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Recombination Hotspots in Nonallelic Homologous Recombination

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Genomic Disorders

Abstract

Rearrangement breakpoints resulting from nonallelic homologous recombination (NAHR) are typically clustered within small, well-defined portions of the segmental duplications that promote the rearrangement. These NAHR “hotspots” have been identified in every NAHR-promoted rearrangement in which breakpoint junctions have been sequenced in sufficient numbers. Enhancement of recombinatorial activity in NAHR hotspots varies from 3 to 237 times more than in the surrounding “cold” duplicated sequence. NAHR hotspots share many features in common with allelic homologous recombination (AHR) hotspots. Both AHR and NAHR hotspots appear to be relatively small (<2 kb) and are initiated by double-strand breaks. Gene conversion events as well as crossovers are enhanced at NAHR hotspots. Recent work has improved our understanding of the origins of NAHR and AHR hotspots, with both appearing to be relatively short-lived phenomena. Our present understanding of NAHR hotspots comes from a limited number of locus-specific studies. In the future, we can expect genome-wide analyses to provide many further insights.

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References

  1. Jeffreys AJ, Kauppi L, Neumann R. Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet 2001;29:217–222.

    Article  PubMed  CAS  Google Scholar 

  2. Reiter LT, Murakami T, Koeuth T, et al. A recombination hotspot responsible for two inherited peripheral neuropathies is located near a mariner transposon-like element. Nat Genet 1996;12:288–297.

    Article  PubMed  CAS  Google Scholar 

  3. Han LL, Keller MP, Navidi W, Chance PF, Arnheim N. Unequal exchange at the Charcot-Marie-Tooth disease type 1A recombination hot-spot is not elevated above the genome average rate. Hum Mol Genet 2000;9:1881–1889.

    Article  PubMed  CAS  Google Scholar 

  4. Pritchard JK, Przeworski M. Linkage disequilibrium in humans: models and data. Am J Hum Genet 2001;69:1–14.

    Article  PubMed  CAS  Google Scholar 

  5. Dawson E, Abecasis GR, Bumpstead S, et al. A first-generation linkage disequilibrium map of human chromosome 22. Nature 2002;418:544–548.

    Article  PubMed  CAS  Google Scholar 

  6. Gabriel SB, Salomon R, Pelet A, et al. The structure of haplotype blocks in the human genome. Science 2002;296:2225–2229.

    Article  PubMed  CAS  Google Scholar 

  7. The International HapMap Consortium. The International HapMap Project. Nature 2003;426:789–796.

    Article  CAS  Google Scholar 

  8. Stephens JC, Reich DE, Goldstein DB, et al. Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes. Am J Hum Genet 1998;62:1507–1515.

    Article  PubMed  CAS  Google Scholar 

  9. Mecsas J, Franklin G, Kuziel WA, Brubaker RR, Falkow S, Mosier DE. Evolutionary genetics: CCR5 mutation and plague protection. Nature 2004;427:606.

    Article  PubMed  CAS  Google Scholar 

  10. Galvani AP, Slatkin M. Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta 32 HIV-resistance allele. Proc Natl Acad Sci USA 2003;100:15,276–15,279.

    Article  PubMed  CAS  Google Scholar 

  11. Kurahashi H, Emanuel BS. Long AT-rich palindromes and the constitutional t(11;22) breakpoint. Hum Mol Genet 2001;10:2605–2617.

    Article  PubMed  CAS  Google Scholar 

  12. Fredman D, White SJ, Potter S, Eichler EE, Den Dunnen JT, Brookes AJ. (2004) Complex SNP-related sequence variation in segmental genome duplications. Nat Genet 2004;36:861–866.

    Article  PubMed  CAS  Google Scholar 

  13. 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 2003;73:5–16.

    Article  PubMed  CAS  Google Scholar 

  14. Jeffreys AJ, Murray J, Neumann R. High-resolution mapping of crossovers in human sperm defines a minisatellite-associated recombination hotspot. Molecular Cell 1998;2:267–273.

