A recurrent translocation is mediated by homologous recombination between HERV-H elements

Molecular Cytogenetics

M Katharine Rudd²  Jannine D Cody¹  Urvashi Surti³  Karen E Hermetz² 

[1] Department of Pediatrics, Chromosome 18 Registry and Research Society, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA;Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

关键词: 18q;    18q22.3;    4q35.1;    recurrent translocation;    18);    t(4;    translocation;    NAHR;    HERV;    HERV-H;   

Others  :  1151757
DOI  :  10.1186/1755-8166-5-6

 received in 2011-10-02, accepted in 2012-01-19,  发布年份 2012

【 摘 要 】

Background

Chromosome rearrangements are caused by many mutational mechanisms; of these, recurrent rearrangements can be particularly informative for teasing apart DNA sequence-specific factors. Some recurrent translocations are mediated by homologous recombination between large blocks of segmental duplications on different chromosomes. Here we describe a recurrent unbalanced translocation casued by recombination between shorter homologous regions on chromosomes 4 and 18 in two unrelated children with intellectual disability.

Results

Array CGH resolved the breakpoints of the 6.97-Megabase (Mb) loss of 18q and the 7.30-Mb gain of 4q. Sequencing across the translocation breakpoints revealed that both translocations occurred between 92%-identical human endogenous retrovirus (HERV) elements in the same orientation on chromosomes 4 and 18. In addition, we find sequence variation in the chromosome 4 HERV that makes one allele more like the chromosome 18 HERV.

Conclusions

Homologous recombination between HERVs on the same chromosome is known to cause chromosome deletions, but this is the first report of interchromosomal HERV-HERV recombination leading to a translocation. It is possible that normal sequence variation in substrates of non-allelic homologous recombination (NAHR) affects the alignment of recombining segments and influences the propensity to chromosome rearrangement.

