Identification of recurrent type-2 NF1 microdeletions reveals a mitotic nonallelic homologous recombination hotspot underlying a human genomic disorder

Human Mutation

Volumn 33, Issue 11, 2012, Pages 1599-1609

  Vogt, Julia ^a   Mussotter, Tanja ^a   Bengesser, Kathrin ^a   Claes, Kathleen ^b   Högel, Josef ^a   Chuzhanova, Nadia ^c   Fu, Chuanhua ^d   van den Ende, Jenneke ^e   Mautner, Victor Felix ^f   Cooper, David N ^g   Messiaen, Ludwine ^d   Kehrer Sawatzki, Hildegard ^a  

^a UNIVERSITY OF ULM   (Germany)

^b GHENT UNIVERSITY HOSPITAL   (Belgium)

^c NOTTINGHAM TRENT UNIVERSITY   (United Kingdom)

^d UNIVERSITY OF ALABAMA AT BIRMINGHAM   (United States)

^e ANTWERP UNIVERSITY HOSPITAL   (Belgium)

^f UNIVERSITY MEDICAL CENTER HAMBURG EPPENDORF   (Germany)

^g CARDIFF UNIVERSITY   (United Kingdom)

Author keywords

Hotspot; Mosaicism; NF1 microdeletions; Nonallelic homologous recombination

Indexed keywords

ARTICLE; CLINICAL ARTICLE; CONTROLLED STUDY; COPY NUMBER VARIATION; GENE; GENE DELETION; GENE SEQUENCE; HOMOLOGOUS RECOMBINATION; HUMAN; MITOTIC RECOMBINATION; MOSAICISM; MULTIPLEX LIGATION DEPENDENT PROBE AMPLIFICATION; NF1 GENE; NF1 MICRODELETION; NONALLELIC HOMOLOGOUS RECOMBINATION; POLYMERASE CHAIN REACTION; PRIORITY JOURNAL; SEQUENCE ANALYSIS; SUZ12 GENE; SUZ12P GENE;

BASE SEQUENCE; CHROMOSOME DELETION; CHROMOSOMES, HUMAN, PAIR 17; CRANIOFACIAL ABNORMALITIES; DNA BREAKS; DNA COPY NUMBER VARIATIONS; GENES, NEUROFIBROMATOSIS 1; HOMOLOGOUS RECOMBINATION; HUMANS; INTELLECTUAL DISABILITY; LEARNING DISORDERS; MITOSIS; MOLECULAR SEQUENCE DATA; MOSAICISM; MULTIPLEX POLYMERASE CHAIN REACTION; NEUROFIBROMATOSES; NEUROFIBROMATOSIS 1; POLYCOMB REPRESSIVE COMPLEX 2; PSEUDOGENES; SEQUENCE DELETION; SEQUENCE HOMOLOGY, NUCLEIC ACID;

EID: 84867471219     PISSN: 10597794     EISSN: 10981004     Source Type: Journal    
DOI: 10.1002/humu.22171     Document Type: Article

References (67)

