Human Genetics

, Volume 117, Issue 5, pp 411–427 | Cite as

A systematic analysis of LINE-1 endonuclease-dependent retrotranspositional events causing human genetic disease

  • Jian-Min Chen
  • Peter D. Stenson
  • David N. Cooper
  • Claude Férec
Review Article


Diverse long interspersed element-1 (LINE-1 or L1)-dependent mutational mechanisms have been extensively studied with respect to L1 and Alu elements engineered for retrotransposition in cultured cells and/or in genome-wide analyses. To what extent the in vitro studies can be held to accurately reflect in vivo events in the human genome, however, remains to be clarified. We have attempted to address this question by means of a systematic analysis of recent L1-mediated retrotranspositional events that have caused human genetic disease, with a view to providing a more complete picture of how L1-mediated retrotransposition impacts upon the architecture of the human genome. A total of 48 such mutations were identified, including those described as L1-mediated retrotransposons, as well as insertions reported to contain a poly(A) tail: 26 were L1 trans-driven Alu insertions, 15 were direct L1 insertions, four were L1 trans-driven SVA insertions, and three were associated with simple poly(A) insertions. The systematic study of these lesions, when combined with previous in vitro and genome-wide analyses, has strengthened several important conclusions regarding L1-mediated retrotransposition in humans: (a) approximately 25% of L1 insertions are associated with the 3′ transduction of adjacent genomic sequences, (b) ~25% of the new L1 inserts are full-length, (c) poly(A) tail length correlates inversely with the age of the element, and (d) the length of target site duplication in vivo is rarely longer than 20 bp. Our analysis also suggests that some 10% of L1-mediated retrotranspositional events are associated with significant genomic deletions in humans. Finally, the identification of independent retrotranspositional events that have integrated at the same genomic locations provides new insight into the L1-mediated insertional process in humans.


Human Genetic Disease Retrotranspositional Event Large Genomic Deletion Simple Insertion IL2RG Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank the many original authors who have reported human disease-associated L1 retrotransposons. We are especially grateful to Frans P.M. Cremers (Nijmegen, Netherlands), Francisco Martínez (Valencia, Spain), Tatsushi Toda (Osaka, Japan), Karin Wulff (Greifswald, Germany), and Kenichiro Yamada (Aichi, Japan) for providing further information on reported mutations. This work was supported by the INSERM (Institut National de la Santé et de la Recherche Médicale), France. DNC wishes to acknowledge the financial assistance of Celera Genomics.

Supplementary material

439_2005_1321_ESM_supp.pdf (194 kb)
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  1. Abdelhak S, Kalatzis V, Heilig R, Compain S, Samson D, Vincent C, Levi-Acobas F, Cruaud C, Le Merrer M, Mathieu M, Konig R, Vigneron J, Weissenbach J, Petit C, Weil D (1997) Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1. Hum Mol Genet 6:2247–2255CrossRefPubMedGoogle Scholar
  2. Arcot SS, Wang Z, Weber JL, Deininger PL, Batzer MA (1995) Alu repeats: a source for the genesis of primate microsatellites. Genomics 29:136–144CrossRefPubMedGoogle Scholar
  3. Audrezet MP, Chen JM, Raguenes O, Chuzhanova N, Giteau K, Le Marechal C, Quere I, Cooper DN, Ferec C (2004) Genomic rearrangements in the CFTR gene: extensive allelic heterogeneity and diverse mutational mechanisms. Hum Mutat 23:343–357CrossRefPubMedGoogle Scholar
  4. Badge RM, Alisch RS, Moran JV (2003) ATLAS: a system to selectively identify human-specific L1 insertions. Am J Hum Genet 72:823–838CrossRefPubMedGoogle Scholar
  5. Batzer MA, Deininger PL (2002) Alu repeats and human genomic diversity. Nat Rev Genet 3:370–379CrossRefPubMedGoogle Scholar
  6. Batzer MA, Kilroy GE, Richard PE, Shaikh TH, Desselle TD, Hoppens CL, Deininger PL (1990) Structure and variability of recently inserted Alu family members. Nucleic Acids Res 18:6793–6798PubMedGoogle Scholar
