Haplotype blocks and linkage disequilibrium in the human genome

Key Points

  • Linkage disequilibrium (LD) is the nonrandom association of alleles at different sites.

  • Recent studies have proposed that patterns of LD in the human genome can be summarized by a series of discrete haplotype blocks: regions of high LD that are separated from other haplotype blocks by many historical recombination events.

  • Patterns of LD and the fit of the haplotype-block model vary tremendously from region to region: some show extensive well-defined haplotype blocks, while others contain essentially no haplotype blocks.

  • This variability across regions is probably the result of several factors, which include large-scale variation in recombination rates (apparent from genetic maps), fine-scale variation in recombination rates (for example, hotspots) and the inherent stochasticity of LD.

  • Simulations indicate that although recombination hotspots generally create haplotype-block boundaries, the converse is not true: most haplotype-block boundaries do not occur at hotspots

  • The identification of haplotype blocks will be of some use for future association studies, but there will be a substantial fraction of the genome (not covered by large haplotype blocks) for which other approaches will be useful.

Abstract

There is great interest in the patterns and extent of linkage disequilibrium (LD) in humans and other species. Characterizing LD is of central importance for gene-mapping studies and can provide insights into the biology of recombination and human demographic history. Here, we review recent developments in this field, including the recently proposed 'haplotype-block' model of LD. We describe some of the recent data in detail and compare the observed patterns to those seen in simulations.

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Figure 2: The proportion of sequence contained in haplotype blocks of various sizes.
Figure 1: Pairwise |D′| plots for representative regions from different studies.
Figure 3: Schematic of the haplotype blocks identified in five genomic regions32.
Figure 4: Schematic of the haplotype blocks found in simulations.

References

  1. 1

    Pritchard, J. K. & Przeworski, M. Linkage disequilibrium in humans: models and data. Am. J. Hum. Genet. 69, 1–14 (2001). This paper discusses ways of quantifying LD, and explores how LD is affected by different demographic models.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Devlin, B. & Risch, N. A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 29, 311–322 (1995).

    CAS  PubMed  Google Scholar 

  3. 3

    Cardon, L. R. & Abecasis, G. R. Using haplotype blocks to map human complex trait loci. Trends Genet. 19, 135–140 (2003).

    CAS  PubMed  Google Scholar 

  4. 4

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

    CAS  PubMed  Google Scholar 

  5. 5

    Ardlie, K. G., Kruglyak, L. & Seielstad, M. Patterns of linkage disequilibrium in the human genome. Nature Rev. Genet. 3, 299–309 (2002).

    CAS  PubMed  Google Scholar 

  6. 6

    Kerem, B. et al. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073–1080 (1989).

    CAS  PubMed  Google Scholar 

  7. 7

    Hastbacka, J. et al. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nature Genet. 2, 204–211 (1992).

    CAS  PubMed  Google Scholar 

  8. 8

    Collins, F. S., Guyer, M. S. & Chakravarti, A. Variations on a theme: cataloging human DNA sequence variation. Science 278, 1580–1581 (1997).

    CAS  PubMed  Google Scholar 

  9. 9

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

    CAS  Google Scholar 

  10. 10

    Risch, N. J. Searching for genetic determinants in the new millennium. Nature 405, 847–856 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Chakravarti, A. et al. Nonuniform recombination within the human β-globin gene cluster. Am. J. Hum. Genet. 36, 1239–1258 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Li, N. & Stephens, M. A new multilocus model for linkage disequilibrium, with application to exploring variations in recombination rate. Genetics (in the press). This study provides an innovative approach to modelling LD, and introduces a powerful new method for quantifying local variation in levels of LD.

  13. 13

    Hilliker, A. J. et al. Meiotic gene conversion tract length distribution within the rosy locus of Drosophila melanogaster. Genetics 137, 1019–1026 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Przeworski, M. & Wall, J. D. Why is there so little intragenic linkage disequilibrium in humans? Genet. Res. 77, 143–151 (2001).