1. Abeysinghe SS, Chuzhanova N, Krawczak M, Ball EV, Cooper DN. 2003. Translocation and gross deletion breakpoints in human inherited disease and cancer I: Nucleotide composition and recombination-associated motifs. Hum Mutat 22:229-244.
2. Ball EV, Stenson PD, Abeysinghe SS, Krawczak M, Cooper DN, Chuzhanova NA. 2005. Microdeletions and microinsertions causing human genetic disease: common mechanisms of mutagenesis and the role of local DNA sequence complexity. Hum Mutat 26:205-213.
3. Baudat F, Buard J, Grey C, Fledel-Alon A, Ober C, Przeworski M, Coop G, de Massy B. 2010. PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science 327:836-840.
4. Bayés M, Magano LF, Rivera N, Flores R, Pérez Jurado LA. 2003. Mutational mechanisms of Williams-Beuren syndrome deletions. Am J Hum Genet 73:131-151.
5. Beert E, Brems H, Daniëls B, De Wever I, Van Calenbergh F, Schoenaers J, Debiec-Rychter M, Gevaert O, De Raedt T, Van Den Bruel A, de Ravel T, Cichowski K, et al. 2011. Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. Genes Chrom Cancer 50:1021-1032.
6. Belancio VP, Roy-Engel AM, Deininger PL. 2010. All y'all need to know 'bout retroelements in cancer. Semin Cancer Biol 20:200-210.
7. Bengesser K, Cooper DN, Steinmann K, Kluwe L, Chuzhanova NA, Wimmer K, Tatagiba M, Tinschert S, Mautner VF, Kehrer-Sawatzki H. 2010. Novel third type of recurrent NF1 microdeletion mediated by nonallelic homologous recombination between LRRC37B-containing low-copy repeats in 17q11.2. Hum Mutat 31:742-751.
8. Benham C, Kohwi-Shigematsu T, Bode J. 1997. Stress-induced duplex DNA destabilization in scaffold/matrix attachment regions. J Mol Biol 274:181-196.
9. Berg IL, Neumann R, Lam KW, Sarbajna S, Odenthal-Hesse L, May CA, Jeffreys AJ. 2010. PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans. Nat Genet 42:859-863.
10. Bi C, Benham CJ. 2004. WebSIDD: server for predicting stress-induced duplex destabilized (SIDD) sites in superhelical DNA. Bioinformatics 20:1477-1479.
11. Bruder CE, Piotrowski A, Gijsbers AA, Andersson R, Erickson S, Diaz de Ståhl T, Menzel U, Sandgren J, von Tell D, Poplawski A, Crowley M, Crasto C, et al. 2008. Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am J Hum Genet 82:763-771.
12. Bzymek M, Thayer NH, Oh SD, Kleckner N, Hunter N. 2010. Double Holliday junctions are intermediates of DNA break repair. Nature 464:937-941.
13. Carvalho CM, Lupski JR. 2008. Copy number variation at the breakpoint region of isochromosome 17q. Genome Res 18:1724-1732.
14. Carvalho CM, Ramocki MB, Pehlivan D, Franco LM, Gonzaga-Jauregui C, Fang P, McCall A, Pivnick EK, Hines-Dowell S, Seaver LH, Friehling L, Lee S et al. 2011. Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nat Genet 43:1074-1081.
15. Chen JM, Cooper DN, Férec C, Kehrer-Sawatzki H, Patrinos GP. 2010. Genomic rearrangements in inherited disease and cancer. Semin Cancer Biol 20:22-33.
16. Chuzhanova N, Chen JM, Bacolla A, Patrinos GP, Férec C, Wells RD, Cooper DN. 2009. Gene conversion causing human inherited disease: evidence for involvement of non-B-DNA-forming sequences and recombination-promoting motifs in DNA breakage and repair. Hum Mutat 30:1189-1198.
17. Cooper DN, Bacolla A, Férec C, Vasquez KM, Kehrer-Sawatzki H, Chen JM. 2011. On the sequence-directed nature of human gene mutation: the role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease. Hum Mutat 32:1075-1099.