    Article  PubMed  CAS  Google Scholar 

  15. Crawford DC, Bhangale T, Li N, et al. Evidence for substantial fine-scale variation in recombination rates across the human genome. Nat Genet 2004;36:700–706.

    Article  PubMed  CAS  Google Scholar 

  16. McVean GA, Myers SR, Hunt S, Deloukas P, Bentley DR, Donnelly P. The fine-scale structure of recombination rate variation in the human genome. Science 2004;304:581–584.

    Article  PubMed  CAS  Google Scholar 

  17. de Massy B. Distribution of meiotic recombination sites. Trends Genet 2003;19:514–522.

    Article  PubMed  CAS  Google Scholar 

  18. Lupski JR. Hotspots of homologous recombination in the human genome: not all homologous sequences are equal. Genome Biology 2004;5:242.

    Article  PubMed  Google Scholar 

  19. Kauppi L, Jeffreys AJ, Keeney S. Where the crossovers are: recombination distributions in mammals. Nat Rev Genet 2004;5:413–424.

    Article  PubMed  CAS  Google Scholar 

  20. Lopes J, Ravise N, Vandenberghe A, et al. Fine mapping of de novo CMT1A and HNPP rearrangements within CMT1 A-REPs evidences two distinct sex-dependent mechanisms and candidate sequences involved in recombination. Hum Mol Genet 1998;7:141–148.

    Article  PubMed  CAS  Google Scholar 

  21. Palau F, Lofgren A, De Jonghe P, et al. Origin of the de novo duplication in Charcot-Marie-Tooth disease type 1A: unequal nonsister chromatid exchange during spermatogenesis. Hum Mol Genet 1993;2:2031–2035.

    Article  PubMed  CAS  Google Scholar 

  22. Jeffreys AJ, Ritchie A, Neumann R. High resolution analysis of haplotype diversity and meiotic crossover in the human TAP2 recombination hotspot. Hum Mol Genet 2000;9:725–733.

    Article  PubMed  CAS  Google Scholar 

  23. Kehrer-Sawatzki H, Kluwe L, Sandig C, et al. High frequency of mosaicism among patients with neurofibro-matosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene. Am J Hum Genet 2004;75:410–423.

    Article  PubMed  CAS  Google Scholar 

  24. Szostak JW, Orr-Weaver TL, Rothstein RJ, Stahl FW. The double-strand-break repair model for recombination. Cell 1983;33:25–35.

    Article  PubMed  CAS  Google Scholar 

  25. Baudat F, Nicolas A. Clustering of meiotic double-strand breaks on yeast chromosome III. Proc Natl Acad Sci USA 1997;94:5213–5218.

    Article  PubMed  CAS  Google Scholar 

  26. Pecina A, Smith KN, Mezard C, Murakami H, Ohta K, Nicolas A. Targeted stimulation of meiotic recombination. Cell 2002;111:173–184.

    Article  PubMed  CAS  Google Scholar 

  27. Ben-Aroya S, Mieczkowski PA, Petes TD, Kupiec M. The compact chromatin structure of a Ty repeated sequence suppresses recombination hotspot activity in Saccharomyces cerevisiae. Mol Cell 2004;15:221–231.

    Article  PubMed  CAS  Google Scholar 

  28. Petes TD. Meiotic recombination hot spots and cold spots. Nat Rev Genet 2001;2:360–369.

    Article  PubMed  CAS  Google Scholar 

  29. Qin J, Richardson LL, Jasin M, Handel MA, Arnheim N. Mouse strains with an active H2-Ea meiotic recombination hot spot exhibit increased levels of H2-Ea-specific DNA breaks in testicular germ cells. Mol Cell Biol 2004;24:1655–1666.