    CAS  PubMed  Google Scholar 

  15. 15

    Frisse, L. et al. Gene conversion and different population histories may explain the contrast between polymorphism and linkage disequilibrium levels. Am. J. Hum. Genet. 69, 831–843 (2001). This paper quantifies differences in levels of LD across populations, and provides the first estimates of gene-conversion rates in humans.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Ardlie, K. et al. Lower-than-expected linkage disequilibrium between tightly linked markers in humans suggests a role for gene conversion. Am. J. Hum. Genet. 69, 582–589 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

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

    CAS  Google Scholar 

  18. 18

    Reich, D. E. et al. Linkage disequilibrium in the human genome. Nature 411, 199–204 (2001). This paper is the first genomic-scale study to document the variability in levels of LD across different populations and genetic regions.

    CAS  Google Scholar 

  19. 19

    McKeigue, P. M., Carpenter, J. R., Parra, E. J. & Shriver, M. D. Estimation of admixture and detection of linkage in admixed populations by a Bayesian approach: application to African-American populations. Ann. Hum. Genet. 64, 171–186 (2000).

    CAS  PubMed  Google Scholar 

  20. 20

    Falush, D. et al. Traces of human migrations in Helicobacter pylori populations. Science 299, 1582–1585 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Falush, D, Stephens, M. & Pritchard, J. K. Inference of population structure: extensions to linked loci and correlated allele frequencies. Genetics (in the press).

  22. 22

    Wall, J. D. Insights from linked single nucleotide polymorphisms: what we can learn from linkage disequilibrium. Curr. Opin. Genet. Dev. 11, 647–651 (2001).

    CAS  PubMed  Google Scholar 

  23. 23

    Wall, J. D. Detecting ancient admixture in humans using sequence polymorphism data. Genetics 154, 1271–1279 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Saunders, M. A., Hammer, M. F. & Nachman, M. W. Nucleotide variability at G6PD and the signature of malarial selection in humans. Genetics 162, 1849–1861 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Tishkoff, S. A. et al. Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance. Science 293, 455–462 (2001). This paper, along with references 24 and 26, shows how recent natural selection can affect patterns of LD.

    CAS  Google Scholar 

  26. 26

    Sabeti, P. C. et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 419, 832–837 (2002).

    CAS  PubMed  Google Scholar 

  27. 27

    Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996).

    CAS  PubMed  Google Scholar 

  28. 28

    Camp, N. J. Genomewide transmission/disequilibrium testing — consideration of the genotypic relative risks at disease loci. Am. J. Hum. Genet. 61, 1424–1430 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Jeffreys, A. J., Ritchie, A. & Neumann, R. High resolution analysis of haplotype diversity and meiotic crossover in the human TAP2 recombination hotspot. Hum. Mol. Genet. 9, 725–733 (2000).

    CAS  PubMed  Google Scholar 

  30. 30

    Jeffreys, A. J., Kauppi, L. & Neumann, R. Intensely punctuate meiotic recombination in the class II region of the major histocompatibility complex. Nature Genet. 29, 217–222 (2001). This high-resolution experimental analysis shows that most recombination events in the class II MHC region occur in just a handful of narrow hotspots.

    CAS  Google Scholar 

  31. 31

    Daly, M., Rioux, J. D., Schaffner, D. F., Hudson, T. J. & Lander, E. S. High-resolution haplotype structure in the human genome. Nature Genet. 29, 229–232 (2001). The notable patterns of LD in this study spurred interest in the haplotype-block concept.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Gabriel, S. B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225–2229 (2002). This study explores haplotype-block patterns across many populations and genomic regions.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

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

    CAS  PubMed  Google Scholar 

  34. 34

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

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

    CAS  PubMed  Google Scholar 

  36. 36

    Bonnen, P. E., Wang, P. J., Kimmel, M., Chakraborty, R. & Nelson, D. L. Haplotype and linkage disequilibrium architecture for human cancer-associated genes. Genome Res. 12, 1846–1853 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Reich, D. E. et al. Human genome sequence variation and the influence of gene history, mutation and recombination. Nature Genet. 32, 135–142 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Hudson, R. R. The sampling distribution of linkage disequilibrium under an infinite allele model without selection. Genetics 109, 611–631 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Hudson, R. R. Two-locus sampling distributions and their application. Genetics 159, 1805–1817 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Nordborg, M. & Tavare, S. Linkage disequilibrium: what history has to tell us. Trends Genet. 18, 83–90 (2002).

