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Meiotic recombination in mammals: localization and regulation

Nature Reviews Genetics volume 14, pages 794–806 (2013)Cite this article

Subjects

Key Points

  • Meiotic recombination is a major source of genetic diversity in a population.

  • Recent advances in mapping recombination hot spots have shed light on the evolutionary dynamics of recombination hotspot localization and on the factors involved in their specification.

  • The localization of meiotic recombination sites in humans and mice is determined by the DNA-binding specificity of PR domain-containing 9 (PRDM9), which is instrumental in the specification of recombination hot spots. The PRDM9 DNA-binding domain has quickly evolved under positive selection. This evolution may be linked to the erosion of PRDM9-binding sites owing to meiotic DNA double-strand break (DSB) repair..

  • Meiotic DSBs are catalysed by the meiotic recombination protein SPO11 in humans and mice and are regulated by other proteins, which leads to the regulation of recombination.

  • Several factors required for DSB formation are localized on chromosome axes, and this association with chromosome axes regulates meiotic recombination, from the formation of DSBs to their resolution into final recombination products that are formed from either crossover or non-crossover intermediates.

  • In mammals, the proteins RING finger protein 212 (RNF212) and human enhancer of invasion 10 (HEI10) have a key role in promoting DSB repair towards crossovers from a subset of recombination intermediates. These findings provide new insights into the control of crossover frequency.

Abstract

During meiosis, a programmed induction of DNA double-strand breaks (DSBs) leads to the exchange of genetic material between homologous chromosomes. These exchanges increase genome diversity and are essential for proper chromosome segregation at the first meiotic division. Recent findings have highlighted an unexpected molecular control of the distribution of meiotic DSBs in mammals by a rapidly evolving gene, PR domain-containing 9 (PRDM9), and genome-wide analyses have facilitated the characterization of meiotic DSB sites at unprecedented resolution. In addition, the identification of new players in DSB repair processes has allowed the delineation of recombination pathways that have two major outcomes, crossovers and non-crossovers, which have distinct mechanistic roles and consequences for genome evolution.

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Figure 1: Chromosome organization and cytology during meiotic prophase I.
Figure 2: Model for the role of PRDM9 in meiotic DSB localization.
Figure 3: Proteins involved in mammalian meiotic recombination.

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Acknowledgements

B.d.M. is supported by the Centre National de la Recherche Scientifique, the Agence Nationale de la Recherche (09-BLAN-0269-01) and the Fondation pour la Recherche Médicale; and Y.I. is supported by a grant from the French Ministry of Research. The authors thank the reviewers for improving the format of this Review and apologize to those whose data could not be cited.

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  1. Institute of Human Genetics, Unité Propre de Recherche 1142, Centre National de la Recherche Scientifique, 141 rue de la Cardonille, Montpellier, 34396, France

    Frédéric Baudat, Yukiko Imai & Bernard de Massy

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  1. Frédéric Baudat
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PowerPoint slides

Glossary

Homologous chromosomes

The two parental chromosomes that are present in a diploid cell.

Crossovers

Reciprocal recombination events that lead to the re-association of genetic markers located on both sides of the crossover point.

Non-crossovers

Recombination events that are detected as gene conversion events without the exchange of flanking markers.

Gene conversion

Unidirectional transfer of genetic information from a donor to a receiver DNA molecule. During meiotic recombination, this refers to the unidirectional transfer of genetic information from one chromosome to the homologous chromosome.

DNA double-strand break

The event, catalysed by the topoisomerase-like meiotic recombination protein SPO11, that initiates the molecular mechanism of recombination during meiosis.

Linkage disequilibrium

(LD). The preferential association of specific alleles between linked markers.

Haplotyping

The characterization of haplotypes — the combination of linked alleles that are transmitted together to the progeny.

Congenic

Pertainint to the situation in which two strains share the same genetic background in the whole genome except at one locus or chromosomal region.

Pseudo-autosomal region

The region of homology between the sex chromosomes.

Positive selection

The evolution force that favours the increase in frequency of advantageous alleles in a population.

Minisatellite

A tandem nucleotide repeat of a 10–100 bp-long unit. The sequence encoding the PR domain-containing 9 (PRDM9) zinc finger array is a minisatellite of 10–15 repeats of an 84-bp unit.

Topoisomerase

An enzyme involved in regulating DNA topology by catalysing DNA breakage and resealing. The DNA breaks generated are either single stranded for type I topoisomerases or double stranded for type II topoisomerases.

Bivalent

A pair of homologues that are associated by synapsis or chiasmata, which are the cytological manifestation of crossover.

Sister chromatids

Pairs of two chromatids that result from a round of DNA replication.

Synaptonemal complex

The protein structure that stabilizes homologous chromosome axes in meiotic prophase during the process named synapsis.

Positive crossover interference

The mechanism leading to a nonrandom distribution of crossovers, in which the presence of a crossover decreases the probability of additional crossover events occuring nearby.

Lateral element

The proteinaceous structure that defines the chromosome axis at the beginning of meiotic prophase.

Cohesin

A protein that holds sister chromatids together.

Non-allelic homologous recombination

(NAHR). The homologous recombination between identical or quasi-identical sequences that are not allelic. It can lead to chromosomal rearrangements such as deletion, duplication or inversion of sequences and translocations.

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Baudat, F., Imai, Y. & de Massy, B. Meiotic recombination in mammals: localization and regulation. Nat Rev Genet 14, 794–806 (2013). https://doi.org/10.1038/nrg3573

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