LINE-1 elements in structural variation and disease.

The completion of the human genome reference sequence ushered in a new era for the study and discovery of human transposable elements. It now is undeniable that transposable elements, historically dismissed as junk DNA, have had an instrumental role in sculpting the structure and function of our genomes. In particular, long interspersed element-1 (LINE-1 or L1) and short interspersed elements (SINEs) continue to affect our genome, and their movement can lead to sporadic cases of disease. Here, we briefly review the types of transposable elements present in the human genome and their mechanisms of mobility. We next highlight how advances in DNA sequencing and genomic technologies have enabled the discovery of novel retrotransposons in individual genomes. Finally, we discuss how L1-mediated retrotransposition events impact human genomes.

[1]  S. Holmes,et al.  Studies on p40, the leucine zipper motif-containing protein encoded by the first open reading frame of an active human LINE-1 transposable element. , 1992, The Journal of biological chemistry.

[2]  C. Y. Yu,et al.  Structure and genetics of the partially duplicated gene RP located immediately upstream of the complement C4A and the C4B genes in the HLA class III region. Molecular cloning, exon-intron structure, composite retroposon, and breakpoint of gene duplication. , 1994, The Journal of biological chemistry.

[3]  Jinchuan Xing,et al.  Mobile element scanning (ME-Scan) by targeted high-throughput sequencing , 2010, BMC Genomics.

[4]  W S Watkins,et al.  Large-scale analysis of the Alu Ya5 and Yb8 subfamilies and their contribution to human genomic diversity. , 2001, Journal of molecular biology.

[5]  P. Deininger,et al.  The impact of multiple splice sites in human L1 elements. , 2008, Gene.

[6]  C. Feschotte,et al.  The evolutionary history of human DNA transposons: evidence for intense activity in the primate lineage. , 2007, Genome research.

[7]  R. Britten,et al.  Regulation of gene expression: possible role of repetitive sequences. , 1979, Science.

[8]  Kenji Nakamura,et al.  Deletion of Peg10, an imprinted gene acquired from a retrotransposon, causes early embryonic lethality , 2006, Nature Genetics.

[9]  N. Saitou,et al.  Possible involvement of SINEs in mammalian-specific brain formation , 2008, Proceedings of the National Academy of Sciences.

[10]  W. Greene,et al.  The APOBEC3 cytidine deaminases: an innate defensive network opposing exogenous retroviruses and endogenous retroelements. , 2008, Annual review of immunology.

[11]  Jerilyn A. Walker,et al.  SVA elements: a hominid-specific retroposon family. , 2005, Journal of molecular biology.

[12]  Fred H. Gage,et al.  L1 retrotransposition in neurons is modulated by MeCP2 , 2010, Nature.

[13]  P. Deininger,et al.  All y'all need to know 'bout retroelements in cancer. , 2010, Seminars in cancer biology.

[14]  M. Speek,et al.  L1 Antisense Promoter Drives Tissue-Specific Transcription of Human Genes , 2006, Journal of biomedicine & biotechnology.

[15]  M. Batzer,et al.  Genomic rearrangements by LINE-1 insertion-mediated deletion in the human and chimpanzee lineages , 2005, Nucleic acids research.

[16]  M. Batzer,et al.  Alu repeats and human genomic diversity , 2002, Nature Reviews Genetics.

[17]  Mark Gerstein,et al.  Millions of years of evolution preserved: a comprehensive catalog of the processed pseudogenes in the human genome. , 2003, Genome research.

[18]  Steffen Lenzner,et al.  Positional cloning of the gene for X-linked retinitis pigmentosa 2 , 1998, Nature Genetics.

[19]  J. Kawai,et al.  The regulated retrotransposon transcriptome of mammalian cells , 2009, Nature Genetics.

[20]  T. Eickbush,et al.  Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: A mechanism for non-LTR retrotransposition , 1993, Cell.

[21]  J. V. Moran,et al.  Distinct mechanisms for trans-mediated mobilization of cellular RNAs by the LINE-1 reverse transcriptase. , 2007, Genome research.

[22]  Peter D Stenson,et al.  Meta‐Analysis of gross insertions causing human genetic disease: Novel mutational mechanisms and the role of replication slippage , 2005, Human mutation.

[23]  H. Kazazian,et al.  Discrete subcellular partitioning of human retrotransposon RNAs despite a common mechanism of genome insertion. , 2010, Human molecular genetics.

[24]  D. Mager,et al.  Endogenous retroviral LTRs as promoters for human genes: a critical assessment. , 2009, Gene.

