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  • Review Article
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Estimating recombination rates from population-genetic data

Nature Reviews Genetics volume 4, pages 959–968 (2003)Cite this article

Key Points

  • One effect of recombination is to determine the extent of linkage disequilibrium in population DNA samples.

  • Direct measurement of the recombination rate is difficult and often impractical. For this reason, population-genetic methods are often used to infer recombination rates from patterns of variation among DNA sequences.

  • Population-genetic methods can detect variation in the recombination rate at the level of single genes.

  • Although simple parsimony methods allow the number of recombination events to be counted, most recombination events are missed using this approach.

  • Sophisticated statistical approaches use population-genetic models to estimate recombination rates.

  • Several statistical methods that estimate the population recombination rate have been developed. These are influenced by population history, but can provide important insights into details of the recombination process.

  • Biologically important inferences can be drawn from these estimators even if the underlying assumptions are oversimplified.

  • Discrepancies between estimated and experimentally measured rates can reveal important biological processes.

  • Estimated recombination rates enable the detailed interpretation of linkage disequilibrium and haplotype data.

Abstract

Obtaining an accurate measure of how recombination rates vary across the genome has implications for understanding the molecular basis of recombination, its evolutionary significance and the distribution of linkage disequilibrium in natural populations. Although measuring the recombination rate is experimentally challenging, good estimates can be obtained by applying population-genetic methods to DNA sequences taken from natural populations. Statistical methods are now providing insights into the nature and scale of variation in the recombination rate, particularly in humans. Such knowledge will become increasingly important owing to the growing use of population-genetic methods in biomedical research.

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Figure 1: Ancestral genealogies and the effects of recombination.
Figure 2: The behaviour of estimators is largely independent of genomic region.
Figure 3: Estimating local recombination rate variation in a known recombination hotspot.
Figure 4: Blocks and the interplay of recombination rate and demography.

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Acknowledgements

We thank A. Jeffreys and P. Donnelly for useful discussions, and C. Wiuf, M. Slatkin, L. Cardon, G. Coop, C. Spencer and three anonymous referees for their helpful comments on earlier drafts of this manuscript. Generous support through research fellowships from the Wellcome Trust (to M.P.H.S) and the Royal Society (to G.A.T.M.) is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Biological Sciences, Imperial College of Science, Technology and Medicine, London, SW7 2AY, UK

    Michael P. H. Stumpf

  2. Department of Statistics, University of Oxford, Oxford, OX1 3TG, UK

    Gilean A. T. McVean

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Glossary

LINKAGE DISEQUILIBRIUM

(LD). A measure of genetic associations between alleles at different loci, which indicates whether allelic or marker associations on the same chromosome are more common than expected.

MARGINAL GENEALOGY

The part of a genealogical graph that corresponds to a single locus or stretch of DNA that is inherited without recombination.

MARKER ASCERTAINMENT

The process by which new genetic markers are obtained — for example, by re-sequencing a subset of chromosomes in a population sample. If those markers are population-specific then inferences that are based on them in other populations might be biased through so-called ascertainment bias.

HAPLOTYPE

The combination of alleles or genetic markers that is found on a single chromosome of a given individual.

INFINITE SITES MUTATION MODEL

A model that assumes that there are an infinite number of nucleotide sites and consequently that each new mutation occurs at a different locus.

FOUR-GAMETE TEST

(FGT). If all four possible gametes are observed for two bi-allelic loci then this test infers that a recombination event must have occurred between them (under an infinite sites mutation model).

PER-GENERATION RECOMBINATION RATE

(r). The probability of a recombination event occurring during meiosis.

EFFECTIVE POPULATION SIZE

(Ne). The size of the ideal constant-size population, in which the effects of random drift would be the same as those seen in the actual population.

POPULATION RECOMBINATION RATE

(ρ). Population-genetic parameters are generally proportional to the product of a molecular per-generation rate (for example, the per-generation recombination rate, r) and the effective population size (Ne). The population recombination rate has therefore often been defined as ρ = 4Ner.

CENSUS POPULATION SIZE

Actual population size (total number of individuals) as compared to the theoretical effective population size.

ESTIMATOR

A statistical method that is used to obtain a numerical estimate for a quantity of interest, such as a model parameter.

SUMMARY STATISTIC

A statistical function that summarizes complex data in terms of simple numbers (examples include the mean and variance).

VARIANCE

A statistic that quantifies the dispersion of data about the mean.

LIKELIHOOD SURFACE

The likelihood of a parameter is proportional to the probability of obtaining the observed data under a parametric model given the model parameter. The likelihood surface is a function/curve that specifies how well the data agrees with the predictions made by a parametric model for different values of the model parameter.

MARKOV CHAIN MONTE CARLO

A computational technique for the efficient numerical calculation of likelihoods.

RECURSION

A repeated mathematical operation that is often used to aid numerical analysis.

GENE CONVERSION

The non-reciprocal transfer of genetic information between homologous genes as a consequence of mismatch repair after heteroduplex formation.

PHASING

Determining the haplotype phase (the arrangement of alleles at two loci on homologous chromosomes) from genotype data using statistical methods.

ASSOCIATION STUDIES

A set of methods that are used to correlate polymorphisms in genotype to polymorphisms in phenotype in populations.

MODEL MIS-SPECIFICATION

The consequence of using a parametric model in the inference process that is different from the true model under which the data was generated.

CPG ISLANDS

Genome sequences of >200 base pairs that have high G+C content and CpG frequency.

TEMPLATE SWITCHING

The process by which RNA templates are switched between viral genomes during reverse transcription.

BOTTLENECK

A temporary marked reduction in population size.

SELECTIVE SWEEP

The process by which positive selection for a mutation eliminates neutral variation at linked sites.

HARDY–WEINBERG EQUILIBRIUM

A state in which the frequency of each diploid genotype at a locus equals that expected from the random union of alleles.

HAPLOTYPE-BASED APPROACH

An approach to association studies in which the co-inheritance of phenotypes and haplotypes — as opposed to single markers — is statistically analysed.

TAGGING APPROACH

Identifying sub-sets of markers ('tags') that describe patterns of association or haplotypes among larger marker sets.

MINIMUM-DESCRIPTION LENGTH APPROACHES

A concept from information theory, in which all of the information contained in a system (for example, a sample of DNA sequences) is described in the most compact form possible.

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Stumpf, M., McVean, G. Estimating recombination rates from population-genetic data. Nat Rev Genet 4, 959–968 (2003). https://doi.org/10.1038/nrg1227

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