    Article  PubMed  CAS  Google Scholar 

  30. Jeffreys AJ, May CA. Intense and highly localized gene conversion activity in human meiotic crossover hot spots. Nat Genet 2004;36:151–156.

    Article  PubMed  CAS  Google Scholar 

  31. Moens PB, Kolas NK, Tarsounas M, Marcon E, Cohen PE, Spyropoulos B. The time course and chromosomal localization of recombination-related proteins at meiosis in the mouse are compatible with models that can resolve the early DNA-DNA interactions without reciprocal recombination. J Cell Sci 2002;115:1611–1622.

    PubMed  CAS  Google Scholar 

  32. Yauk CL, Bois PR, Jeffreys AJ. High-resolution sperm typing of meiotic recombination in the mouse MHC Ebeta gene. Embo J 2003;22:1389–1397.

    Article  PubMed  CAS  Google Scholar 

  33. Rozen S, Skaletsky H, Marszalek JD, et al. Abundant gene conversion between arms of palindromes in human and ape Y chromosomes. Nature 2003;423:873–876.

    Article  PubMed  CAS  Google Scholar 

  34. Timmerman V, Rautenstrauss B, Reiter LT, et al. Detection of the CMT1A/HNPP recombination hotspot in unrelated patients of European descent. J Med Genet 1997;34:43–49.

    Article  PubMed  CAS  Google Scholar 

  35. Warner LE, Reiter LT, Murakami T, Lupski JR. Molecular mechanisms for Charcot-Marie-Tooth disease and related demyelinating peripheral neuropathies. Cold Spring Harb Symp Quant Biol 1996;61:659–671.

    PubMed  CAS  Google Scholar 

  36. Kauppi L, Sajantila A, Jeffreys AJ. Recombination hotspots rather than population history dominate linkage disequilibrium in the MHC class II region. Hum Mol Genet 2003;12:33–40.

    Article  PubMed  CAS  Google Scholar 

  37. Ptak SE, Roeder AD, Stephens M, Gilad Y, Paabo S, Przeworski M. Absence of the TAP2 human recombination hotspot in chimpanzees. PLoS Biol 2004;2:849–855.

    Article  CAS  Google Scholar 

  38. Boulton A, Myers RS, Redfield RJ. The hotspot conversion paradox and the evolution of meiotic recombination. Proc Natl Acad Sci USA 1997;94:8058–8063.

    Article  PubMed  CAS  Google Scholar 

  39. Jeffreys AJ, Neumann R. Reciprocal crossover asymmetry and meiotic drive in a human recombination hot spot. Nat Genet 2002;31:267–271.

    Article  PubMed  CAS  Google Scholar 

  40. Monckton DG, Neumann R, Guram T, et al. Minisatellite mutation-rate variation associated with a flanking DNA sequence polymorphism. Nat Genet 1994;8:162–170.

    Article  PubMed  CAS  Google Scholar 

  41. Hurles ME, Willey D, Matthews L, Hussain SS. Origins of chromosomal rearrangement hotspots in the human genome: evidence from the AZFa deletion hotspots. Genome Biol 2004;5:R55.

    Article  PubMed  Google Scholar 

  42. Hey J. What’s so hot about recombination hotspots? PLoS Biol 2004;2:730–733.

    Article  CAS  Google Scholar 

  43. Waldman AS, Liskay RM. Dependence of intrachromosomal recombination in mammalian cells on uninterrupted homology. Mol Cell Biol 1988;8:5350–5357.

    PubMed  CAS  Google Scholar 

  44. Hurles ME, Jobling MA. A singular chromosome. Nat Genet 2003;34:246–247.

    Article  PubMed  CAS  Google Scholar 

  45. Bailey JA, Gu Z, Clark RA, et al. Recent segmental duplications in the human genome. Science 2002;297:1003–1007.

    Article  PubMed  CAS  Google Scholar 

  46. May CA, Shone AC, Kalaydjieva L, Sajantila A, Jeffreys AJ. Crossover clustering and rapid decay of linkage disequilibrium in the Xp/Yp pseudoautosomal gene SHOX. Nat Genet 2002;31:272–275.