  7. Batzer MA, Rubin CM, Hellmann-Blumberg U, Alegria-Hartman M, Leeflang EP, Stern JD, Bazan HA, Shaikh TH, Deininger PL, Schmid CW (1995) Dispersion and insertion polymorphism in two small subfamilies of recently amplified human Alu repeats. J Mol Biol 247:418–427CrossRefPubMedGoogle Scholar
  8. Batzer MA, Deininger PL, Hellmann-Blumberg U, Jurka J, Labuda D, Rubin CM, Schmid CW, Zietkiewicz E, Zuckerkandl E (1996) Standardized nomenclature for Alu repeats. J Mol Evol 42:3–6CrossRefPubMedGoogle Scholar
  9. Beauchamp NJ, Makris M, Preston FE, Peake IR, Daly ME (2000) Major structural defects in the antithrombin gene in four families with type I antithrombin deficiency–partial/complete deletions and rearrangement of the antithrombin gene. Thromb Haemost 83:715–721PubMedGoogle Scholar
  10. Bennett EA, Coleman LE, Tsui C, Pittard WS, Devine SE (2004) Natural genetic variation caused by transposable elements in humans. Genetics 168:933–951CrossRefPubMedGoogle Scholar
  11. Boissinot S, Chevret P, Furano AV (2000) L1 (LINE-1) retrotransposon evolution and amplification in recent human history. Mol Biol Evol 17:915–928PubMedGoogle Scholar
  12. Boissinot S, Entezam A, Young L, Munson PJ, Furano AV (2004) The insertional history of an active family of L1 retrotransposons in humans. Genome Res 14:1221–1231CrossRefPubMedGoogle Scholar
  13. Brouha B, Meischl C, Ostertag E, de Boer M, Zhang Y, Neijens H, Roos D, Kazazian HH Jr (2002) Evidence consistent with human L1 retrotransposition in maternal meiosis I. Am J Hum Genet 71:327–336CrossRefPubMedGoogle Scholar
  14. Brouha B, Schustak J, Badge RM, Lutz-Prigge S, Farley AH, Moran JV, Kazazian HH Jr (2003) Hot L1s account for the bulk of retrotransposition in the human population. Proc Natl Acad Sci USA 100:5280–5285Google Scholar
  15. Carter AB, Salem AH, Hedges DJ, Keegan CN, Kimball B, Walker JA, Watkins WS, Jorde LB, Batzer MA (2004) Genome-wide analysis of the human Alu Yb-lineage. Hum Genomics 1:167–178PubMedGoogle Scholar
  16. Chen JM, Chuzhanova N, Stenson PD, Ferec C, Cooper DN (2005) Meta-analysis of gross insertions causing human genetic disease: novel mutational mechanisms and the role of replication slippage. Hum Mutat 25:207–221CrossRefPubMedGoogle Scholar
  17. Claverie-Martin F, Gonzalez-Acosta H, Flores C, Anton-Gamero M, Garcia-Nieto V (2003) De novo insertion of an Alu sequence in the coding region of the CLCN5 gene results in Dent’s disease. Hum Genet 113:480–485PubMedGoogle Scholar
  18. Conley ME, Partain JD, Norland SM, Shurtleff SA, Kazazian HH Jr (2005) Two independent retrotransposon insertions at the same site within the coding region of BTK. Hum Mutat 25:324–325CrossRefGoogle Scholar
  19. Cordaux R, Hedges DJ, Batzer MA (2004) Retrotransposition of Alu elements: how many sources? Trends Genet 20:464–467CrossRefPubMedGoogle Scholar
  20. Cost GJ, Boeke JD (1998) Targeting of human retrotransposon integration is directed by the specificity of the L1 endonuclease for regions of unusual DNA structure. Biochemistry 37:18081–18093CrossRefPubMedGoogle Scholar
  21. Cost GJ, Feng Q, Jacquier A, Boeke JD (2002) Human L1 element target-primed reverse transcription in vitro. EMBO J 21:5899–5910CrossRefPubMedGoogle Scholar
  22. Courseaux A, Nahon JL (2001) Birth of two chimeric genes in the Hominidae lineage. Science 291:1293–1297CrossRefPubMedGoogle Scholar
  23. DeBerardinis RJ, Kazazian HH Jr (1988) Full-length L1 elements have arisen recently in the same 1-kb region of the gorilla and human genomes. J Mol Evol 47:292–301Google Scholar
  24. Deininger PL, Batzer MA (2002) Mammalian retroelements. Genome Res 12:1455–1465CrossRefPubMedGoogle Scholar
  25. Deininger PL, Moran JV, Batzer MA, Kazazian HH Jr (2003) Mobile elements and mammalian genome evolution. Curr Opin Genet Dev 13:651–658PubMedGoogle Scholar
  26. Dewannieux M, Esnault C, Heidmann T (2003) LINE-mediated retrotransposition of marked Alu sequences. Nat Genet 35:41–48PubMedGoogle Scholar
  27. Divoky V, Indrak K, Mrug M, Brabec V, Huisman THJ, Prchal JT (1996) A novel mechanism of β thalassemia: the insertion of L1 retrotransposable element into β globin IVS II. Blood 88(Suppl 1):148a (abstract)Google Scholar
