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. 2003 Dec;165(4):2213–2233. doi: 10.1093/genetics/165.4.2213

Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data.

Na Li 1, Matthew Stephens 1
PMCID: PMC1462870  PMID: 14704198

Abstract

We introduce a new statistical model for patterns of linkage disequilibrium (LD) among multiple SNPs in a population sample. The model overcomes limitations of existing approaches to understanding, summarizing, and interpreting LD by (i) relating patterns of LD directly to the underlying recombination process; (ii) considering all loci simultaneously, rather than pairwise; (iii) avoiding the assumption that LD necessarily has a "block-like" structure; and (iv) being computationally tractable for huge genomic regions (up to complete chromosomes). We examine in detail one natural application of the model: estimation of underlying recombination rates from population data. Using simulation, we show that in the case where recombination is assumed constant across the region of interest, recombination rate estimates based on our model are competitive with the very best of current available methods. More importantly, we demonstrate, on real and simulated data, the potential of the model to help identify and quantify fine-scale variation in recombination rate from population data. We also outline how the model could be useful in other contexts, such as in the development of more efficient haplotype-based methods for LD mapping.

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Selected References

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  1. Clark A. G. Inference of haplotypes from PCR-amplified samples of diploid populations. Mol Biol Evol. 1990 Mar;7(2):111–122. doi: 10.1093/oxfordjournals.molbev.a040591. [DOI] [PubMed] [Google Scholar]
  2. Clark A. G., Weiss K. M., Nickerson D. A., Taylor S. L., Buchanan A., Stengård J., Salomaa V., Vartiainen E., Perola M., Boerwinkle E. Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase. Am J Hum Genet. 1998 Aug;63(2):595–612. doi: 10.1086/301977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Daly M. J., Rioux J. D., Schaffner S. F., Hudson T. J., Lander E. S. High-resolution haplotype structure in the human genome. Nat Genet. 2001 Oct;29(2):229–232. doi: 10.1038/ng1001-229. [DOI] [PubMed] [Google Scholar]
  4. Ewens W. J. The sampling theory of selectively neutral alleles. Theor Popul Biol. 1972 Mar;3(1):87–112. doi: 10.1016/0040-5809(72)90035-4. [DOI] [PubMed] [Google Scholar]
  5. Fearnhead P., Donnelly P. Estimating recombination rates from population genetic data. Genetics. 2001 Nov;159(3):1299–1318. doi: 10.1093/genetics/159.3.1299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Frisse L., Hudson R. R., Bartoszewicz A., Wall J. D., Donfack J., Di Rienzo A. Gene conversion and different population histories may explain the contrast between polymorphism and linkage disequilibrium levels. Am J Hum Genet. 2001 Aug 29;69(4):831–843. doi: 10.1086/323612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Griffiths R. C., Marjoram P. Ancestral inference from samples of DNA sequences with recombination. J Comput Biol. 1996 Winter;3(4):479–502. doi: 10.1089/cmb.1996.3.479. [DOI] [PubMed] [Google Scholar]
  8. Hammer M. F., Karafet T., Rasanayagam A., Wood E. T., Altheide T. K., Jenkins T., Griffiths R. C., Templeton A. R., Zegura S. L. Out of Africa and back again: nested cladistic analysis of human Y chromosome variation. Mol Biol Evol. 1998 Apr;15(4):427–441. doi: 10.1093/oxfordjournals.molbev.a025939. [DOI] [PubMed] [Google Scholar]
  9. Harding R. M., Fullerton S. M., Griffiths R. C., Bond J., Cox M. J., Schneider J. A., Moulin D. S., Clegg J. B. Archaic African and Asian lineages in the genetic ancestry of modern humans. Am J Hum Genet. 1997 Apr;60(4):772–789. [PMC free article] [PubMed] [Google Scholar]
  10. Hey J., Wakeley J. A coalescent estimator of the population recombination rate. Genetics. 1997 Mar;145(3):833–846. doi: 10.1093/genetics/145.3.833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hudson R. R. Estimating the recombination parameter of a finite population model without selection. Genet Res. 1987 Dec;50(3):245–250. doi: 10.1017/s0016672300023776. [DOI] [PubMed] [Google Scholar]
  12. Hudson R. R., Kaplan N. L. Statistical properties of the number of recombination events in the history of a sample of DNA sequences. Genetics. 1985 Sep;111(1):147–164. doi: 10.1093/genetics/111.1.147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hudson R. R. Properties of a neutral allele model with intragenic recombination. Theor Popul Biol. 1983 Apr;23(2):183–201. doi: 10.1016/0040-5809(83)90013-8. [DOI] [PubMed] [Google Scholar]
