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Mammalian recombination hot spots: properties, control and evolution

Key Points

  • Recombination events in many organisms are concentrated in highly localized areas termed 'hot spots'.

  • Hot spots can be detected by statistical analysis of genetic variation, analysis of pedigrees and analysis of sperm genomes.

  • Hot spot activities vary in orders of magnitude and can show sex specificity and imprinting effects.

  • The location and relative activity of hot spots is determined by both their own DNA sequence, acting in a cis manner on each chromatid, and by trans-acting factors, such as the zinc finger histone trimethylase PR domain-containing 9 (PRDM9).

  • The two sexes differ in their overall recombination activity and the distribution of crossing over along individual chromosomes.

  • Total recombination activity is genetically regulated and is affected by the number of chromosomes and chromosomal arms in each species.

  • Recombination hot spots evolve rapidly.

Abstract

Recombination, together with mutation, generates the raw material of evolution, is essential for reproduction and lies at the heart of all genetic analysis. Recent advances in our ability to construct genome-scale, high-resolution recombination maps and new molecular techniques for analysing recombination products have substantially furthered our understanding of this important biological phenomenon in humans and mice: from describing the properties of recombination hot spots in male and female meiosis to the recombination landscape along chromosomes. This progress has been accompanied by the identification of trans-acting systems that regulate the location and relative activity of individual hot spots.

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Figure 1: Hot spot positioning and intensity.
Figure 2: High-resolution sex-specific maps of a mouse chromosome segment.
Figure 3: Distribution of crossover exchange points in hot spots.

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Acknowledgements

The authors are thankful to M. A. Handel for her thoughtful comments. This work was supported by US National Institutes of Health grants GM078643 and GM083408 to K.P., grant GM078452 to P.P., project grant GM076468 (part of which is managed by P.P.) to G. Churchill and grant CA34196 to The Jackson Laboratory.

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Glossary

Cosmid

A bacterial recombination vector that contains long inserted DNA sequences.

Single-nucleotide polymorphism

Single-nucleotide polymorphisms (SNPs) distinguish the chromosomes of two individuals or mouse strains. There are millions of SNPs in mammalian genomes, and they have become the preferred markers for genetic studies.

Haplotype

A set of genetic markers that are present on a single chromosome and that show complete or nearly complete linkage disequilibrium — that is, they are inherited through generations without being changed by crossing over or other recombination mechanisms.

Linkage disequilibrium

Preferential association of allelic combinations among groups of nearby genes.

Genetic drift

The random fluctuations in allele frequencies over time that are due to chance alone.

Coalescent-based statistical methods

Methods of reconstructing population history by simulating the genealogy of genes back to the most recent common ancestor of all alleles currently in the population.

Genome-wide association study

An examination of common genetic variation across the genome that is designed to identify associations with traits, such as common diseases.

Imprinting

The epigenetic marking of a gene on the basis of parental origin, which in somatic tissues results in monoallelic expression.

Crossover

A reciprocal exchange of DNA along chromatids such that the proximal end of one homologue becomes attached to the distal end of the other.

Double-strand break

A cut made across a DNA molecule in which both strands are broken. In recombination the cut is made by the enzyme sporulation-specific 11 (SPO11).

Pseudoautosomal

A region on a sex chromosome that is homologous between the X chromosome and the Y chromosome. Successful meiosis in males requires a crossover in this pseudoautosomal region.

Gene conversion

The process during recombination in which a short segment of DNA on the initiating chromatid is replaced by the DNA sequence of its partner without the exchange of flanking markers.

Holliday junction

The point at which the strands of two dsDNA molecules exchange partners as an intermediate step in crossing over. Typically, two Holliday junctions are formed in the recombination pathway that gives rise to crossovers.

Topoisomerase

An ATP-dependent enzyme that normally creates transient breaks in both strands of the DNA sugar-phosphate backbone, then passes one strand through the other and reseals the break. In the case of the topoisomerase sporulation-specific 11 (SPO11), which initiates recombination, the breaks are not immediately resealed because the 5′ strand on each end is rapidly resected, leaving a free 3′ overhang.

Chromatid

The product of chromosome replication in meiosis I. Chromatids are distinguished from chromosomes by the fact that the two daughter chromatids of one chromosome remain attached at their centromeres through meiosis I cell division.

Recombination nodules

The early, visible manifestations of sites of chiasmata and crossing over. They are recognized by immunochemical staining, typically for the protein MutL homologue 1, which is a component of late recombination nodules.

Zinc finger

A protein loop in which cysteine or cysteine-histidine residues coordinate a zinc ion to form the base of the loop. Three of the amino acids in the loop cooperate to recognize three base pairs of DNA, and a tandem array of zinc fingers can show considerable DNA-binding specificity.

Positive selection

A process by which natural selection favours a single beneficial genotype over other genotypes and may drive this genotype to a high frequency in a population.

Minisatellite

A region of DNA in which repeat units of 10–50 bp are tandemly arranged in arrays 0.5–30 kb in length.

Genetic interference

The presence of a recombinational event in one region that affects the occurrence of recombinational events in adjacent regions. Positive interference, which is seen in eukaryotes, reduces the probability of using nearby hot spots in the same meiosis and causes a more even spacing of crossovers than would occur by chance.

Synaptonemal complex

A linear protein complex that forms the backbone of each chromatid during prophase I of meiosis and promotes genetic recombination. The DNA of the chromatid is attached to the complex in long loops. The name is derived from the word synapsis, which has been used to describe chromatid pairing.

Bouquet formation

The clustering of telomeres together on the nuclear membrane early in meiosis.

Chiasmata

A chiasma (plural chiasmata) is the cytologically visible physical connection between homologous chromatids during meiosis that corresponds to the sites of genetic crossing over.

MutL homologue 1 foci

Sites of staining for MutL homologue 1 that identify sites of genetic crossing over.

RAD51

The human homologue of bacterial RecA. RAD51 is required for homologous recombination, during which it promotes strand invasion, forming nucleoprotein filaments around ssDNA. Immunohistochemical staining of RAD51 foci identifies sites of DNA double-strand breaks.>>

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Paigen, K., Petkov, P. Mammalian recombination hot spots: properties, control and evolution. Nat Rev Genet 11, 221–233 (2010). https://doi.org/10.1038/nrg2712

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