  28. Dombroski BA, Mathias SL, Nanthakumar E, Scott AF, Kazazian HH Jr (1991) Isolation of an active human transposable element. Science 254:1805–1808PubMedGoogle Scholar
  29. Dombroski BA, Scott AF, Kazazian HH Jr (1993) Two additional potential retrotransposons isolated from a human L1 subfamily that contains an active retrotransposable element. Proc Natl Acad Sci USA 90:6513–6517Google Scholar
  30. Eickbush TH (2002) Repair by retrotransposition. Nat Genet 31:126–127CrossRefPubMedGoogle Scholar
  31. Ejima Y, Yang L (2003) Trans mobilization of genomic DNA as a mechanism for retrotransposon-mediated exon shuffling. Hum Mol Genet 12:1321–1328CrossRefPubMedGoogle Scholar
  32. Esnault C, Maestre J, Heidmann T (2000) Human LINE retrotransposons generate processed pseudogenes. Nat Genet 24:363–367CrossRefPubMedGoogle Scholar
  33. Farley AH, Luning Prak ET, Kazazian HH Jr (2004) More active human L1 retrotransposons produce longer insertions. Nucleic Acids Res 32:502–510Google Scholar
  34. Feng Q, Moran JV, Kazazian HH Jr, Boeke JD (1996) Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition. Cell 87:905–916CrossRefPubMedGoogle Scholar
  35. Ganguly A, Dunbar T, Chen P, Godmilow L, Ganguly T (2003) Exon skipping caused by an intronic insertion of a young Alu Yb9 element leads to severe hemophilia A. Hum Genet 113:348–352CrossRefPubMedGoogle Scholar
  36. Gilbert N, Lutz-Prigge S, Moran JV (2002) Genomic deletions created upon LINE-1 retrotransposition. Cell 110:315–325CrossRefPubMedGoogle Scholar
  37. Goodier JL, Ostertag EM, Kazazian HH Jr (2000) Transduction of 3’-flanking sequences is common in L1 retrotransposition. Hum Mol Genet 9:653–657CrossRefPubMedGoogle Scholar
  38. Grimaldi G, Skowronski J, Singer MF (1984) Defining the beginning and end of KpnI family segments. EMBO J 3:1753–1759PubMedGoogle Scholar
  39. Hagan CR, Sheffield RF, Rudin CM (2003) Human Alu element retrotransposition induced by genotoxic stress. Nat Genet 35:219–220CrossRefPubMedGoogle Scholar
  40. Halling KC, Lazzaro CR, Honchel R, Bufill JA, Powell SM, Arndt CA, Lindor NM (1999) Hereditary desmoid disease in a family with a germline Alu I repeat mutation of the APC gene. Hum Hered 49:97–102CrossRefPubMedGoogle Scholar
  41. Han JS, Szak ST, Boeke JD (2004) Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes. Nature 429:268–274CrossRefPubMedGoogle Scholar
  42. Hassoun H, Coetzer TL, Vassiliadis JN, Sahr KE, Maalouf GJ, Saad ST, Catanzariti L, Palek J (1994) A novel mobile element inserted in the alpha spectrin gene: spectrin dayton. A truncated alpha spectrin associated with hereditary elliptocytosis. J Clin Invest 94:643–648PubMedGoogle Scholar
  43. den Hollander AI, ten Brink JB, de Kok YJ, van Soest S, van den Born LI, van Driel MA, van de Pol DJ, Payne AM, Bhattacharya SS, Kellner U, Hoyng CB, Westerveld A, Brunner HG, Bleeker-Wagemakers EM, Deutman AF, Heckenlively JR, Cremers FP, Bergen AA (1999) Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). Nat Genet 23:217–221CrossRefPubMedGoogle Scholar
  44. Holmes SE, Dombroski BA, Krebs CM, Boehm CD, Kazazian HH Jr (1994) A new retrotransposable human L1 element from the LRE2 locus on chromosome 1q produces a chimaeric insertion. Nat Genet 7:143–148CrossRefPubMedGoogle Scholar
  45. van den Hurk JA, van de Pol DJ, Wissinger B, van Driel MA, Hoefsloot LH, de Wijs IJ, van den Born LI, Heckenlively JR, Brunner HG, Zrenner E, Ropers HH, Cremers FP (2003) Novel types of mutation in the choroideremia (CHM) gene: a full-length L1 insertion and an intronic mutation activating a cryptic exon. Hum Genet 113:268–275CrossRefPubMedGoogle Scholar
  46. Ishihara N, Yamada K, Yamada Y, Miura K, Kato J, Kuwabara N, Hara Y, Kobayashi Y, Hoshino K, Nomura Y, Mimaki M, Ohya K, Matsushima M, Nitta H, Tanaka K, Segawa M, Ohki T, Ezoe T, Kumagai T, Onuma A, Kuroda T, Yoneda M, Yamanaka T, Saeki M, Segawa M, Saji T, Nagaya M, Wakamatsu N (2004) Clinical and molecular analysis of Mowat-Wilson syndrome associated with ZFHX1B mutations and deletions at 2q22-q24.1. J Med Genet 41:387–393Google Scholar