【 授权许可】

   
2012 Hermetz et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Shaffer LG, Kashork CD, Saleki R, Rorem E, Sundin K, Ballif BC, Bejjani BA: Targeted genomic microarray analysis for identification of chromosome abnormalities in 1500 consecutive clinical cases. J Pediatr 2006, 149:98-102.
• [2]Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, Williams C, Stalker H, Hamid R, Hannig V, et al.: A copy number variation morbidity map of developmental delay. Nat Genet 2011, 43:838-846.
• [3]Kaminsky EB, Kaul V, Paschall J, Church DM, Bunke B, Kunig D, Moreno-De-Luca D, Moreno-De-Luca A, Mulle JG, Warren ST, et al.: An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genetics in medicine 2011, 13:777-784.
• [4]Hastings PJ, Lupski JR, Rosenberg SM, Ira G: Mechanisms of change in gene copy number. Nat Rev Genet 2009, 10:551-564.
• [5]Vissers LE, Bhatt SS, Janssen IM, Xia Z, Lalani SR, Pfundt R, Derwinska K, de Vries BB, Gilissen C, Hoischen A, et al.: Rare pathogenic microdeletions and tandem duplications are microhomology-mediated and stimulated by local genomic architecture. Hum Mol Genet 2009, 18:3579-3593.
• [6]Luo Y, Hermetz KE, Jackson JM, Mulle JG, Dodd A, Tsuchiya KD, Ballif BC, Shaffer LG, Cody JD, Ledbetter DH, et al.: Diverse mutational mechanisms cause pathogenic subtelomeric rearrangements. Hum Mol Genet 2011, 20:3769-3778.
• [7]Sharp AJ, Hansen S, Selzer RR, Cheng Z, Regan R, Hurst JA, Stewart H, Price SM, Blair E, Hennekam RC, et al.: Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 2006, 38:1038-1042.
• [8]Rudd MK, Keene J, Bunke B, Kaminsky EB, Adam MP, Mulle JG, Ledbetter DH, Martin CL: Segmental duplications mediate novel, clinically relevant chromosome rearrangements. Hum Mol Genet 2009, 18:2957-2962.
• [9]Mefford HC, Eichler EE: Duplication hotspots, rare genomic disorders, and common disease. Curr Opin Genet Dev 2009, 19:196-204.
• [10]Lupski JR: Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet 1998, 14:417-422.
• [11]Stankiewicz P, Lupski JR: Genome architecture, rearrangements and genomic disorders. Trends Genet 2002, 18:74-82.
• [12]Giglio S, Calvari V, Gregato G, Gimelli G, Camanini S, Giorda R, Ragusa A, Guerneri S, Selicorni A, Stumm M, et al.: Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation. Am J Hum Genet 2002, 71:276-285.
• [13]van der Maarel SM, Deidda G, Lemmers RJ, van Overveld PG, van der Wielen M, Hewitt JE, Sandkuijl L, Bakker B, van Ommen GJ, Padberg GW, Frants RR: De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10. Am J Hum Genet 2000, 66:26-35.
• [14]South ST, Whitby H, Maxwell T, Aston E, Brothman AR, Carey JC: Co-occurrence of 4p16.3 deletions with both paternal and maternal duplications of 11p15: modification of the Wolf-Hirschhorn syndrome phenotype by genetic alterations predicted to result in either a Beckwith-Wiedemann or Russell-Silver phenotype. Am J Med Genet A 2008, 146A:2691-2697.
• [15]Ou Z, Stankiewicz P, Xia Z, Breman AM, Dawson B, Wiszniewska J, Szafranski P, Cooper ML, Rao M, Shao L, et al.: Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes. Genome Res 2011, 21:33-46.
• [16]Kurahashi H, Shaikh TH, Hu P, Roe BA, Emanuel BS, Budarf ML: Regions of genomic instability on 22q11 and 11q23 as the etiology for the recurrent constitutional t(11;22). Hum Mol Genet 2000, 9:1665-1670.
• [17]Sheridan MB, Kato T, Haldeman-Englert C, Jalali GR, Milunsky JM, Zou Y, Klaes R, Gimelli G, Gimelli S, Gemmill RM, et al.: A palindrome-mediated recurrent translocation with 3:1 meiotic nondisjunction: the t(8;22)(q24.13;q11.21). Am J Hum Genet 2010, 87:209-218.
• [18]Gajecka M, Gentles AJ, Tsai A, Chitayat D, Mackay KL, Glotzbach CD, Lieber MR, Shaffer LG: Unexpected complexity at breakpoint junctions in phenotypically normal individuals and mechanisms involved in generating balanced translocations t(1;22)(p36;q13). Genome Res 2008, 18:1733-1742.
• [19]Higgins AW, Alkuraya FS, Bosco AF, Brown KK, Bruns GA, Donovan DJ, Eisenman R, Fan Y, Farra CG, Ferguson HL, et al.: Characterization of apparently balanced chromosomal rearrangements from the developmental genome anatomy project. Am J Hum Genet 2008, 82:712-722.
• [20]Chen W, Kalscheuer V, Tzschach A, Menzel C, Ullmann R, Schulz MH, Erdogan F, Li N, Kijas Z, Arkesteijn G, et al.: Mapping translocation breakpoints by next-generation sequencing. Genome Res 2008, 18:1143-1149.
• [21]Batzer MA, Deininger PL: Alu repeats and human genomic diversity. Nat Rev Genet 2002, 3:370-379.
• [22]Deininger PL, Moran JV, Batzer MA, Kazazian HH Jr: Mobile elements and mammalian genome evolution. Curr Opin Genet Dev 2003, 13:651-658.
