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. 2004 Aug;167(4):2067–2081. doi: 10.1534/genetics.103.021584

Application of coalescent methods to reveal fine-scale rate variation and recombination hotspots.

Paul Fearnhead 1, Rosalind M Harding 1, Julie A Schneider 1, Simon Myers 1, Peter Donnelly 1
PMCID: PMC1470991  PMID: 15342541

Abstract

There has been considerable recent interest in understanding the way in which recombination rates vary over small physical distances, and the extent of recombination hotspots, in various genomes. Here we adapt, apply, and assess the power of recently developed coalescent-based approaches to estimating recombination rates from sequence polymorphism data. We apply full-likelihood estimation to study rate variation in and around a well-characterized recombination hotspot in humans, in the beta-globin gene cluster, and show that it provides similar estimates, consistent with those from sperm studies, from two populations deliberately chosen to have different demographic and selectional histories. We also demonstrate how approximate-likelihood methods can be used to detect local recombination hotspots from genomic-scale SNP data. In a simulation study based on 80 100-kb regions, these methods detect 43 out of 60 hotspots (ranging from 1 to 2 kb in size), with only two false positives out of 2000 subregions that were tested for the presence of a hotspot. Our study suggests that new computational tools for sophisticated analysis of population diversity data are valuable for hotspot detection and fine-scale mapping of local recombination rates.