    Article  PubMed  CAS  Google Scholar 

  47. Kamp C, Hirschmann P, Voss H, Huellen K, Vogt PH. Two long homologous retroviral sequence blocks in proximal Yq1 1 cause AZFa microdeletions as a result of intrachromosomal recombination events. Hum Mol Genet 2000;9:2563–2572.

    Article  PubMed  CAS  Google Scholar 

  48. Blanco P, Shlumukova M, Sargent CA, Jobling MA, Affara N, Hurles ME. Divergent outcomes of intrachromosomal recombination on the human Y chromosome: male infertility and recurrent polymorphism. J Med Genet 2000;37:752–758.

    Article  PubMed  CAS  Google Scholar 

  49. Bosch E, Jobling MA. Duplications of the AZFa region of the human Y chromosome are mediated by homologous recombination between HERVs and are compatible with male fertility. Hum Mol Genet 2003;12:341–347.

    Article  PubMed  CAS  Google Scholar 

  50. Sun C, Skaletsky H, Rozen S, et al. Deletion of azoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 proviruses. Hum Mol Genet 2000;9:2291–2296.

    Article  PubMed  CAS  Google Scholar 

  51. Repping S, Skaletsky H, Lange J, et al. Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure. Am J Hum Genet 2002;71:906–922.

    Article  PubMed  Google Scholar 

  52. Lopez-Correa C, Dorschner M, Brems H, et al. Recombination hotspot in NF1 microdeletion patients. Hum Mol Genet 2001;10:1387–1392.

    Article  PubMed  CAS  Google Scholar 

  53. Reiter LT, Hastings PJ, Nelis E, De Jonghe P, Van Broeckhoven C, Lupski JR. Human meiotic recombination products revealed by sequencing a hotspot for homologous strand exchange in multiple HNPP deletion patients. Am J Hum Genet 1998;62:1023–1033.

    Article  PubMed  CAS  Google Scholar 

  54. Bi W, Park SS, Shaw CJ, Withers MA, Patel PI, Lupski JR. Reciprocal crossovers and a positional preference for strand exchange in recombination events resulting in deletion or duplication of chromosome 17p1 1.2. Am J Hum Genet 2003;73:1302–1315.

    Article  PubMed  CAS  Google Scholar 

  55. Shaw CJ, Withers MA, Lupski JR. Uncommon deletions of the Smith-Magenis syndrome region can be recurrent when alternate low-copy repeats act as homologous recombination substrates. Am J Hum Genet 2004;75:75–81.

    Article  PubMed  CAS  Google Scholar 

  56. Bayes M, Magano LF, Rivera N, Flores R, Perez Jurado LA. Mutational mechanisms of Williams-Beuren syndrome deletions. Am J Hum Genet 2003;73:131–151.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. The Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK

    Matthew E. Hurles PhD

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

    James R. Lupski MD, PhD

  3. Department of Pediatrics, Baylor College of Medicine, Houston, TX

    James R. Lupski MD, PhD

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  1. Matthew E. Hurles PhD
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  2. James R. Lupski MD, PhD
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Editors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

    James R. Lupski MD, PhD  & Pawel Stankiewicz MD, PhD  & 

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© 2006 Humana Press Inc., Totowa, NJ

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Hurles, M.E., Lupski, J.R. (2006). Recombination Hotspots in Nonallelic Homologous Recombination. In: Lupski, J.R., Stankiewicz, P. (eds) Genomic Disorders. Humana Press. https://doi.org/10.1007/978-1-59745-039-3_24

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  • DOI: https://doi.org/10.1007/978-1-59745-039-3_24

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-559-0

  • Online ISBN: 978-1-59745-039-3

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