  47. Jalanko A, Manninen T, Peltonen L (1995) Deletion of the C-terminal end of aspartylglucosaminidase resulting in a lysosomal accumulation disease: evidence for a unique genomic rearrangement. Hum Mol Genet 4:435–441PubMedGoogle Scholar
  48. Janicic N, Pausova Z, Cole DE, Hendy GN (1995) Insertion of an Alu sequence in the Ca2+ -sensing receptor gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Am J Hum Genet 56:880–886PubMedGoogle Scholar
  49. Jurka J (1997) Sequence patterns indicate an enzymatic involvement in integration of mammalian retroposons. Proc Natl Acad Sci USA 94:1872–1877CrossRefPubMedGoogle Scholar
  50. Jurka J, Klonowski P, Dagman V, Pelton P (1996) CENSOR–a program for identification and elimination of repetitive elements from DNA sequences. Comput Chem 20:119–122CrossRefPubMedGoogle Scholar
  51. Jurka J, Krnjajic M, Kapitonov VV, Stenger JE, Kokhanyy O (2002) Active Alu elements are passed primarily through paternal germlines. Theor Popul Biol 61:519–530PubMedGoogle Scholar
  52. Jurka J, Kohany O, Pavlicek A, Kapitonov VV, Jurka MV (2004) Duplication, coclustering, and selection of human Alu retrotransposons. Proc Natl Acad Sci USA 101:1268–1272PubMedGoogle Scholar
  53. Kapitonov V, Jurka J (1996) The age of Alu subfamilies. J Mol Evol 42:59–65PubMedGoogle Scholar
  54. Kazazian HH Jr (2004) Mobile elements: drivers of genome evolution. Science 303:1626–1632CrossRefPubMedGoogle Scholar
  55. Kazazian HH Jr, Goodier JL (2002) LINE drive. retrotransposition and genome instability. Cell 110:277–280CrossRefPubMedGoogle Scholar
  56. Kazazian HH Jr, Wong C, Youssoufian H, Scott AF, Phillips DG, Antonarakis SE (1988) Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man. Nature 332:164–166CrossRefPubMedGoogle Scholar
  57. Kimberland ML, Divoky V, Prchal J, Schwahn U, Berger W, Kazazian HH Jr (1999) Full-length human L1 insertions retain the capacity for high frequency retrotransposition in cultured cells. Hum Mol Genet 8:1557–1560CrossRefPubMedGoogle Scholar
  58. Kobayashi K, Nakahori Y, Miyake M, Matsumura K, Kondo-Iida E, Nomura Y, Segawa M, Yoshioka M, Saito K, Osawa M, Hamano K, Sakakihara Y, Nonaka I, Nakagome Y, Kanazawa I, Nakamura Y, Tokunaga K, Toda T (1998) An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394:388–392PubMedGoogle Scholar
  59. Kolosha VO, Martin SL (2003) High-affinity, non-sequence-specific RNA binding by the open reading frame 1 (ORF1) protein from long interspersed nuclear element 1 (LINE-1). J Biol Chem 278:8112–8117CrossRefPubMedGoogle Scholar
  60. Kondo-Iida E, Kobayashi K, Watanabe M, Sasaki J, Kumagai T, Koide H, Saito K, Osawa M, Nakamura Y, Toda T (1999) Novel mutations and genotype-phenotype relationships in 107 families with Fukuyama-type congenital muscular dystrophy (FCMD). Hum Mol Genet 8:2303–2309CrossRefPubMedGoogle Scholar
  61. Korenberg JR, Rykowski MC (1988) Human genome organization: Alu, lines, and the molecular structure of metaphase chromosome bands. Cell 53:391–400CrossRefPubMedGoogle Scholar
  62. Kutsche K, Ressler B, Katzera HG, Orth U, Gillessen-Kaesbach G, Morlot S, Schwinger E, Gal A (2002) Characterization of breakpoint sequences of five rearrangements in L1CAM and ABCD1 (ALD) genes. Hum Mutat 19:526–535CrossRefPubMedGoogle Scholar
  63. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann N, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M, Gibbs RA, Muzny DM, Scherer SE, Bouck JB, Sodergren EJ, Worley KC, Rives CM, Gorrell JH, Metzker ML, Naylor SL, Kucherlapati RS, Nelson DL, Weinstock GM, Sakaki Y, Fujiyama A, Hattori M, Yada T, Toyoda A, Itoh T, Kawagoe C, Watanabe H, Totoki Y, Taylor T, Weissenbach J, Heilig R, Saurin W, Artiguenave F, Brottier P, Bruls T, Pelletier E, Robert C, Wincker P, Smith DR, Doucette-Stamm L, Rubenfield M, Weinstock K, Lee HM, Dubois J, Rosenthal A, Platzer M, Nyakatura G, Taudien S, Rump A, Yang H, Yu J, Wang J, Huang G, Gu J, Hood L, Rowen L, Madan A, Qin S, Davis RW, Federspiel NA, Abola AP, Proctor MJ, Myers RM, Schmutz J, Dickson M, Grimwood J, Cox DR, Olson MV, Kaul R, Raymond C, Shimizu N, Kawasaki K, Minoshima S, Evans GA, Athanasiou M, Schultz R, Roe BA, Chen F, Pan H, Ramser J, Lehrach H, Reinhardt R, McCombie