• [23]Abeysinghe SS, Chuzhanova N, Krawczak M, Ball EV, Cooper DN: Translocation and gross deletion breakpoints in human inherited disease and cancer I: Nucleotide composition and recombination-associated motifs. Human mutation 2003, 22:229-244.
• [24]Rouyer F, Simmler MC, Page DC, Weissenbach J: A sex chromosome rearrangement in a human XX male caused by Alu-Alu recombination. Cell 1987, 51:417-425.
• [25]Lehrman MA, Schneider WJ, Sudhof TC, Brown MS, Goldstein JL, Russell DW: Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. Science 1985, 227:140-146.
• [26]Pousi B, Hautala T, Heikkinen J, Pajunen L, Kivirikko KI, Myllyla R: Alu-Alu recombination results in a duplication of seven exons in the lysyl hydroxylase gene in a patient with the type VI variant of Ehlers-Danlos syndrome. Am J Hum Genet 1994, 55:899-906.
• [27]Sun C, Skaletsky H, Rozen S, Gromoll J, Nieschlag E, Oates R, Page DC: Deletion of azoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 proviruses. Hum Mol Genet 2000, 9:2291-2296.
• [28]Kamp C, Hirschmann P, Voss H, Huellen K, Vogt PH: Two long homologous retroviral sequence blocks in proximal Yq11 cause AZFa microdeletions as a result of intrachromosomal recombination events. Hum Mol Genet 2000, 9:2563-2572.
• [29]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.
• [30]Sanchez-Valle A, Wang X, Potocki L, Xia Z, Kang SH, Carlin ME, Michel D, Williams P, Cabrera-Meza G, Brundage EK, et al.: HERV-mediated genomic rearrangement of EYA1 in an individual with branchio-oto-renal syndrome. Am J Med Genet A 2010, 152A:2854-2860.
• [31]Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, et al.: Initial sequencing and analysis of the human genome. Nature 2001, 409:860-921.
• [32]Paces J, Pavlicek A, Paces V: HERVd: database of human endogenous retroviruses. Nucleic Acids Res 2002, 30:205-206.
• [33]Patience C, Wilkinson DA, Weiss RA: Our retroviral heritage. Trends Genet 1997, 13:116-120.
• [34]Turner G, Barbulescu M, Su M, Jensen-Seaman MI, Kidd KK, Lenz J: Insertional polymorphisms of full-length endogenous retroviruses in humans. Curr Biol 2001, 11:1531-1535.
• [35]Bannert N, Kurth R: Retroelements and the human genome: new perspectives on an old relation. Proc Natl Acad Sci USA 2004, 101(Suppl 2):14572-14579.
• [36]Hughes JF, Coffin JM: Evidence for genomic rearrangements mediated by human endogenous retroviruses during primate evolution. Nat Genet 2001, 29:487-489.
• [37]Hughes JF, Coffin JM: Human endogenous retroviral elements as indicators of ectopic recombination events in the primate genome. Genetics 2005, 171:1183-1194.
• [38]Gunn SR, Mohammed M, Reveles XT, Viskochil DH, Palumbos JC, Johnson-Pais TL, Hale DE, Lancaster JL, Hardies LJ, Boespflug-Tanguy O, et al.: Molecular characterization of a patient with central nervous system dysmyelination and cryptic unbalanced translocation between chromosomes 4q and 18q. Am J Med Genet A 2003, 120A:127-135.
• [39]Horbinski C, Carter EM, Heard PL, Sathanoori M, Hu J, Vockley J, Gunn S, Hale DE, Surti U, Cody JD: Molecular and clinical characterization of a recurrent cryptic unbalanced t(4q;18q) resulting in an 18q deletion and 4q duplication. Am J Med Genet A 2008.
• [40]Hirose Y, Takamatsu M, Harada F: Presence of env genes in members of the RTVL-H family of human endogenous retrovirus-like elements. Virology 1993, 192:52-61.
• [41]Naylor JA, Buck D, Green P, Williamson H, Bentley D, Giannelli F: Investigation of the factor VIII intron 22 repeated region (int22h) and the associated inversion junctions. Hum Mol Genet 1995, 4:1217-1224.
• [42]Reiter LT, Murakami T, Koeuth T, Gibbs RA, Lupski JR: The human COX10 gene is disrupted during homologous recombination between the 24 kb proximal and distal CMT1A-REPs. Hum Mol Genet 1997, 6:1595-1603.
• [43]Inoue K, Lupski JR: Molecular mechanisms for genomic disorders. Annu Rev Genomics Hum Genet 2002, 3:199-242.
• [44]Kidd JM, Graves T, Newman TL, Fulton R, Hayden HS, Malig M, Kallicki J, Kaul R, Wilson RK, Eichler EE: A human genome structural variation sequencing resource reveals insights into mutational mechanisms. Cell 2010, 143:837-847.
• [45]Conrad DF, Bird C, Blackburne B, Lindsay S, Mamanova L, Lee C, Turner DJ, Hurles ME: Mutation spectrum revealed by breakpoint sequencing of human germline CNVs. Nat Genet 2010, 42:385-391.
• [46]Kent WJ: BLAT--the BLAST-like alignment tool. Genome Res 2002, 12:656-664.
• [47]Benson G: Tandem repeats finder: a program to analyze DNA sequences. Nucleic Acids Res 1999, 27:573-580.