[25]  H. Kazazian,et al.  A new retrotransposable human L1 element from the LRE2 locus on chromosome 1q produces a chimaeric insertion , 1994, Nature Genetics.

[26]  J. Boeke,et al.  Transposon-mediated genome manipulation in vertebrates , 2009, Nature Methods.

[27]  E. L. Luning Prak,et al.  More active human L1 retrotransposons produce longer insertions. , 2004, Nucleic acids research.

[28]  K. Tokunaga,et al.  Deletion of entire HLA-A gene accompanied by an insertion of a retrotransposon. , 2007, Tissue antigens.

[29]  Thierry Heidmann,et al.  LINE-mediated retrotransposition of marked Alu sequences , 2003, Nature Genetics.

[30]  M. Batzer,et al.  An alternative pathway for Alu retrotransposition suggests a role in DNA double-strand break repair. , 2009, Genomics.

[31]  E. Ostertag,et al.  Evidence consistent with human L1 retrotransposition in maternal meiosis I. , 2002, American journal of human genetics.

[32]  J. V. Moran,et al.  Cis-preferential LINE-1 reverse transcriptase activity in ribonucleoprotein particles , 2006, Nature Structural &Molecular Biology.

[33]  M. Batzer,et al.  Alu Recombination-Mediated Structural Deletions in the Chimpanzee Genome , 2007, PLoS genetics.

[34]  D. Haussler,et al.  Species-specific endogenous retroviruses shape the transcriptional network of the human tumor suppressor protein p53 , 2007, Proceedings of the National Academy of Sciences.

[35]  B. Burwinkel,et al.  Unequal homologous recombination between LINE-1 elements as a mutational mechanism in human genetic disease. , 1998, Journal of molecular biology.

[36]  H. Heng,et al.  Amplification of CFTR exon 9 sequences to multiple locations in the human genome. , 1997, Genomics.

[37]  Timothy B. Stockwell,et al.  The Diploid Genome Sequence of an Individual Human , 2007, PLoS biology.

[38]  G. Montana,et al.  Efficiency of Xist-mediated silencing on autosomes is linked to chromosomal domain organisation , 2010, Epigenetics & Chromatin.

[39]  C. Schmid,et al.  RNA polymerase III promoter and terminator elements affect Alu RNA expression. , 1995, Nucleic acids research.

[40]  J. Boeke,et al.  Reverse transcriptase encoded by a human transposable element. , 1991, Science.

[41]  T. Südhof,et al.  Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. , 1985, Science.

[42]  R. E. Thayer,et al.  Binding of the ubiquitous nuclear transcription factor YY1 to a cis regulatory sequence in the human LINE-1 transposable element. , 1993, Human molecular genetics.

[43]  I. Arkhipova,et al.  Telomere-associated endonuclease-deficient Penelope-like retroelements in diverse eukaryotes , 2007, Proceedings of the National Academy of Sciences.

[44]  Kathryn A. O’Donnell,et al.  Mobilizing diversity: transposable element insertions in genetic variation and disease , 2010, Mobile DNA.

[45]  James J. Cai,et al.  Widespread establishment and regulatory impact of Alu exons in human genes , 2011, Proceedings of the National Academy of Sciences.

[46]  E. Meese,et al.  The human L1 promoter: variable transcription initiation sites and a major impact of upstream flanking sequence on promoter activity. , 2004, Genome research.

[47]  T. Heidmann,et al.  Members of the SRY family regulate the human LINE retrotransposons. , 2000, Nucleic acids research.

[48]  Jef D. Boeke,et al.  Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes , 2004, Nature.

[49]  J. V. Moran,et al.  Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells , 2010, Nature.

[50]  Fred Dyda,et al.  Transposition of hAT elements links transposable elements and V(D)J recombination , 2004, Nature.

[51]  D. Largaespada,et al.  A transposon and transposase system for human application. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[52]  M. Batzer,et al.  Extensive individual variation in L1 retrotransposition capability contributes to human genetic diversity. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[53]  E. H. Margulies,et al.  An Expressed Fgf4 Retrogene Is Associated with Breed-Defining Chondrodysplasia in Domestic Dogs , 2009, Science.

[54]  M. Speek.  Antisense Promoter of Human L1 Retrotransposon Drives Transcription of Adjacent Cellular Genes , 2001, Molecular and Cellular Biology.

[55]  D. Keller,et al.  Spatial assembly and RNA binding stoichiometry of a LINE-1 protein essential for retrotransposition. , 2006, Journal of molecular biology.

[56]  Stéphane Boissinot,et al.  Molecular evolution and tempo of amplification of human LINE-1 retrotransposons since the origin of primates. , 2005, Genome research.