WR, de la Bastide M, Dedhia N, Blocker H, Hornischer K, Nordsiek G, Agarwala R, Aravind L, Bailey JA, Bateman A, Batzoglou S, Birney E, Bork P, Brown DG, Burge CB, Cerutti L, Chen HC, Church D, Clamp M, Copley RR, Doerks T, Eddy SR, Eichler EE, Furey TS, Galagan J, Gilbert JG, Harmon C, Hayashizaki Y, Haussler D, Hermjakob H, Hokamp K, Jang W, Johnson LS, Jones TA, Kasif S, Kaspryzk A, Kennedy S, Kent WJ, Kitts P, Koonin EV, Korf I, Kulp D, Lancet D, Lowe TM, McLysaght A, Mikkelsen T, Moran JV, Mulder N, Pollara VJ, Ponting CP, Schuler G, Schultz J, Slater G, Smit AF, Stupka E, Szustakowski J, Thierry-Mieg D, Thierry-Mieg J, Wagner L, Wallis J, Wheeler R, Williams A, Wolf YI, Wolfe KH, Yang SP, Yeh RF, Collins F, Guyer MS, Peterson J, Felsenfeld A, Wetterstrand KA, Patrinos A, Morgan MJ, Szustakowki J, de Jong P, Catanese JJ, Osoegawa K, Shizuya H, Choi S, Chen YJ; International Human Genome Sequencing Consortium (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921CrossRefPubMedGoogle Scholar
  64. Lester T, McMahon C, Van Regemorter N, Jones A, Genet S (1997) X-linked immunodeficiency caused by insertion of Alu repeat sequences. J Med Genet 34(Supp1):S81 (abstract)Google Scholar
  65. Li X, Scaringe WA, Hill KA, Roberts S, Mengos A, Careri D, Pinto MT, Kasper CK, Sommer SS (2001) Frequency of recent retrotransposition events in the human factor IX gene. Hum Mutat 17:511–519CrossRefPubMedGoogle Scholar
  66. Luan DD, Korman MH, Jakubczak JL, Eickbush TH (1993) Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: a mechanism for non-LTR retrotransposition. Cell 72:595–605PubMedGoogle Scholar
  67. Mager DL, Henthorn PS, Smithies O (1985) A Chinese Gγ+ (Aγδβ)° thalassemia deletion: comparison to other deletions in the human β-globin gene cluster and sequence analysis of the breakpoints. Nucleic Acids Res 13:6559–6575PubMedGoogle Scholar
  68. Martinez-Garay I, Ballesta MJ, Oltra S, Orellana C, Palomeque A, Molto MD, Prieto F, Martinez F (2003) Intronic L1 insertion and F268S, novel mutations in RPS6KA3 (RSK2) causing Coffin-Lowry syndrome. Clin Genet 64:491–496CrossRefPubMedGoogle Scholar
  69. Mathias SL, Scott AF, Kazazian HH Jr, Boeke JD, Gabriel A (1991) Reverse transcriptase encoded by a human transposable element. Science 254:1808–1810PubMedGoogle Scholar
  70. Meischl C, Boer M, Ahlin A, Roos D (2000) A new exon created by intronic insertion of a rearranged LINE-1 element as the cause of chronic granulomatous disease. Eur J Hum Genet 8:697–703CrossRefPubMedGoogle Scholar
  71. Miki Y, Nishisho I, Horii A, Miyoshi Y, Utsunomiya J, Kinzler KW, Vogelstein B, Nakamura Y (1992) Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Res 52:643–645PubMedGoogle Scholar
  72. Miki Y, Katagiri T, Kasumi F, Yoshimoto T, Nakamura Y (1996) Mutation analysis in the BRCA2 gene in primary breast cancers. Nat Genet 13:245–247CrossRefPubMedGoogle Scholar
  73. Moran JV, Gilbert N (2002) Mammalian LINE-1 retrotransposons and related elements. In: Craig N, Craggie R, Gellert M, Lambowitz A (eds) Mobile DNA II. ASM, Washington D.C., pp 836–869Google Scholar
  74. Moran JV, Holmes SE, Naas TP, DeBerardinis RJ, Boeke JD, Kazazian HH Jr (1996) High frequency retrotransposition in cultured mammalian cells. Cell 87:917–927CrossRefPubMedGoogle Scholar
  75. Moran JV, DeBerardinis RJ, Kazazian HH Jr (1999) Exon shuffling by L1 retrotransposition. Science 283:1530–1534Google Scholar
  76. Morrish TA, Gilbert N, Myers JS, Vincent BJ, Stamato TD, Taccioli GE, Batzer MA, Moran JV (2002) DNA repair mediated by endonuclease-independent LINE-1 retrotransposition. Nat Genet 31:159–165CrossRefPubMedGoogle Scholar
  77. Mukherjee S, Mukhopadhyay A, Banerjee D, Chandak GR, Ray K (2004) Molecular pathology of haemophilia B: identification of five novel mutations including a LINE 1 insertion in Indian patients. Haemophilia 10:259–263CrossRefPubMedGoogle Scholar
  78. Muratani K, Hada T, Yamamoto Y, Kaneko T, Shigeto Y, Ohue T, Furuyama J, Higashino K (1991) Inactivation of the cholinesterase gene by Alu insertion: possible mechanism for human gene transposition. Proc Natl Acad Sci USA 88:11315–11319Google Scholar
