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Linkage disequilibrium — understanding the evolutionary past and mapping the medical future

Key Points

  • Linkage disequilibrium (LD) is the nonrandom association of alleles of different loci. There is no single best statistic that quantifies the extent of LD. Several statistics have been proposed that are useful for different purposes.

  • Recombination interacts in a complex way with selection, mutation and genetic drift to determine levels of LD. As a consequence, local and genome-wide patterns of LD can provide insight into patterns of natural selection and the past history of population growth and dispersal.

  • In humans and other model organisms, LD between marker alleles and traits of interest allow fine-scale gene mapping. Many recent genome-wide association studies have successfully mapped SNPs associated with complex inherited diseases in humans.

  • Unusually high local LD can indicate an allele that has recently increased to high frequency under strong selection. Several methods have been developed to detect selected loci and to estimate the age of alleles using patterns of LD.

  • In humans, the analysis of LD is well underway. The pace is slower in other species, although some model organisms, including mice, dogs, Drosophila and Arabidopsis thaliana, are catching up fast. Extensive analysis of LD in non-model species will be undertaken soon.

Abstract

Linkage disequilibrium — the nonrandom association of alleles at different loci — is a sensitive indicator of the population genetic forces that structure a genome. Because of the explosive growth of methods for assessing genetic variation at a fine scale, evolutionary biologists and human geneticists are increasingly exploiting linkage disequilibrium in order to understand past evolutionary and demographic events, to map genes that are associated with quantitative characters and inherited diseases, and to understand the joint evolution of linked sets of genes. This article introduces linkage disequilibrium, reviews the population genetic processes that affect it and describes some of its uses. At present, linkage disequilibrium is used much more extensively in the study of humans than in non-humans, but that is changing as technological advances make extensive genomic studies feasible in other species.

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Figure 1: Haplotype blocks.

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Acknowledgements

The writing of this paper was supported in part by a grant from the US National Institutes of Health, R01-GM40282. I thank J. Felsenstein for discussions of this topic and the translation of Weinberg's paper, and M. Kirkpatrick and the referees for comments on an earlier version of this paper.

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FURTHER INFORMATION

Montgomery Slatkin's Research Group

Genepop

1000 Genomes Project

International HapMap Project

Likelihood analysis with metropolis algorithm using random coalescence (LAMARC)

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Slatkin, M. Linkage disequilibrium — understanding the evolutionary past and mapping the medical future. Nat Rev Genet 9, 477–485 (2008). https://doi.org/10.1038/nrg2361

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