Key Points
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Meiotic recombination is initiated by developmentally programmed double-strand breaks (DSBs), which are subsequently repaired by genetic exchange with allelic sequences.
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Meiotic recombination pathways are conserved from smaller to larger eukaryotes.
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Recombination is distributed non-randomly throughout the genome, with most recombination events occurring in narrow domains termed 'hotspots'.
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The human genome is replete with low-copy repeats (LCRs), which can act as substrates for non-allelic homologous recombination (NAHR) in the germ line. These events lead to genome rearrangements associated with a wide array of diseases.
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Accumulating evidence suggests that NAHR in the germ line shares mechanistic similarities with allelic recombination during meiosis, consistent with the hypothesis that both are initiated by the same type of programmed DSBs.
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The spatial organization of repeated sequences in a nucleus might influence the frequency of meiotic NAHR.
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Meiotic NAHR between natural repetitive elements occurs at low levels, at least in yeast, suggesting the existence of mechanisms that suppress NAHR.
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Suppression of meiotic DSBs in repetitive elements might be one of the conserved cellular strategies for preventing NAHR.
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Recombination-dependent homologue pairing might favour allelic recombination over NAHR by bringing allelic sequences in closer proximity.
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In many organisms, crossover formation is suppressed between divergent sequences.
Abstract
Meiotic recombination, which promotes proper homologous chromosome segregation at the first meiotic division, normally occurs between allelic sequences on homologues. However, recombination can also take place between non-allelic DNA segments that share high sequence identity. Such non-allelic homologous recombination (NAHR) can markedly alter genome architecture during gametogenesis by generating chromosomal rearrangements. Indeed, NAHR-mediated deletions, duplications, inversions and other alterations have been implicated in numerous human genetic disorders. Studies in yeast have provided insights into the molecular mechanisms of meiotic NAHR as well as the cellular strategies that limit it.
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Acknowledgements
We thank members of the Keeney laboratory for comments on the manuscript. Work from the authors' laboratory is supported in part by the Howard Hughes Medical Institute and in part by grants from the US National Institutes of Health.
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DATABASES
OMIM
FURTHER INFORMATION
Glossary
- Homologous chromosomes
-
Chromosome pairs in a diploid individual that share the same genes, but not necessarily the same alleles, at loci along their lengths.
- Aneuploidy
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The condition of a cell or organism that is associated with having an extra or a missing chromosome, caused by inaccurate chromosome segregation during cell division.
- Heteroduplex DNA
-
Hybrid, double-stranded DNA that consists of one strand from each homologue. It is formed by strand invasion of one DSB end into a homologous DNA duplex during recombination.
- D-loop
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A single DNA strand that is displaced when strand invasion induces the dissociation of a DNA duplex.
- Holliday junction
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A four-stranded, branched DNA structure that is formed as an intermediate in homologous recombination.
- Gene conversion
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The transfer of DNA sequence information that 'overwrites' the sequence of one allele with the sequence of the other allele. It is carried out by mismatch repair on heteroduplex DNA.
- Mismatch repair
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The repair system that recognizes and corrects mismatches that form during DNA replication and recombination.
- Isodicentric chromosome
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A mirror-image duplication of part of a chromosome, including the centromere.
- Genomic disorder
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A group of conditions that arise in the germ line by submicroscopic, regional chromosomal rearrangements, which alter the copy number of dosage-sensitive genes, disrupt genes or generate fusion genes.
- Recombination breakpoint
-
The place in the product of a recombination reaction at which the DNA molecule switches from being of one parental origin to the other.
- Tetrad analysis
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The analysis of all four products (spores in yeast) of a single meiosis. Spores in a tetrad are grouped together in an ascus and can be individually isolated by micromanipulation and grown in culture for further analysis.
- Heteroallele
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One of two different alleles of a gene, each of which carries a mutation or mutations at a different position in the coding sequence.
- Telomere
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A segment at the end of each chromosome arm that consists of repetitive sequences and that prevents the normal chromosome ends from being recognized as DSBs.
- Heterologous chromosomes
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Chromosomes that are neither homologues nor sister chromatids.
- Ty element
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A retrotransposon in yeast that is ˜ 5–6 kb in length and comprises a central domain that is flanked by ˜ 330 bp of long terminal repeats (LTRs). The yeast genome contains full Ty elements as well as solo LTRs and LTR fragments.
- Synaptonemal complex
-
A proteinaceous structure that is formed between homologues during meiosis. Synaptonemal complexes are composed of lateral elements that are assembled between the entire length of sister chromatids and transverse filaments that connect lateral elements to the central element. In the context of synaptonemal complexes, homologues are intimately connected.
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Sasaki, M., Lange, J. & Keeney, S. Genome destabilization by homologous recombination in the germ line. Nat Rev Mol Cell Biol 11, 182–195 (2010). https://doi.org/10.1038/nrm2849
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DOI: https://doi.org/10.1038/nrm2849
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