  79. Mustajoki S, Ahola H, Mustajoki P, Kauppinen R (1999) Insertion of Alu element responsible for acute intermittent porphyria. Hum Mutat 13:431–438CrossRefPubMedGoogle Scholar
  80. Myers JS, Vincent BJ, Udall H, Watkins WS, Morrish TA, Kilroy GE, Swergold GD, Henke J, Henke L, Moran JV, Jorde LB, Batzer MA (2002) A comprehensive analysis of recently integrated human Ta L1 elements. Am J Hum Genet 71:312–326PubMedGoogle Scholar
  81. Narita N, Nishio H, Kitoh Y, Ishikawa Y, Ishikawa Y, Minami R, Nakamura H, Matsuo M (1993) Insertion of a 5’ truncated L1 element into the 3’ end of exon 44 of the dystrophin gene resulted in skipping of the exon during splicing in a case of Duchenne muscular dystrophy. J Clin Invest 91:1862–1867PubMedGoogle Scholar
  82. Ohshima K, Hattori M, Yada T, Gojobori T, Sakaki Y, Okada N (2003) Whole-genome screening indicates a possible burst of formation of processed pseudogenes and Alu repeats by particular L1 subfamilies in ancestral primates. Genome Biol 4:R74CrossRefPubMedGoogle Scholar
  83. Oldridge M, Zackai EH, McDonald-McGinn DM, Iseki S, Morriss-Kay GM, Twigg SR, Johnson D, Wall SA, Jiang W, Theda C, Jabs EW, Wilkie AO (1999) De novo alu-element insertions in FGFR2 identify a distinct pathological basis for Apert syndrome. Am J Hum Genet 64:446–461CrossRefPubMedGoogle Scholar
  84. Ostertag EM, Kazazian HH Jr (2001a) Biology of mammalian L1 retrotransposons. Annu Rev Genet 35:501–538CrossRefGoogle Scholar
  85. Ostertag EM, Kazazian HH Jr (2001b) Twin priming: a proposed mechanism for the creation of inversions in L1 retrotransposition. Genome Res 11:2059–2065CrossRefGoogle Scholar
  86. Ostertag EM, Goodier JL, Zhang Y, Kazazian HH Jr (2003) SVA elements are nonautonomous retrotransposons that cause disease in humans. Am J Hum Genet 73:1444–1451CrossRefPubMedGoogle Scholar
  87. Otieno AC, Carter AB, Hedges DJ, Walker JA, Ray DA, Garber RK, Anders BA, Stoilova N, Laborde ME, Fowlkes JD, Huang CH, Perodeau B, Batzer MA (2004) Analysis of the human Alu Ya-lineage. J Mol Biol 342:109–118CrossRefPubMedGoogle Scholar
  88. Ovchinnikov I, Troxel AB, Swergold GD (2001) Genomic characterization of recent human LINE-1 insertions: evidence supporting random insertion. Genome Res 11:2050–2058CrossRefPubMedGoogle Scholar
  89. Ovchinnikov I, Rubin A, Swergold GD (2002) Tracing the LINEs of human evolution. Proc Natl Acad Sci USA 99:10522–10527Google Scholar
  90. Pavlicek A, Paces J, Zika R, Hejnar J (2002) Length distribution of long interspersed nucleotide elements (LINEs) and processed pseudogenes of human endogenous retroviruses: implications for retrotransposition and pseudogene detection. Gene 300:189–194CrossRefPubMedGoogle Scholar
  91. Pickeral OK, Makalowski W, Boguski MS, Boeke JD (2000) Frequent human genomic DNA transduction driven by LINE-1 retrotransposition. Genome Res 10:411–415CrossRefPubMedGoogle Scholar
  92. Read LR, Raynard SJ, Ruksc A, Baker MD (2004) Gene repeat expansion and contraction by spontaneous intrachromosomal homologous recombination in mammalian cells. Nucleic Acids Res 32:1184–1196Google Scholar
  93. Rohrer J, Minegishi Y, Richter D, Eguiguren J, Conley ME (1999) Unusual mutations in Btk: an insertion, a duplication, an inversion, and four large deletions. Clin Immunol 90:28–37CrossRefPubMedGoogle Scholar
  94. Roy AM, Carroll ML, Nguyen SV, Salem AH, Oldridge M, Wilkie AO, Batzer MA, Deininger PL (2000) Potential gene conversion and source genes for recently integrated Alu elements. Genome Res 10:1485–1495CrossRefPubMedGoogle Scholar
  95. Roy-Engel AM, Carroll ML, Vogel E, Garber RK, Nguyen SV, Salem AH, Batzer MA, Deininger PL (2001) Alu insertion polymorphisms for the study of human genomic diversity. Genetics 159:279–290PubMedGoogle Scholar
  96. Roy-Engel AM, Salem AH, Oyeniran OO, Deininger L, Hedges DJ, Kilroy GE, Batzer MA, Deininger PL (2002) Active Alu element “A-tails”: size does matter. Genome Res 12:1333–1344CrossRefPubMedGoogle Scholar
  97. Rozmahel R, Heng HH, Duncan AM, Shi XM, Rommens JM, Tsui LC (1997) Amplification of CFTR exon 9 sequences to multiple locations in the human genome. Genomics 45:554–561CrossRefPubMedGoogle Scholar
