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Linkage disequilibrium in the human genome

Nature volume 411, pages 199–204 (2001)Cite this article

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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References

  1. Sachidanandam, R. et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409, 928–933 (2001).

    Article  ADS  CAS  Google Scholar 

  2. Kruglyak, L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nature Genet. 22, 139–144 (1999).

    Article  CAS  Google Scholar 

  3. Dunning, A. M. et al. The extent of linkage disequilibrium in four populations with distinct demographic histories. Am. J. Hum. Genet. 67, 1544–1554 (2000).

    Article  CAS  Google Scholar 

  4. Abecasis, G. R. et al. Extent and distribution of linkage disequilibrium in three genomic regions. Am. J. Hum. Genet. 68, 191–197 (2001).

    Article  CAS  Google Scholar 

  5. Taillon-Miller, P. et al. Juxtaposed regions of extensive and minimal linkage disequilibrium in human Xq25 and Xq28. Nature Genet. 25, 324–328 (2000).

    Article  CAS  Google Scholar 

  6. Collins, A., Lonjou, C. & Morton, N. E. Genetic epidemiology of single-nucleotide polymorphisms. Proc. Natl Acad. Sci. USA 96, 15173–15177 (1999).

    Article  ADS  CAS  Google Scholar 

  7. Goddard, K. A. B., Hopkins, P. J., Hall, J. M. & Witte, J. S. Linkage disequilibrium and allele-frequency distributions for 114 single-nucleotide polymorphisms in five populations. Am. J. Hum. Genet. 66, 216–234 (2000).

    Article  CAS  Google Scholar 

  8. Watterson, G. A. & Guess, H. A. Is the most frequent allele the oldest? Theor. Pop. Biol. 11, 141–160 (1977).

    Article  CAS  Google Scholar 

  9. Lander, E. S. The new genomics: global views of biology. Science 274, 536–539 (1996).

    Article  ADS  CAS  Google Scholar 

  10. Schneider, S., Kueffler, J. M., Roessli, D. & Excoffier, L. Arlequin (ver. 2.0): A software for population genetic data analysis (Genetics and Biometry Laboratory, Univ. Geneva, Switzerland, 2000).

  11. Lewontin, R. C. On measures of gametic disequilibrium. Genetics 120, 849–852 (1988).

    CAS  Google Scholar 

  12. Jorde, L. B. Linkage disequilibrium and the search for complex disease genes. Genome Res. 10, 1435–1444 (2000).

    Article  CAS  Google Scholar 

  13. Hudson, R. R. in Oxford Surveys in Evolutionary Biology (eds Futuyma, D. J. & Antonovics, J.) 1–44 (Oxford Univ. Press, Oxford, 1990).

    Google Scholar 

  14. Clark, A. G. et al. Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase. Am. J. Hum. Genet. 63, 595–612 (1998).

    Article  CAS  Google Scholar 

  15. Hartl, D. L. & Clark, A. G. Principles of Population Genetics (Sinauer, Massachusetts, 1997).

    Google Scholar 

  16. Chakraborty, R. & Weiss, K. M. Admixture as a tool for finding linked genes and detecting that difference from allelic association between loci. Proc. Natl Acad. Sci. USA 85, 9119–9123 (1988).

    Article  ADS  CAS  Google Scholar 

  17. Eaves, I. A. et al. The genetically isolated populations of Finland and Sardinia may not be a panacea for linkage disequilibrium mapping of common disease genes. Nature Genet. 25, 320–322 (2000).

    Article  CAS  Google Scholar 

  18. Goldstein, D. B., Ruiz Linares, A., Cavalli-Sforza, L. L. & Feldman, M. W. Genetic absolute dating based on microsatellites and the origin of modern humans. Proc. Natl Acad. Sci. USA 92, 6723–6727 (1995).

    Article  ADS  CAS  Google Scholar 

  19. Tishkoff, S. A. et al. Global patterns of linkage disequilibrium at the CD4 locus and modern human origins. Science 271, 1380–1387 (1996).