18. Cullen M, Perfetto SP, Klitz W, Nelson G, Carrington M. 2002. High-resolution patterns of meiotic recombination across the human major histocompatibility complex. Am J Hum Genet 71:759-776.
19. Deem A, Keszthelyi A, Blackgrove T, Vayl A, Coffey B, Mathur R, Chabes A, Malkova A. 2011. Break-induced replication is highly inaccurate. PLoS Biol 9:e1000594.
20. De Raedt T, Stephens M, Heyns I, Brems H, Thijs D, Messiaen L, Stephens K, Lazaro C, Wimmer K, Kehrer-Sawatzki H, Vidaud D, Kluwe L, et al. 2006. Conservation of hotspots for recombination in low-copy repeats associated with the NF1 microdeletion. Nat Genet 38:1419-1423.
21. Dorschner MO, Sybert VP, Weaver M, Pletcher BA, Stephens K. 2000. NF1 microdeletion breakpoints are clustered at flanking repetitive sequences. Hum Mol Genet 9:35-46.
22. Duret L, Galtier N. 2009. Biased gene conversion and the evolution of mammalian genomic landscapes. Annu Rev Genomics Hum Genet 10:285-311.
23. Fiorini A, Gouveia FS, Fernandez MA. 2006. Scaffold/matrix attachment regions and intrinsic DNA curvature. Biochemistry (Mosc.) 71:481-488.
24. Forbes SH, Dorschner MO, Le R, Stephens K. 2004. Genomic context of paralogous recombination hotspots mediating recurrent NF1 region microdeletion. Genes Chrom Cancer 41:12-25.
25. Girod PA, Nguyen DQ, Calabrese D, Puttini S, Grandjean M, Martinet D, Regamey A, Saugy D, Beckmann JS, Bucher P, Mermod N. 2007. Genome-wide prediction of matrix attachment regions that increase gene expression in mammalian cells. Nat Methods 4:747-753.
26. Gusev VD, Nemytikova LA, Chuzhanova NA. 1999. On the complexity measures of genetic sequences. Bioinformatics 15:994-999.
27. Halder A, Jain M, Kabra M, Gupta N. 2008. Mosaic 22q11.2 microdeletion syndrome: diagnosis and clinical manifestations of two cases. Mol Cytogenet 1:18.
28. Jenne DE, Tinschert S, Reimann H, Lasinger W, Thiel G, Hameister H, Kehrer-Sawatzki H. 2001. Molecular characterization and gene content of breakpoint boundaries in patients with neurofibromatosis type 1 with 17q11.2 microdeletions. Am J Hum Genet 69:516-527.
29. Kehrer-Sawatzki H, Kluwe L, Sandig C, Kohn M, Wimmer K, Krammer U, Peyrl A, Jenne DE, Hansmann I, Mautner VF. 2004. High frequency of mosaicism among patients with neurofibromatosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene. Am J Hum Genet 75:410-423.
30. Kehrer-Sawatzki H, Schmid E, Fünsterer C, Kluwe L, Mautner VF. 2008. Absence of cutaneous neurofibromas in an NF1 patient with an atypical deletion partially overlapping the common 1.4 Mb microdeleted region. Am J Med Genet A 146:691-699.
31. Kluwe L, Siebert R, Gesk S, Friedrich RE, Tinschert S, Kehrer-Sawatzki H, Mautner V-F. 2004. Screening of 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene. Hum Mutat 23:111-116.
32. Koolen DA, Dupont J, de Leeuw N, Vissers LE, van den Heuvel SP, Bradbury A, Steer J, de Brouwer AP, Ten Kate LP, Nillesen WM, de Vries BB, Parker MJ. 2012. Two families with sibling recurrence of the 17q21.31 microdeletion syndrome due to low-grade mosaicism. Eur J Hum Genet 20:729-733.
33. Lam KWG, Jeffreys AJ. 2006. Processes of copy-number change in human DNA: The dynamics of α-globin gene deletion. Proc Natl Acad Sci USA 103:8921-8927.
34. Lam KWG, Jeffreys AJ. 2007. Processes of de novo duplication of human α-globin genes. Proc Natl Acad Sci USA 104:10950-10955.
35. Lee JA, Carvalho CM, Lupski JR. 2007. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131:1235-1247.