  98. Salem AH, Kilroy GE, Watkins WS, Jorde LB, Batzer MA (2003a) Recently integrated Alu elements and human genomic diversity. Mol Biol Evol 20:1349–1361CrossRefGoogle Scholar
  99. Salem AH, Myers JS, Otieno AC, Watkins WS, Jorde LB, Batzer MA (2003b) LINE-1 preTa elements in the human genome. J Mol Biol 326:1127–1146CrossRefGoogle Scholar
  100. Salem AH, Ray DA, Batzer MA (2005) Identity by descent and DNA sequence variation of human SINE and LINE elements. Cytogenet Genome Res 108:63–72CrossRefPubMedGoogle Scholar
  101. Sassaman DM, Dombroski BA, Moran JV, Kimberland ML, Naas TP, DeBerardinis RJ, Gabriel A, Swergold GD, Kazazian HH Jr (1997) Many human L1 elements are capable of retrotransposition. Nat Genet 16:37–43CrossRefPubMedGoogle Scholar
  102. Schwahn U, Lenzner S, Dong J, Feil S, Hinzmann B, van Duijnhoven G, Kirschner R, Hemberger M, Bergen AA, Rosenberg T, Pinckers AJ, Fundele R, Rosenthal A, Cremers FP, Ropers HH, Berger W (1998) Positional cloning of the gene for X-linked retinitis pigmentosa 2. Nat Genet 19:327–332CrossRefPubMedGoogle Scholar
  103. Scott AF, Schmeckpeper BJ, Abdelrazik M, Comey CT, O’Hara B, Rossiter JP, Cooley T, Heath P, Smith KD, Margolet L (1987) Origin of the human L1 elements: proposed progenitor genes deduced from a consensus DNA sequence. Genomics 1:113–125CrossRefPubMedGoogle Scholar
  104. Segal Y, Peissel B, Renieri A, de Marchi M, Ballabio A, Pei Y, Zhou J (1999) LINE-1 elements at the sites of molecular rearrangements in Alport syndrome-diffuse leiomyomatosis. Am J Hum Genet 64:62–69CrossRefPubMedGoogle Scholar
  105. Sheen FM, Sherry ST, Risch GM, Robichaux M, Nasidze I, Stoneking M, Batzer MA, Swergold GD (2000) Reading between the LINEs: human genomic variation induced by LINE-1 retrotransposition. Genome Res 10:1496–1508CrossRefPubMedGoogle Scholar
  106. Skowronski J, Fanning TG, Singer MF (1988) Unit-length line-1 transcripts in human teratocarcinoma cells. Mol Cell Biol 8:1385–1397PubMedGoogle Scholar
  107. Smit AF, Toth G, Riggs AD, Jurka J (1995) Ancestral, mammalian-wide subfamilies of LINE-1 repetitive sequences. J Mol Biol 246:401–417CrossRefPubMedGoogle Scholar
  108. Soriano P, Meunier-Rotival M, Bernardi G (1983) The distribution of interspersed repeats is nonuniform and conserved in the mouse and human genomes. Proc Natl Acad Sci USA 80:1816–1820Google Scholar
  109. Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, Abeysinghe S, Krawczak M, Cooper DN (2003) Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat 21:577–581CrossRefPubMedGoogle Scholar
  110. Stoppa-Lyonnet D, Carter PE, Meo T, Tosi M (1990) Clusters of intragenic Alu repeats predispose the human C1 inhibitor locus to deleterious rearrangements. Proc Natl Acad Sci USA 87:1551–1555Google Scholar
  111. Strichman-Almashanu LZ, Lee RS, Onyango PO, Perlman E, Flam F, Frieman MB, Feinberg AP (2002) A genome-wide screen for normally methylated human CpG islands that can identify novel imprinted genes. Genome Res 12:543–554PubMedGoogle Scholar
  112. Su LK, Steinbach G, Sawyer JC, Hindi M, Ward PA, Lynch PM (2000) Genomic rearrangements of the APC tumor-suppressor gene in familial adenomatous polyposis. Hum Genet 106:101–107PubMedGoogle Scholar
  113. Sukarova E, Dimovski AJ, Tchacarova P, Petkov GH, Efremov GD (2001) An Alu insert as the cause of a severe form of hemophilia A. Acta Haematol 106:126–129CrossRefPubMedGoogle Scholar
  114. Symer DE, Connelly C, Szak ST, Caputo EM, Cost GJ, Parmigiani G, Boeke JD (2002) Human L1 retrotransposition is associated with genetic instability in vivo. Cell 110:327–338CrossRefPubMedGoogle Scholar
  115. Szak ST, Pickeral OK, Makalowski W, Boguski MS, Landsman D, Boeke JD (2002) Molecular archeology of L1 insertions in the human genome. Genome Biol 3:research0052.1–18CrossRefPubMedGoogle Scholar
  116. Tighe PJ, Stevens SE, Dempsey S, Le Deist F, Rieux-Laucat F, Edgar JD (2002) Inactivation of the Fas gene by Alu insertion: retrotransposition in an intron causing splicing variation and autoimmune lymphoproliferative syndrome. Genes Immunol 3(Suppl 1):S66–S70CrossRefGoogle Scholar