    Article  ADS  CAS  Google Scholar 

  20. Tishkoff, S. A. et al. Short tandem-repeat polymorphism/Alu haplotype variation at the PLAT locus: Implications for modern human origins. Am. J. Hum. Genet. 67, 901–925 (2000).

    Article  CAS  Google Scholar 

  21. Kidd, J. R. et al. Haplotypes and linkage disequilibrium at the phenylalanine hydroxylase locus, PAH, in a global representation of populations. Am. J. Hum. Genet. 66, 1882–1899 (2000).

    Article  CAS  Google Scholar 

  22. Mateu, E. et al. Worldwide genetic analysis of the CFTR region. Am. J. Hum. Genet. 68, 103–117 (2001).

    Article  CAS  Google Scholar 

  23. Housley, R. A., Gamble, C. S., Street, M. & Pettitt, P. Radiocarbon evidence for the Late glacial human recolonisation of northern Europe. Proc. Prehist. Soc. 63, 25–54 (1994).

    Article  Google Scholar 

  24. Richards, M. et al. Tracing European founder lineages in the Near Eastern mtDNA pool. Am. J. Hum. Genet. 67, 1251–1276 (2000).

    Article  CAS  Google Scholar 

  25. Reich, D. E. & Goldstein, D. B. Genetic evidence for a Paleolithic human population expansion in Africa. Proc. Natl Acad. Sci. USA 95, 8119–8123 (1998).

    Article  ADS  CAS  Google Scholar 

  26. Ingman, M., Kaessmann, H., Pääbo, S. & Gyllensten, U. Mitochondrial genome variation and the origin of modern humans. Nature 408, 708–713 (2000).

    Article  ADS  CAS  Google Scholar 

  27. Altshuler, D., Daly, M. & Kruglyak, L. Guilt by association. Nature Genet. 26, 135–137 (2000).

    Article  CAS  Google Scholar 

  28. Cargill, M. et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature Genet. 22, 231–238 (1999).

    Article  CAS  Google Scholar 

  29. Nickerson, D. B., Tobe, V. O. & Taylor, S. L. PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based sequencing. Nucleic Acids Res. 25, 2745–2751 (1997).

    Article  CAS  Google Scholar 

  30. Ross, P., Hall, L., Smirnov, I. & Haff, L. High level multiplex genotyping by MALDI-TOF mass spectroscopy. Nature Biotech. 16, 1347–1351 (1998).

    Article  CAS  Google Scholar 

  31. Chen, X., Levine, L. & Kwok, P. Y. Fluorescence polarization in homogenous nucleic acid analysis. Genome Res. 9, 492–498 (1999).

    CAS  Google Scholar 

  32. Lindblad-Toh, K. et al. Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse. Nature Genet. 24, 381–386 (2000).

    Article  CAS  Google Scholar 

  33. Excoffier, L. & Slatkin, M. Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol. Biol. Evol. 12, 921–927 (1995).

    CAS  Google Scholar 

  34. Broman, K. W., Murray, J. C., Sheffield, V. C., White, R. L. & Weber, J. L. Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am. J. Hum. Genet. 63, 861–689 (1998).

    Article  CAS  Google Scholar 

  35. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921.

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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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Author notes

  1. Michele Cargill

    Present address: Celera Genomics, 45 West Gude Drive, Rockville, Maryland, 20850, USA

Authors and Affiliations

  1. Whitehead Institute / MIT Center for Genome Research, Nine Cambridge Center, Cambridge, 02142, Massachusetts, USA

    David E. Reich, Michele Cargill, Stacey Bolk, James Ireland, Daniel J. Richter, Thomas Lavery, Rose Kouyoumjian, Shelli F. Farhadian & Eric S. Lander

  2. Institute of Biological Anthropology, University of Oxford, Oxford, OX2 6QS, UK

    Pardis C. Sabeti & Ryk Ward

  3. Department of Biology, MIT, Cambridge, 02139, Massachusetts, USA

    Eric S. Lander

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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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