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Triggers for genomic rearrangements: insights into genomic, cellular and environmental influences

Subjects

A Corrigendum to this article was published on 18 January 2011

This article has been updated

Key Points

  • Genomic rearrangements are broadly defined as DNA alterations that range from a few hundred base pairs to several megabases and they cause structural variation in the genome.

  • Genomic rearrangements are involved in cancers, genomic disorders caused by rearrangements passed through the germ line, as well as in the normal generation of T cell and B cell receptor diversity.

  • Many genomic rearrangements are nonrandom, cell type-, cell stage- and locus-specific events that are triggered by a range of cellular mechanisms and environmental cues.

  • Triggers for genomic rearrangements can broadly be classified into four categories: spatial proximity, cellular stress, inappropriate repair or recombination, and DNA sequence and chromatin features.

  • These triggers function synergistically and are not mutually exclusive. Elucidating their relative influences and how they act together is likely to be an important area for future research.

Abstract

Genomic rearrangements are associated with many human genomic disorders, including cancers. It was previously thought that most genomic rearrangements formed randomly but emerging data suggest that many are nonrandom, cell type-, cell stage- and locus-specific events. Recent studies have revealed novel cellular mechanisms and environmental cues that influence genomic rearrangements. In this Review, we consider the multitude of influences on genomic rearrangements by grouping these influences into four categories: proximity of chromosomal regions in the nucleus, cellular stress, inappropriate DNA repair or recombination, and DNA sequence and chromatin features. The synergy of these triggers can poise a cell for rearrangements and here we aim to provide a conceptual framework for understanding the genesis of genomic rearrangements.

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Figure 1: Triggers for genomic rearrangements.
Figure 2: Spatial proximity and genomic rearrangements.
Figure 3: Cellular stress coupled with defective DNA repair or recombination can result in genomic rearrangements.
Figure 4: Mechanisms of DNA double-strand break repair.
Figure 5: VDJ recombination, class switch recombination and genomic rearrangements.

Change history

  • 18 January 2011

    The figures 3 and 4 are corrected in the PDF and the html versions

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Acknowledgements

We apologize to those whose relevant research was not cited owing to space limitations. We thank K. Callahan for help in figure preparation and J. Lupski and S. Girirajan for insightful comments. R.S.M. is supported by the Stewart Rahr–PCF Young Investigator Award from the Prostate Cancer Foundation. A.M.C. is supported by the Doris Duke Charitable Foundation Clinical Scientist Award, a Burroughs Welcome Foundation Award in Clinical Translational Research and the Prostate Cancer Foundation. A.M.C. is an American Cancer Society Research Professor.

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Glossary

VDJ recombination

A specialized DNA rearrangement that takes place in B and T lymphocytes at specific loci to generate the vast diversity of immunoglobulins and T cell receptors.

Class switch recombination

A deletion recombination that occurs in B lymphocytes in response to antigen stimulation and co-stimulatory signals. It replaces the Ig heavy chain constant region without affecting its specificity and results in isotype switching from IgM to IgG, IgE, or IgA, thereby enhancing the immune response.

Chromosome conformation capture

A technique to detect the frequency of interactions between any specified two loci in the genome. Interactions between loci are captured by formaldehyde fixation, followed by restriction enzyme digestion and ligation. The frequencies of interactions between loci are determined by quantitative real-time PCR.

Chromatin interaction analysis by paired-end tag sequencing

A genome-wide integration of chromatin immunoprecipitation with the chromosome conformation capture principle to detect all global chromatin interactions mediated by proteins of interest.

Hi-C

A genome-scale adaptation of the chromosome conformation capture approach that interrogates all genomic regions that are in close proximity in the nucleus and gives information on the three-dimensional architecture of whole genomes.

Activation-induced cytidine deaminase

This enzyme is essential for CSR. It functions by deaminating cytosine residues, which converts them to uracil. Repair of the uracil residues leads to single-strand DNA breaks, which are then converted to DNA double-strand breaks; subsequent action by NHEJ results in CSR.

Low-copy repeat

Often referred to as a segmental duplication. LCRs are DNA fragments of >1 Kb size and >95% sequence identity and they constitute approximately 5% of the human genome.

Complex chromosomal rearrangements

Genomic rearrangements that involve three or more breakpoints and the interchange of genetic material between two or more chromosomes.

Microhomology

Short stretches of nucleotide sequence homology, from 1–75 bp in length.

Alu element

A DNA element in the retrotransposon class that is approximately 300 nucleotides long. Alus are the most abundant repetitive elements in the human genome.

Charcot–Marie–Tooth disease type 1A

A sensory motor peripheral polyneuropathy caused by the 1.4 Mb heterozygous duplication of the dosage-sensitive gene PMP22 on human chromosome 17p12.

Hereditary neuropathy with liability to pressure palsies

A peripheral neuropathy caused by the deletion of the dosage-sensitive gene PMP22 on human chromosome 17p12.

Recombination signal sequence

A sequence located adjacent to the V, D or J segments that is composed of heptamer and nonamer consensus sequence with an intervening spacer of 12 or 23 bp.

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Mani, RS., Chinnaiyan, A. Triggers for genomic rearrangements: insights into genomic, cellular and environmental influences. Nat Rev Genet 11, 819–829 (2010). https://doi.org/10.1038/nrg2883

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