    CAS  PubMed  Google Scholar 

  41. 41

    Weiss, K. M. & Clark, A. G. Linkage disequilibrium and the mapping of complex human traits. Trends Genet. 18, 19–24 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Laan, M. & Pääbo, S. Demographic history and linkage disequilibrium in human populations. Nature Genet. 17, 435–438 (1997).

    CAS  PubMed  Google Scholar 

  43. 43

    Kaessmann, H. et al. Extensive linkage disequilibrium in small human populations in Eurasia. Am. J. Hum. Genet. 70, 673–685 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    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, 320–323 (2000).

    CAS  PubMed  Google Scholar 

  45. 45

    Patil, N. et al. Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science 294, 1719–1723 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Dawson, E. et al. A first generation linkage disequilibrium map of human chromosome 22. Nature 418, 544–548 (2002).

    CAS  PubMed  Google Scholar 

  47. 47

    Johnson, G. C. et al. Haplotype tagging for the identification of common disease genes. Nature Genet. 29, 233–237 (2001). This paper explores how haplotype tag SNPs might aid future association studies.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Phillips, M. S. et al. Chromosome-wide distribution of haplotype blocks and the role of recombination hotspots. Nature Genet. 33, 382–387 (2003).

    CAS  PubMed  Google Scholar 

  49. 49

    Innan, H., Padhukasahasram, B. & Nordborg, M. The pattern of polymorphism on human chromosome 21. Genome Res. 13, 1158–1168 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Petes, T. D. Meiotic recombination hot spots and cold spots. Nature Rev. Genet. 2, 360–369 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    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, 861–869 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Yu, A. et al. Comparison of human genetic and sequence-based physical maps. Nature 409, 951–953 (2001).

    CAS  PubMed  Google Scholar 

  53. 53

    Kong, A. et al. A high-resolution recombination map of the human genome. Nature Genet. 31, 241–247 (2002).

    CAS  Google Scholar 

  54. 54

    Smith, R. A., Ho, P. J., Clegg, J. B., Kidd, J. R. & Thein, S. L. Recombination breakpoints in the human β-globin gene cluster. Blood 92, 4415–4421 (1998).

    CAS  PubMed  Google Scholar 

  55. 55

    Yip, S. P., Lovegrove, J. U., Rana, N. A., Hopkinson, D. A. & Whitehouse, D. B. Mapping recombination hotspots in human phosphoglucomutase (PGM1). Hum. Mol. Genet. 8, 1699–1706 (1999).

    CAS  PubMed  Google Scholar 

  56. 56

    Badge, R. M., Yardley, J., Jeffreys, A. J. & Armour, J. A. Crossover breakpoint mapping identifies a subtelomeric hotspot for male meiotic recombination. Hum. Mol. Genet. 9, 1239–1244 (2000).

    CAS  PubMed  Google Scholar 

  57. 57

    Li, H. H. et al. Amplification and analysis of DNA sequences in single human sperm and diploid cells. Nature 335, 414–417 (1988).

    CAS  PubMed  Google Scholar 

  58. 58

    Hubert, R., MacDonald, M., Gusella, J. & Arnheim, N. High resolution localization of recombination hot spots using sperm typing. Nature Genet. 7, 420–424 (1994).

    CAS  PubMed  Google Scholar 

  59. 59

    Jeffreys, A. J., Murray, J. & Neumann, R. High-resolution mapping of crossovers in human sperm defines a minisatellite-associated recombination hotspot. Mol. Cell 2, 267–273 (1998).

    CAS  PubMed  Google Scholar 

  60. 60

    Lien, S., Szyda, J. Schechinger, B., Rappold, G. & Arnheim, N. Evidence for heterogeneity in recombination in the human pseudoautosomal region: high resolution analysis by sperm typing and radiation-hybrid mapping. Am. J. Hum. Genet. 66, 557–566 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    May, C. A., Shone, A. C., Kalaydjieva, L., Sajantila, A. & Jeffreys, A. J. Crossover clustering and rapid decay of linkage disequilibrium in the Xp/Yp pseudoautosomal gene SHOX. Nature Genet. 31, 272–275 (2002).

    CAS  PubMed  Google Scholar 

  62. 62

    Schneider, J. A., Peto, T. E., Boone, R. A., Boyce, A. J. & Clegg, J. B. Direct measurement of the male recombination fraction in the human β-globin hot spot. Hum. Mol. Genet. 11, 207–215 (2002).