  117. Torrents D, Suyama M, Zdobnov E, Bork P (2003) A genome-wide survey of human pseudogenes. Genome Res 13:2559–2567CrossRefPubMedGoogle Scholar
  118. Vanin EF (1985) Processed pseudogenes: characteristics and evolution. Annu Rev Genet 19:253–272CrossRefPubMedGoogle Scholar
  119. Viale A, Ortola C, Richard F, Vernier P, Presse F, Schilling S, Dutrillaux B, Nahon JL (1998) Emergence of a brain-expressed variant melanin-concentrating hormone gene during higher primate evolution: a gene “in search of a function”. Mol Biol Evol 15:196–214PubMedGoogle Scholar
  120. Vidaud D, Vidaud M, Bahnak BR, Siguret V, Gispert Sanchez S, Laurian Y, Meyer D, Goossens M, Lavergne JM (1993) Haemophilia B due to a de novo insertion of a human-specific Alu subfamily member within the coding region of the factor IX gene. Eur J Hum Genet 1:30–36PubMedGoogle Scholar
  121. Vincent BJ, Myers JS, Ho HJ, Kilroy GE, Walker JA, Watkins WS, Jorde LB, Batzer MA (2003) Following the LINEs: an analysis of primate genomic variation at human-specific LINE-1 insertion sites. Mol Biol Evol 20:1338–1348CrossRefPubMedGoogle Scholar
  122. Voliva CF, Jahn CL, Comer MB, Hutchison CA III, Edgell MH (1983) The L1Md long interspersed repeat family in the mouse: almost all examples are truncated at one end. Nucleic Acids Res 11:8847–8859Google Scholar
  123. Wallace MR, Andersen LB, Saulino AM, Gregory PE, Glover TW, Collins FS (1991) A de novo Alu insertion results in neurofibromatosis type 1. Nature 353:864–866CrossRefPubMedGoogle Scholar
  124. Wang T, Lerer I, Gueta Z, Sagi M, Kadouri L, Peretz T, Abeliovich D (2001) A deletion/insertion mutation in the BRCA2 gene in a breast cancer family: a possible role of the Alu-polyA tail in the evolution of the deletion. Genes Chromosomes Cancer 31:91–95CrossRefPubMedGoogle Scholar
  125. van de Water N, Williams R, Ockelford P, Browett P (1998) A 20.7 kb deletion within the factor VIII gene associated with LINE-1 element insertion. Thromb Haemost 79:938–942PubMedGoogle Scholar
  126. Wei W, Gilbert N, Ooi SL, Lawler JF, Ostertag EM, Kazazian HH, Boeke JD, Moran JV (2001) Human L1 retrotransposition: cis preference versus trans complementation. Mol Cell Biol 21:1429–1439CrossRefPubMedGoogle Scholar
  127. Wilund KR, Yi M, Campagna F, Arca M, Zuliani G, Fellin R, Ho YK, Garcia JV, Hobbs HH, Cohen JC (2002) Molecular mechanisms of autosomal recessive hypercholesterolemia. Hum Mol Genet 11:3019–3030CrossRefPubMedGoogle Scholar
  128. Wulff K, Gazda H, Schroder W, Robicka-Milewska R, Herrmann FH (2000) Identification of a novel large F9 gene mutation-an insertion of an Alu repeated DNA element in exon e of the factor 9 gene. Hum Mutat 15:299CrossRefGoogle Scholar
  129. Yoshida K, Nakamura A, Yazaki M, Ikeda S, Takeda S (1998) Insertional mutation by transposable element, L1, in the DMD gene results in X-linked dilated cardiomyopathy. Hum Mol Genet 7:1129–1132CrossRefPubMedGoogle Scholar
  130. Zhang Z, Gerstein M (2004) Large-scale analysis of pseudogenes in the human genome. Curr Opin Genet Dev 14:328–335CrossRefPubMedGoogle Scholar
  131. Zhang Y, Dipple KM, Vilain E, Huang BL, Finlayson G, Therrell BL, Worley K, Deininger P, McCabe ER (2000) AluY insertion (IVS4-52ins316 alu) in the glycerol kinase gene from an individual with benign glycerol kinase deficiency. Hum Mutat 15:316–323CrossRefPubMedGoogle Scholar
  132. Zhang Z, Harrison PM, Liu Y, Gerstein M (2003) Millions of years of evolution preserved: a comprehensive catalog of the processed pseudogenes in the human genome. Genome Res 13:2541–2558CrossRefPubMedGoogle Scholar
  133. Zietkiewicz E, Richer C, Sinnett D, Labuda D (1998) Monophyletic origin of Alu elements in primates. J Mol Evol 47:172–182PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Jian-Min Chen
    • 1
  • Peter D. Stenson
    • 2
  • David N. Cooper
    • 2
  • Claude Férec
    • 1
  1. 1.INSERM (Institut National de la Santé et de la Recherche Médicale) U613–Génétique Moléculaire et Génétique Epidémiologique, Etablissement Français du Sang–BretagneUniversité de Bretagne Occidentale, Centre Hospitalier UniversitaireBrestFrance
  2. 2.Institute of Medical GeneticsCardiff UniversityCardiffUK

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