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Linkage disequilibrium in the human genome

Abstract

With the availability of a dense genome-wide map of single nucleotide polymorphisms (SNPs)1, a central issue in human genetics is whether it is now possible to use linkage disequilibrium (LD) to map genes that cause disease. LD refers to correlations among neighbouring alleles, reflecting ‘haplotypes’ descended from single, ancestral chromosomes. The size of LD blocks has been the subject of considerable debate. Computer simulations2 and empirical data3 have suggested that LD extends only a few kilobases (kb) around common SNPs, whereas other data have suggested that it can extend much further, in some cases greater than 100 kb4,5,6. It has been difficult to obtain a systematic picture of LD because past studies have been based on only a few (1–3) loci and different populations. Here, we report a large-scale experiment using a uniform protocol to examine 19 randomly selected genomic regions. LD in a United States population of north-European descent typically extends 60 kb from common alleles, implying that LD mapping is likely to be practical in this population. By contrast, LD in a Nigerian population extends markedly less far. The results illuminate human history, suggesting that LD in northern Europeans is shaped by a marked demographic event about 27,000–53,000 years ago.

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Figure 1: LD versus physical distance between SNPs.
Figure 2: LD profiles for each genomic region.
Figure 3: Effect on LD of assumptions about population history and recombination. a, The effect of a population bottleneck instantaneously reducing the population to a constant size of 50 individuals for 40 generations (F  = 0.4) and occurring 400, 800, 1,600 or 3,200 generations ago.
Figure 4: LD curve for Swedish and Yoruban samples.

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Acknowledgements

We thank L. Groop for the Swedish samples; R. Cooper and C. Rotimi for the Yoruban samples; and D. Altshuler, M. Daly, D. Goldstein, J. Hirschhorn, C. Lindgren and S. Schaffner for discussions. This work was supported in part by grants from the National Institutes of Health, Affymetrix, Millennium Pharmaceuticals, and Bristol-Myers Squibb Company, and by a National Defense Science and Engineering Fellowship to D.E.R.

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Correspondence to David E. Reich.

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Reich, D., Cargill, M., Bolk, S. et al. Linkage disequilibrium in the human genome. Nature 411, 199–204 (2001). https://doi.org/10.1038/35075590

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