    CAS  PubMed  Google Scholar 

  63. 63

    Arnheim, N., Calabrese, P. & Nordborg, M. Hot and cold spots of recombination in the human genome: the reason we should find them and how this can be achieved. Am. J. Hum. Genet. 73, 5–16 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Nicolas, A., Treco, D., Schultes, N. P. & Szostak, J. W. An initiation site for meiotic gene conversion in the yeast Saccharomyces cerevisiae. Nature 338, 35–39 (1989).

    CAS  PubMed  Google Scholar 

  65. 65

    Jeffreys, A. J. & Neumann, R. Reciprocal crossover asymmetry and meiotic drive in a human recombination hot spot. Nature Genet. 31, 267–271.

  66. 66

    Boulton, A., Myers, R. S. & Redfield, R. J. The hotspot conversion paradox and the evolution of meiotic recombination. Proc. Natl Acad. Sci. USA 94, 8058–8063 (1997).

    CAS  PubMed  Google Scholar 

  67. 67

    True, J. R., Mercer, J. M. & Laurie, C. C. Differences in crossover frequency and distribution among three sibling species of Drosophila. Genetics 142, 507–523 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Rogers, J. et al. A genetic linkage map of the baboon (Papio hamadryas) genome based on human microsatellite polymorphisms. Genomics 67, 237–247 (2000).

    CAS  PubMed  Google Scholar 

  69. 69

    Kauppi, L., Sajantila, A. & Jeffreys, A. J. Recombination hotspots rather than population history dominate linkage disequilibrium in the MHC class II region. Hum. Mol. Genet. 12, 33–40 (2003).

    CAS  PubMed  Google Scholar 

  70. 70

    Carlson, C. S. et al. Additional SNPs and linkage-disequilibrium analysis in whole-genome association studies in humans. Nature Genet. 33, 518–521 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Wall, J. D. & Pritchard, J. K. Assessing the performance of the haplotype block model of linkage disequilibrium. Am. J. Hum. Genet. (in the press).

  72. 72

    Wang, N. Akey, J. M., Zhang, K., Chakraborty, R. & Jin, L. Distribution of recombination crossovers and the origin of haplotype blocks: the interplay of population history, recombination, and mutation. Am. J. Hum. Genet. 71, 1227–1234 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Schwartz, R., Halldorsson, B. V., Bafna, V., Clark, A. G. & Istrail, S. Robustness of inference of haplotype block structure. J. Comp. Biol. 10, 13–19 (2003).

    CAS  Google Scholar 

  74. 74

    Pluzhnikov, A., Di Rienzo, A. & Hudson, R. R. Inferences about human demography based on multilocus analyses of noncoding sequences. Genetics 161, 1209–1218 (2002).

    PubMed  PubMed Central  Google Scholar 

  75. 75

    Cann, R. L., Stoneking, M. & Wilson, A. C. Mitochondrial DNA and human evolution. Nature 325, 31–36 (1987).

    CAS  Google Scholar 

  76. 76

    Stringer, C. B. & Andrews, P. Genetic and fossil evidence for the origin of modern humans. Science 239, 1263–1268 (1988).

    CAS  Google Scholar 

  77. 77

    Wall, J. D., Andolfatto, P. & Przeworski, M. Testing models of selection and demography in Drosophila simulans. Genetics 162, 203–216 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Stumpf, M. P. & Goldstein, D. B. Demography, recombination hotspot intensity, and the block structure of linkage disequilibrium. Curr. Biol. 13, 1–8 (2003).

    CAS  PubMed  Google Scholar 

  79. 79

    Rioux, J. D. et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nature Genet. 29, 223–228 (2001).

