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Genomic Rearrangements: Mutational Mechanisms

  1. Jian-Min Chen

Published Online: 15 FEB 2011

DOI: 10.1002/9780470015902.a0022926

eLS

eLS

How to Cite

Chen, J.-M. 2011. Genomic Rearrangements: Mutational Mechanisms. eLS. .

Author Information

  1. Institut National de la Santé et de la Recherche Médicale (INSERM), U613 and Etablissement Français du Sang (EFS) – Bretagne, Brest, France

Publication History

  1. Published Online: 15 FEB 2011

Abstract

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