36. Lee PS, Greenwell PW, Dominska M, Gawel M, Hamilton M, Petes TD. 2009. A fine-structure map of spontaneous mitotic crossovers in the yeast Saccharomyces cerevisiae. PLoS Genet 5:e1000410.
37. Lindsay SJ, Khajavi M, Lupski JR, Hurles ME. 2006. A chromosomal rearrangement hotspot can be identified from population genetic variation and is coincident with a hotspot for allelic recombination. Am J Hum Genet 79:890-902.
38. Lopes J, Tardieu S, Silander K, Blair I, Vandenberghe A, Palau F, Ruberg M, Brice A, LeGuern E. 1999. Homologous DNA exchanges in humans can be explained by the yeast double-strand break repair model: a study of 17p11.2 rearrangements associated with CMT1A and HNPP. Hum Mol Genet 8:2285-2292.
39. López C, Baumann T, Costa D, López-Guerra M, Navarro A, Gómez C, Arias A, Muñoz C, Rozman M, Villamor N, Colomer D, Montserrat E, Campo E, Carrió A. 2012. A new genetic abnormality leading to TP53 gene deletion in chronic lymphocytic leukaemia. Br J Haematol 156:612-618.
40. López-Correa C, Brems H, Lázaro C, Marynen P, Legius E. 2000. Unequal meiotic crossover: a frequent cause of NF1 microdeletions. Am J Hum Genet 66:1969-1974.
41. López-Correa C, Dorschner M, Brems H, Lázaro C, Clementi M, Upadhyaya M, Dooijes D, Moog U, Kehrer-Sawatzki H, Rutkowski JL, Fryns JP, Marynen P, et al. 2001. Recombination hotspot in NF1 microdeletion patients. Hum Mol Genet 10:1387-1392.
42. Makridakis NM, Caldas Ferraz LF, Reichardt JK. 2009. Genomic analysis of cancer tissue reveals that somatic mutations commonly occur in a specific motif. Hum Mutat 30:39-48.
43. Malkova A, Naylor ML, Yamaguchi M, Ira G, Haber JE. 2005. RAD51-dependent break-induced replication differs in kinetics and checkpoint responses from RAD51-mediated gene conversion. Mol Cell Biol 25:933-944.
44. Mantripragada KK, Thuresson AC, Piotrowski A, Díaz de Stahl T, Menzel U, Grigelionis G, Ferner RE, Griffiths S, Bolund L, Mautner V, Nordling M, Legius E, et al. 2006. Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH. J Med Genet 43:28-38.
45. Massey JR. 1951. The Kolmogorov-Smirnov test for goodness of fit. J Am Stat Assoc 253:68-78.
46. Messiaen L, Vogt J, Bengesser K, Fu C, Mikhail F, Serra E, Garcia-Linares C, Cooper DN, Lazaro C, Kehrer-Sawatzki H. 2011. Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1). Hum Mutat 32:213-219.
47. Myers S, Freeman C, Auton A, Donnelly P, McVean G. 2008. A common sequence motif associated with recombination hot spots and genome instability in humans. Nat Genet 40:1124-1129.
48. National Institutes of Health Consensus Development Conference. 1988. Neurofibromatosis conference statement. Arch Neurol 45:575-578.
49. Neumann R, Lawson VE, Jeffreys AJ. 2010. Dynamics and processes of copy number instability in human gamma-globin genes. Proc Natl Acad Sci USA 107:8304-8309.
50. Parvanov ED, Petkov PM, Paigen K. 2010. Prdm9 controls activation of mammalian recombination hotspots. Science 327:835.
51. Pasmant E, Sabbagh A, Masliah-Planchon J, Haddad V, Hamel MJ, Laurendeau I, Soulier J, Parfait B, Wolkenstein P, Bièche I, Vidaud M, Vidaud D. 2009. Detection and characterization of NF1 microdeletions by custom high resolution array CGH. J Mol Diagn 11:524-529.
52. Pasmant E, Sabbagh A, Spurlock G, Laurendeau I, Grillo E, Hamel MJ, Martin L, Barbarot S, Leheup B, Rodriguez D, Lacombe D, Dollfus H et al. 2010. NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat 31:1506-1518.