    CAS  Google Scholar 

  80. 80

    McPeek, M. S. & Strahs, A. Assessment of linkage disequilibrium by the decay of haplotype sharing, with application to fine-scale genetic mapping. Am. J. Hum. Genet. 65, 858–875 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Morris, A. P., Whittaker, J. C. & Balding, D. J. Fine-scale mapping of disease loci via shattered coalescent modeling of genealogies. Am. J. Hum. Genet. 70, 686–707 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Lewontin, R. C. The interaction of selection and linkage. I. General considerations: heterotic models. Genetics 49, 49–67 (1964).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Hudson, R. R. & Kaplan, N. L. Statistical properties of the number of recombination events in the history of a sample of DNA sequences. Genetics 111, 147–164 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Long, A. D. & Langley, C. H. The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits. Genome Res. 9, 720–731 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Hudson, R. R. Estimating the recombination parameter of a finite population model without selection. Genet. Res. 50, 245–250 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    McVean, G., Awadalla, P. & Fearnhead, P. A coalescent-based method for detecting and estimating recombination from gene sequences. Genetics 160, 1231–1241 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Fearnhead, P. & Donnelly, P. Estimating recombination rates from population genetic data. Genetics 159, 1299–1318 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Wall, J. D. A comparison of estimators of the population recombination rate. Mol. Biol. Evol. 17, 156–163 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Kuhner, M. K., Yamato, J. & Felsenstein, J. Maximum likelihood estimation of recombination rates from population data. Genetics 156, 1393–1401 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Griffiths, R. C. & Marjoram, P. Ancestral inference from samples of DNA sequences with recombination. J. Comp. Biol. 3, 479–502 (1996).

    CAS  Google Scholar 

  91. 91

    Zhang, K., Deng, M., Chen, T., Waterman, M. S. & Sun, F. A dynamic programming algorithm for haplotype block partitioning. Proc. Natl Acad. Sci. USA 99, 7335–7339 (2002).

    CAS  PubMed  Google Scholar 

  92. 92

    Zhang, K., Calabrese, P., Nordborg, M. & Sun, F. Haplotype block structure and its applications to association studies: power and study designs. Am. J. Hum. Genet. 71, 1386–1394 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Ayres, K. L. & Balding, D. J. Measuring gametic disequilibrium from multilocus data. Genetics 157, 413–423 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Vermeire, S. et al. CARD15 genetic variation in a Quebec populations: prevalence, genotype-phenotype relationship, and haplotype structure. Am. J. Hum. Genet. 71, 74–83 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Pritchard, J. K. & Cox, N. J. The allelic architecture of human disease genes: common disease-common variant... or not? Hum. Mol. Genet. 11, 2417–2423 (2002).

    CAS  PubMed  Google Scholar 

  96. 96

    Pritchard, J. K. Are rare variants responsible for susceptibility to complex diseases? Am. J. Hum. Genet. 69, 124–137 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Hudson, R. R. Properties of a neutral allele model with intragenic recombination. Theor. Popul. Biol. 23, 183–201 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Akey, J. M., Zhang, K., Xiong, M. & Jin, L. The effect of single nucleotide polymorphism identification strategies on estimates of linkage disequilibrium. Mol. Biol. Evol. 20, 232–242 (2003).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank D. Nickerson, S. Gabriel, M. Daly, D. Altshuler and S. Schaffner for help in accessing and interpreting their data, and A. DiRienzo and S. Zoellner for discussions. We also thank M. Przeworski and the anonymous reviewers for comments on an earlier version of this manuscript. This work was supported by a National Institutes of Health grant to J.K.P.

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Jonathan K. Pritchard's laboratory

UW-FHCRC Variation Discovery Resource website

Glossary

BOTTLENECK

A temporary reduction in population size that causes the loss of genetic variation.

ADMIXTURE

The mixture of two or more genetically distinct populations.

PAIRWISE LINKAGE DISEQUILIBRIUM

(Pairwise LD). The strength of association between alleles at two different markers.

PRE-ASCERTAINED SINGLE NUCLEOTIDE POLYMORPHISMS

(Pre-ascertained SNPs). SNPs that have already been detected in previous studies, usually from an extremely small sample of chromosomes.

UNPHASED DIPLOID DATA

Sequence data in which the phase of double heterozygotes was not determined.

BAYESIAN APPROACH

A statistical approach that, given a set of assumptions about the underlying model, can provide a rigorous assessment of uncertainty.

COALESCENT SIMULATION

A method of simulating data under a population genetic model.

ASCERTAINMENT BIAS

The bias in patterns of variation that results from using pre-ascertained SNPs.

GENE CONVERSION

Recombination that involves the nonreciprocal transfer of information from one sister chromatid to another.

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Wall, J., Pritchard, J. Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet 4, 587–597 (2003). https://doi.org/10.1038/nrg1123

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