  14. Hudson R. R. Two-locus sampling distributions and their application. Genetics. 2001 Dec;159(4):1805–1817. doi: 10.1093/genetics/159.4.1805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hudson Richard R. Generating samples under a Wright-Fisher neutral model of genetic variation. Bioinformatics. 2002 Feb;18(2):337–338. doi: 10.1093/bioinformatics/18.2.337. [DOI] [PubMed] [Google Scholar]
  16. Jeffreys A. J., Kauppi L., Neumann R. Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet. 2001 Oct;29(2):217–222. doi: 10.1038/ng1001-217. [DOI] [PubMed] [Google Scholar]
  17. 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. 2000 Mar 22;9(5):725–733. doi: 10.1093/hmg/9.5.725. [DOI] [PubMed] [Google Scholar]
  18. Jeffreys Alec J., Neumann Rita. Reciprocal crossover asymmetry and meiotic drive in a human recombination hot spot. Nat Genet. 2002 Jun 24;31(3):267–271. doi: 10.1038/ng910. [DOI] [PubMed] [Google Scholar]
  19. Johnson G. C., Esposito L., Barratt B. J., Smith A. N., Heward J., Di Genova G., Ueda H., Cordell H. J., Eaves I. A., Dudbridge F. Haplotype tagging for the identification of common disease genes. Nat Genet. 2001 Oct;29(2):233–237. doi: 10.1038/ng1001-233. [DOI] [PubMed] [Google Scholar]
  20. Kruglyak L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet. 1999 Jun;22(2):139–144. doi: 10.1038/9642. [DOI] [PubMed] [Google Scholar]
  21. Kuhner M. K., Yamato J., Felsenstein J. Maximum likelihood estimation of recombination rates from population data. Genetics. 2000 Nov;156(3):1393–1401. doi: 10.1093/genetics/156.3.1393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Liu J. S., Sabatti C., Teng J., Keats B. J., Risch N. Bayesian analysis of haplotypes for linkage disequilibrium mapping. Genome Res. 2001 Oct;11(10):1716–1724. doi: 10.1101/gr.194801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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. 1999 Sep;65(3):858–875. doi: 10.1086/302537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. McVean Gil, Awadalla Philip, Fearnhead Paul. A coalescent-based method for detecting and estimating recombination from gene sequences. Genetics. 2002 Mar;160(3):1231–1241. doi: 10.1093/genetics/160.3.1231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Morris A. P., Whittaker J. C., Balding D. J. Bayesian fine-scale mapping of disease loci, by hidden Markov models. Am J Hum Genet. 2000 Jun 1;67(1):155–169. doi: 10.1086/302956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nickerson D. A., Taylor S. L., Weiss K. M., Clark A. G., Hutchinson R. G., Stengård J., Salomaa V., Vartiainen E., Boerwinkle E., Sing C. F. DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nat Genet. 1998 Jul;19(3):233–240. doi: 10.1038/907. [DOI] [PubMed] [Google Scholar]
  27. Nielsen R. Estimation of population parameters and recombination rates from single nucleotide polymorphisms. Genetics. 2000 Feb;154(2):931–942. doi: 10.1093/genetics/154.2.931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Olivier M., Bustos V. I., Levy M. R., Smick G. A., Moreno I., Bushard J. M., Almendras A. A., Sheppard K., Zierten D. L., Aggarwal A. Complex high-resolution linkage disequilibrium and haplotype patterns of single-nucleotide polymorphisms in 2.5 Mb of sequence on human chromosome 21. Genomics. 2001 Nov;78(1-2):64–72. doi: 10.1006/geno.2001.6646. [DOI] [PubMed] [Google Scholar]
  29. Pritchard J. K., Przeworski M. Linkage disequilibrium in humans: models and data. Am J Hum Genet. 2001 Jun 14;69(1):1–14. doi: 10.1086/321275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pritchard J. K., Stephens M., Donnelly P. Inference of population structure using multilocus genotype data. Genetics. 2000 Jun;155(2):945–959. doi: 10.1093/genetics/155.2.945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Stephens M., Smith N. J., Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001 Mar 9;68(4):978–989. doi: 10.1086/319501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Templeton A. R., Clark A. G., Weiss K. M., Nickerson D. A., Boerwinkle E., Sing C. F. Recombinational and mutational hotspots within the human lipoprotein lipase gene. Am J Hum Genet. 2000 Jan;66(1):69–83. doi: 10.1086/302699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wakeley J. Using the variance of pairwise differences to estimate the recombination rate. Genet Res. 1997 Feb;69(1):45–48. doi: 10.1017/s0016672396002571. [DOI] [PubMed] [Google Scholar]
  34. Wang Ning, Akey Joshua M., Zhang Kun, Chakraborty Ranajit, Jin Li. Distribution of recombination crossovers and the origin of haplotype blocks: the interplay of population history, recombination, and mutation. Am J Hum Genet. 2002 Oct 15;71(5):1227–1234. doi: 10.1086/344398. [DOI] [PMC free article] [PubMed] [Google Scholar]

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