53. Piotrowski A, Bruder CE, Andersson R, Diaz de Ståhl T, Menzel U, Sandgren J, Poplawski A, von Tell D, Crasto C, Bogdan A, Bartoszewski R, Bebok Z et al. 2008. Somatic mosaicism for copy number variation in differentiated human tissues. Hum Mutat 29:1118-1124.
54. Reiter LT, Hastings PJ, Nelis E, De Jonghe P, van Broeckhoven C, Lupski JR. 1998. Human meiotic recombination products revealed by sequencing a hotspot for homologous strand exchange in multiple HNPP deletion patients. Am J Hum Genet 62:1023-1033.
55. Repping S, Skaletsky H, Lange J, Silber S, Van Der Veen F, Oates RD, Page DC, Rozen S. 2002. Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure. Am J Hum Genet 71:906-922.
56. Rodríguez-Santiago B, Malats N, Rothman N, Armengol L, Garcia-Closas M, Kogevinas M, Villa O, Hutchinson A, Earl J, Marenne G, Jacobs K, Rico D et al. 2010. Mosaic uniparental disomies and aneuploidies as large structural variants of the human genome. Am J Hum Genet 87:129-138.
57. Roehl AC, Mussotter T, Cooper DN, Kluwe L, Wimmer K, Högel J, Zetzmann M, Vogt J, Mautner VF, Kehrer-Sawatzki H. 2012. Tissue-specific differences in the proportion of mosaic large NF1 deletions are suggestive of a selective growth advantage of hematopoietic del(+/-) stem cells. Hum Mutat 33:541-550.
58. Roehl AC, Vogt J, Mussotter T, Zickler AN, Spöri H, Högel J, Chuzhanova NA, Wimmer K, Kluwe L, Mautner VF, Cooper DN, Kehrer-Sawatzki H. 2010. Intrachromosomal mitotic nonallelic homologous recombination is the major molecular mechanism underlying type-2 NF1 deletions. Hum Mutat 31:1163-1173.
59. Scott SA, Cohen N, Brandt T, Warburton PE, Edelmann L. 2011. Large inverted repeats within Xp11.2 are present at the breakpoints of isodicentric X chromosomes in Turner syndrome. Hum Mol Genet 19:3383-3393.
60. Sheen CR, Jewell UR, Morris CM, Brennan SO, Férec C, George PM, Smith MP, Chen JM. 2007. Double complex mutations involving F8 and FUNDC2 caused by distinct break-induced replication. Hum Mutat 28:1198-1206.
61. Singh GB, Kramer JA, Krawetz SA. 1997. Mathematical model to predict regions of chromatin attachment to the nuclear matrix. Nucleic Acids Res 25:1419-1425.
62. Steinmann K, Cooper DN, Kluwe L, Chuzhanova NA, Senger C, Serra E, Lazaro C. 2007. Type 2 NF1 deletions are highly unusual by virtue of the absence of nonallelic homologous recombination hotspots and an apparent preference for female mitotic recombination. Am J Hum Genet 81:1201-1220.
63. Steinmann K, Kluwe L, Cooper DN, Brems H, De Raedt T, Legius E, Mautner VF, Kehrer-Sawatzki H. 2008. Copy number variations in the NF1 gene region are infrequent and do not predispose to recurrent type-1 deletions. Eur J Hum Genet 16:572-580.
64. Turner DJ, Miretti M, Rajan D, Fiegler H, Carter NP, Blayney ML, Beck S, Hurles ME. 2008. Germline rates of de novo meiotic deletions and duplications causing several genomic disorders. Nat Genet 40:90-95.
65. Visser R, Shimokawa O, Harada N, Kinoshita A, Ohta T, Niikawa N, Matsumoto N. 2005. Identification of a 3.0-kb major recombination hotspot in patients with Sotos syndrome who carry a common 1.9-Mb microdeletion. Am J Hum Genet 76:52-67.
66. Wells RD. 2007. Non-B DNA conformations, mutagenesis and disease. Trends Biochem Sci 32:271-278.
67. Zickler AM, Hampp S, Messiaen L, Bengesser K, Mussotter T, Roehl AC, Wimmer K, Mautner VF, Kluwe L, Upadhyaya M, Pasmant E, Chuzhanova N et al. 2012. Characterization of the nonallelic homologous recombination hotspot PRS3 associated with type-3 NF1 deletions. Hum Mutat 33:372-383.