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Mechanisms of change in gene copy number

Key Points

  • Copy number variants (CNVs) arise by homologous recombination (HR) between repeated sequences (recurrent CNVs) or by non-homologous recombination mechanisms that occur throughout the genome (non-recurrent CNVs).

  • Non-recurrent CNVs frequently show microhomology at their end-points, and can have a complex structure.

  • The locus-specific mutation frequencies for copy number variation and other structural changes are two to four orders of magnitude greater than for point mutations.

  • HR mechanisms generally achieve accurate repair of DNA damage.

  • Double-stranded breaks are repaired by HR or by end-joining mechanisms, which can be non-homologous.

  • Broken replication forks with single double-stranded ends are also repaired by HR.

  • There is evidence that repair of broken replication forks underlies some non-homologous recombination.

  • Repair of broken forks in stressed cells could cause non-homologous repair because of a downregulation of HR proteins induced by stress.

  • Models are presented for mechanisms by which stress might induce non-homologous events leading to copy number variation.

Abstract

Deletions and duplications of chromosomal segments (copy number variants, CNVs) are a major source of variation between individual humans and are an underlying factor in human evolution and in many diseases, including mental illness, developmental disorders and cancer. CNVs form at a faster rate than other types of mutation, and seem to do so by similar mechanisms in bacteria, yeast and humans. Here we review current models of the mechanisms that cause copy number variation. Non-homologous end-joining mechanisms are well known, but recent models focus on perturbation of DNA replication and replication of non-contiguous DNA segments. For example, cellular stress might induce repair of broken replication forks to switch from high-fidelity homologous recombination to non-homologous repair, thus promoting copy number change.

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Figure 1: Complex structural variation.
Figure 2: Mechanisms of homologous recombination.
Figure 3: Change in copy number by homologous recombination.
Figure 4: The breakage–fusion–bridge cycle.
Figure 5: Replicative mechanisms for non-homologous structural change.

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Acknowledgements

This work was supported by grants from the National Institutes of Health, R01 GM64022 to P.J.H., R01 NS59529 to J.R.L., R01 GM53158 and R01 CA85777 to S.M.R., and R01 GM80600 to G.I.

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Glossary

Array comparative genomic hybridization

A microarray-based technique to measure the relative amount of any DNA sequence.

Paired-end mapping

A technique whereby novel linkage relationships are detected by finding short sequences linked to other short sequences in DNA fragments of uniform size.

Non-allelic homologous recombination

Homologous recombination between lengths of homology in different genomic positions.

Double-stranded end

An end of dsDNA that is not protected by a telomere, which is the structure found at the ends of linear chromosomes.

Holliday junction

A point at which the strands of two dsDNA molecules exchange partners. This structure occurs as an intermediate in crossing over.

Gene conversion

A non-reciprocal transfer of an allelic difference from one chromosome to its homologue.

Crossover

A precisely reciprocal breakage of two DNA molecules followed by rejoining with exchanged partners.

Loss of heterozygosity

Loss of an allelic difference between two chromosomes in a diploid cell.

Helicase

An enzyme that separates the two nucleic acid strands of a double helix, resulting in the formation of regions of ssDNA or ssRNA.

Topoisomerase

An enzyme that can remove (or create) supercoiling and concatenation (interlocking) in duplex DNA by creating transitory breaks in one (type I topoisomerase) or both (type II topoisomerase) strands of the sugar–phosphate backbone.

Single-strand annealing

A double-stranded break repair mechanism that deletes sequence between repeats.

Alu

A family of short interspersed nuclear elements that are common in human and primate genomes.

Mismatch repair

A DNA repair system that corrects a mismatched base pair in duplex DNA by excision of a length of one strand followed by synthesis of the sequence complementary to the remaining strand.

Retrotransposon

A transposon (mobile element) that is copied from the host genome by transcription as RNA, and is later reverse-transcribed into DNA and reintegrated into the host genome.

Endonuclease

An enzyme that breaks the sugar–phosphate backbone of a DNA or RNA molecule where there is no free end.

Telomere

A structure at the ends of linear chromosomes that avoids shortening of chromosomes after replication, and that protects the end from homologous and non-homologous recombination.

Dicentric chromosome

A chromosome with two centromeres. These are pulled to opposite poles during mitosis but are unable to separate without chromosome breakage.

Amplification

Also called gene amplification. The formation of more than two repetitions of a chromosomal segment in tandem, dispersed or as autonomous circular molecules.

Fragile site

A position on a chromosome where spontaneous breaks occur frequently.

Okazaki fragment

The discontinuous length of DNA that is synthesized as one piece on the lagging strand template during DNA replication.

Amplicon

The repeat unit, or unit length of genome, that is amplified.

Exonuclease

An enzyme that degrades DNA or RNA from an end.

Heterochromatin

A highly condensed form of chromatin (the eukaryotic complex of DNA with proteins) that shows reduced gene expression and is replicated late in S phase.

LINE

Long interspersed nuclear elements. A class of transposable element lacking long terminal repeats.

SINE

Short interspersed nuclear elements. A class of short (<500 bp) transposable elements.

Evolvability

The capacity of an organism to evolve.

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Hastings, P., Lupski, J., Rosenberg, S. et al. Mechanisms of change in gene copy number. Nat Rev Genet 10, 551–564 (2009). https://doi.org/10.1038/nrg2593

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