure 3.

Examples of genomic rearrangements resulting from NHEJ. Ends ligated are indicated by dotted lines. In (b) and (c), the final outcome, unlike NAHR, is not necessarily reciprocal. In theory, the flexibility of NHEJ implies an unlimited number of different types of genomic rearrangement. IHC, interhomologous chromosomes and INHC, inter‐nonhomologous chromosomes. Reproduced from Chen et al..



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Chen, Jian‐Min(Feb 2011) Genomic Rearrangements: Mutational Mechanisms. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022926]