An evolutionary view of human recombination

Key Points

  • Recombination has a key role in ensuring proper disjunction during meiosis, and in maintaining genome integrity. This role leads to a number of constraints on the recombination process.

  • Despite the importance of recombination in meiosis, there is a large variation in the number of crossover events among humans. This variation is more pronounced in females, but is also seen in males.

  • Recent studies have shown that there is extensive fine-scale heterogeneity in human recombination rates along the genome, with most events occurring in 'hotspots'. Activity of these hotspots seems to be modulated, at least in part, by sequence motifs that lie in cis.

  • Sperm-typing studies have shown that recombination hotspot intensities and locations vary among human males.

  • The selective forces that shape recombination rates are largely unknown. Selection that is related to the role of recombination in meiosis is bound to have an important role in shaping broad-scale rates. Furthermore, selection to maintain genome integrity, indirect selection on recombination modifiers and meiotic drive might influence fine-scale recombination rates. In particular, modifiers that increase recombination rates might have been favoured in regions that are subject to recurrent natural selection.

  • Mammalian species, even those that are closely related, differ in the length of their genetic map, the extent of sexual dimorphism for recombination rates, and their hotspot locations. These observations indicate that many aspects of recombination are not under strong constraint, but whether changes in these aspects are neutral or advantageous is an open question.

  • The increasing availability of genomic resources, coupled with the development of new statistical methods, should enable us to address enduring questions about the determinants of recombination and the selective pressures that influence them.

Abstract

Recombination has essential functions in mammalian meiosis, which impose several constraints on the recombination process. However, recent studies have shown that, in spite of these roles, recombination rates vary tremendously among humans, and show marked differences between humans and closely related species. These findings provide important insights into the determinants of recombination rates and raise new questions about the selective pressures that affect recombination over different genomic scales, with implications for human genetics and evolutionary biology.

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Figure 1: Genetic maps in mammals.
Figure 2: Heterogeneity in recombination rates along the human genome.
Figure 3: The genome-wide genetic map in humans and other primates.

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Acknowledgements

Many thanks to D. Bishop, B. Charlesworth, D. Charlesworth, D. Conrad, G. Hellenthal, Y. Gilad, T. Hassold, J. Pritchard and three anonymous reviewers for helpful comments on the manuscript, as well as to P. Andolfatto, B. Charlesworth and T. Hassold for helpful discussions. G.C. is supported by an NIH grant to J. K. Pritchard. M.P. is supported by an Alfred P. Sloan Fellowship in Computational and Evolutionary Molecular Biology.

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Correspondence to Molly Przeworski.

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DATABASES

Entrez Gene

MLH1

Spo11

FURTHER INFORMATION

University of Chicago Department of Human Genetics

Glossary

Disjunction

The segregation of homologous chromosomes during meiosis.

Aneuploidy

Having more or less than the typical chromosome number (46 for humans).

Ectopic exchange

Homologous recombination between non-allelic copies.

Haplotype

The combination of alleles on a chromosome.

Synapsis

A process through which homologous chromosomes are brought into close alignment with one another.

Crossing over

A type of homologous-recombination event during which there is a reciprocal exchange of flanking regions. Also referred to as a crossover.

Chromatid

An individual daughter chromosome after replication.

Bivalent

A pair of homologous chromosomes after replication; each chromosome consists of two chromatids.

Holliday junction

An intermediate step in homologous recombination; the point of exchange between four strands of DNA.

Gene conversion

Recombination that involves non-reciprocal exchange of a small segment of a chromosome. We note that this population-genetic definition differs from the more widespread definition, which is based on non-Mendelian segregation.

Metacentric

Chromosomes in which the centromere is not close to either end.

Acrocentric

Chromosomes in which the centromere is close to one end.

Genetic map

A map of markers along the genome, in which the distance between markers reflects the recombination frequencies between them. The longer the total genetic map, the more recombination occurs in the genome. Also referred to as a linkage map.

Positive interference

The process through which a crossover event reduces the probability of a second such event in its neighborhood.

Recombination hotspot

A short segment of DNA that experiences much more recombination than the flanking regions.

Linkage disequilibrium

In a sample, an association of alleles at different loci beyond what would be expected by chance.

Chiasma

Connection between homologous chromosomes resulting from crossing over.

Population recombination rate

Usually defined as 4Nr, where N is the effective population size and r the recombination rate per meiosis.

Biased gene conversion

A bias in the process of gene conversion in favour of one type of allele over another, also referred to as disparity of gene conversion.

Interchromosomal effect

In heterozygotes, the effect of an inversion on recombination rates on other chromosomes.

Pseudoautosomal region 1

A region of homology between the X and Y chromosomes that experiences obligate crossing over in males.

Antagonistic pleiotropy

The case in which a single loci has multiple effects, some advantageous and some deleterious; for example, when a gene causes higher fitness early in life, but decreased fitness at older ages.

Negative disequilibrium

Two alleles are in negative linkage disequilibrium if they are found on different chromosomes more often than expected by chance.

Effective population size

Reflects the extent of genetic drift and can be far lower than the census population size.

Meiotic drive

Any non-adaptive process that leads an allele to be over-transmitted in gametes during meiosis.

Heterogametic sex

The sex that has differently shaped sex chromosomes. In mammals, the heterogametic sex is male (XY) and homogametic sex is female (XX), whereas in other species, such as birds, the heterogametic sex is female (ZW).

Background selection

The effect of strong purifying selection on linked neutral variation.

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Coop, G., Przeworski, M. An evolutionary view of human recombination. Nat Rev Genet 8, 23–34 (2007). https://doi.org/10.1038/nrg1947

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