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Selected References

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  1. Abecasis G. R., Noguchi E., Heinzmann A., Traherne J. A., Bhattacharyya S., Leaves N. I., Anderson G. G., Zhang Y., Lench N. J., Carey A. Extent and distribution of linkage disequilibrium in three genomic regions. Am J Hum Genet. 2000 Nov 13;68(1):191–197. doi: 10.1086/316944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C. R., Lim E. P., Kalyanaraman N. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet. 1999 Jul;22(3):231–238. doi: 10.1038/10290. [DOI] [PubMed] [Google Scholar]
  3. Chakravarti A., Buetow K. H., Antonarakis S. E., Waber P. G., Boehm C. D., Kazazian H. H. Nonuniform recombination within the human beta-globin gene cluster. Am J Hum Genet. 1984 Nov;36(6):1239–1258. [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Dawson Elisabeth, Abecasis Gonçalo R., Bumpstead Suzannah, Chen Yuan, Hunt Sarah, Beare David M., Pabial Jagjit, Dibling Thomas, Tinsley Emma, Kirby Susan. A first-generation linkage disequilibrium map of human chromosome 22. Nature. 2002 Jul 10;418(6897):544–548. doi: 10.1038/nature00864. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Fearnhead Paul. Consistency of estimators of the population-scaled recombination rate. Theor Popul Biol. 2003 Aug;64(1):67–79. doi: 10.1016/s0040-5809(03)00041-8. [DOI] [PubMed] [Google Scholar]
  8. Flint J., Harding R. M., Boyce A. J., Clegg J. B. The population genetics of the haemoglobinopathies. Baillieres Clin Haematol. 1998 Mar;11(1):1–51. doi: 10.1016/s0950-3536(98)80069-3. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. Griffiths R. C., Tavaré S. Unrooted genealogical tree probabilities in the infinitely-many-sites model. Math Biosci. 1995 May;127(1):77–98. doi: 10.1016/0025-5564(94)00044-z. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. 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]
  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. 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]
  16. 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]
  17. Jeffreys Alec J., May Celia A. Intense and highly localized gene conversion activity in human meiotic crossover hot spots. Nat Genet. 2004 Jan 4;36(2):151–156. doi: 10.1038/ng1287. [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. Jorde L. B. Linkage disequilibrium and the search for complex disease genes. Genome Res. 2000 Oct;10(10):1435–1444. doi: 10.1101/gr.144500. [DOI] [PubMed] [Google Scholar]
  20. Kong Augustine, Gudbjartsson Daniel F., Sainz Jesus, Jonsdottir Gudrun M., Gudjonsson Sigurjon A., Richardsson Bjorgvin, Sigurdardottir Sigrun, Barnard John, Hallbeck Bjorn, Masson Gisli. A high-resolution recombination map of the human genome. Nat Genet. 2002 Jun 10;31(3):241–247. doi: 10.1038/ng917. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Kuhner M. K., Yamato J., Felsenstein J. Estimating effective population size and mutation rate from sequence data using Metropolis-Hastings sampling. Genetics. 1995 Aug;140(4):1421–1430. doi: 10.1093/genetics/140.4.1421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Li Na, Stephens Matthew. Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data. Genetics. 2003 Dec;165(4):2213–2233. doi: 10.1093/genetics/165.4.2213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Li W. H., Sadler L. A. Low nucleotide diversity in man. Genetics. 1991 Oct;129(2):513–523. doi: 10.1093/genetics/129.2.513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Myers Simon R., Griffiths Robert C. Bounds on the minimum number of recombination events in a sample history. Genetics. 2003 Jan;163(1):375–394. doi: 10.1093/genetics/163.1.375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nachman Michael W. Variation in recombination rate across the genome: evidence and implications. Curr Opin Genet Dev. 2002 Dec;12(6):657–663. doi: 10.1016/s0959-437x(02)00358-1. [DOI] [PubMed] [Google Scholar]
  28. Petes T. D. Meiotic recombination hot spots and cold spots. Nat Rev Genet. 2001 May;2(5):360–369. doi: 10.1038/35072078. [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. Przeworski M., Wall J. D. Why is there so little intragenic linkage disequilibrium in humans? Genet Res. 2001 Apr;77(2):143–151. doi: 10.1017/s0016672301004967. [DOI] [PubMed] [Google Scholar]
  31. Reich D. E., Cargill M., Bolk S., Ireland J., Sabeti P. C., Richter D. J., Lavery T., Kouyoumjian R., Farhadian S. F., Ward R. Linkage disequilibrium in the human genome. Nature. 2001 May 10;411(6834):199–204. doi: 10.1038/35075590. [DOI] [PubMed] [Google Scholar]
  32. Rogers A. R., Jorde L. B. Genetic evidence on modern human origins. Hum Biol. 1995 Feb;67(1):1–36. [PubMed] [Google Scholar]
  33. Schneider Julie A., Peto Timothy E. A., Boone Reginald A., Boyce Anthony J., Clegg John B. Direct measurement of the male recombination fraction in the human beta-globin hot spot. Hum Mol Genet. 2002 Feb 1;11(3):207–215. doi: 10.1093/hmg/11.3.207. [DOI] [PubMed] [Google Scholar]
  34. Sherry S. T., Rogers A. R., Harpending H., Soodyall H., Jenkins T., Stoneking M. Mismatch distributions of mtDNA reveal recent human population expansions. Hum Biol. 1994 Oct;66(5):761–775. [PubMed] [Google Scholar]
  35. Smith R. A., Ho P. J., Clegg J. B., Kidd J. R., Thein S. L. Recombination breakpoints in the human beta-globin gene cluster. Blood. 1998 Dec 1;92(11):4415–4421. [PubMed] [Google Scholar]
  36. 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]
  37. Stephens Matthew, Donnelly Peter. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003 Oct 20;73(5):1162–1169. doi: 10.1086/379378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wall Jeffrey D., Frisse Linda A., Hudson Richard R., Di Rienzo Anna. Comparative linkage-disequilibrium analysis of the beta-globin hotspot in primates. Am J Hum Genet. 2003 Nov 18;73(6):1330–1340. doi: 10.1086/380311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wall Jeffrey D., Pritchard Jonathan K. Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet. 2003 Aug;4(8):587–597. doi: 10.1038/nrg1123. [DOI] [PubMed] [Google Scholar]
  40. Weatherall D. J., Clegg J. B. Thalassemia--a global public health problem. Nat Med. 1996 Aug;2(8):847–849. doi: 10.1038/nm0896-847. [DOI] [PubMed] [Google Scholar]
  41. Webster Matthew T., Clegg John B., Harding Rosalind M. Common 5' beta-globin RFLP haplotypes harbour a surprising level of ancestral sequence mosaicism. Hum Genet. 2003 May 8;113(2):123–139. doi: 10.1007/s00439-003-0954-0. [DOI] [PubMed] [Google Scholar]

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