[57]  S. Boissinot,et al.  Adaptive evolution in LINE-1 retrotransposons. , 2001, Molecular biology and evolution.

[58]  Li Wang,et al.  PBmice: an integrated database system of piggyBac (PB) insertional mutations and their characterizations in mice , 2007, Nucleic Acids Res..

[59]  A. Ballabio,et al.  LINE-1 elements at the sites of molecular rearrangements in Alport syndrome-diffuse leiomyomatosis. , 1999, American journal of human genetics.

[60]  J. V. Moran,et al.  LINE-1 retrotransposition in human embryonic stem cells. , 2007, Human molecular genetics.

[61]  J. V. Moran,et al.  Many human L1 elements are capable of retrotransposition , 1997, Nature Genetics.

[62]  M. Batzer,et al.  Retrotransposition of Alu elements: how many sources? , 2004, Trends in genetics : TIG.

[63]  Oliver H. Tam,et al.  Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes , 2008, Nature.

[64]  P. Deininger,et al.  Mammalian non-LTR retrotransposons: for better or worse, in sickness and in health. , 2008, Genome research.

[65]  E. Ostertag,et al.  Transduction of 3'-flanking sequences is common in L1 retrotransposition. , 2000, Human molecular genetics.

[66]  Eric C. Rouchka,et al.  Assessment of genetic variation for the LINE-1 retrotransposon from next generation sequence data , 2010, BMC Bioinformatics.

[67]  Ryan E. Mills,et al.  Recently mobilized transposons in the human and chimpanzee genomes. , 2006, American journal of human genetics.

[68]  Andrew F. Neuwald,et al.  Natural Mutagenesis of Human Genomes by Endogenous Retrotransposons , 2010, Cell.

[69]  Agnes Hotz-Wagenblatt,et al.  Characteristics of Transposable Element Exonization within Human and Mouse , 2010, PloS one.

[70]  H. Kazazian,et al.  Progress in understanding the biology of the human mutagen LINE‐1 , 2007, Human mutation.

[71]  H. Kazazian,et al.  Retrotransposition of marked SVA elements by human L1s in cultured cells. , 2011, Human molecular genetics.

[72]  W A Scaringe,et al.  Frequency of recent retrotransposition events in the human factor IX gene , 2001, Human mutation.

[73]  T. Eickbush,et al.  R2 Target-Primed Reverse Transcription: Ordered Cleavage and Polymerization Steps by Protein Subunits Asymmetrically Bound to the Target DNA , 2005, Molecular and Cellular Biology.

[74]  K. Kawakami.  Transposon tools and methods in zebrafish , 2005, Developmental dynamics : an official publication of the American Association of Anatomists.

[75]  C. Alonso,et al.  Characterization of a non-long terminal repeat retrotransposon cDNA (L1Tc) from Trypanosoma cruzi: homology of the first ORF with the ape family of DNA repair enzymes. , 1995, Journal of molecular biology.

[76]  J. V. Moran,et al.  Characterization of LINE-1 Ribonucleoprotein Particles , 2010, PLoS genetics.

[77]  M. Matsuo,et al.  Branchio-oto-renal syndrome caused by partial EYA1 deletion due to LINE-1 insertion , 2010, Pediatric Nephrology.

[78]  T. Fanning,et al.  The LINE-1 DNA sequences in four mammalian orders predict proteins that conserve homologies to retrovirus proteins. , 1987, Nucleic acids research.

[79]  C. Hutchison,et al.  Master genes in mammalian repetitive DNA amplification. , 1992, Trends in genetics : TIG.

[80]  Stephen L. Gasior,et al.  The human LINE-1 retrotransposon creates DNA double-strand breaks. , 2006, Journal of molecular biology.

[81]  P. Deininger,et al.  RNA truncation by premature polyadenylation attenuates human mobile element activity , 2003, Nature Genetics.

[82]  M. Batzer,et al.  Alu retrotransposition-mediated deletion. , 2005, Journal of molecular biology.

[83]  Min Han,et al.  Efficient Transposition of the piggyBac (PB) Transposon in Mammalian Cells and Mice , 2005, Cell.

[84]  E. Eichler,et al.  Fine-scale structural variation of the human genome , 2005, Nature Genetics.

[85]  P. Stenson,et al.  A systematic analysis of LINE-1 endonuclease-dependent retrotranspositional events causing human genetic disease , 2005, Human Genetics.

[86]  David Gresham,et al.  Global Mapping of Transposon Location , 2006, PLoS genetics.

[87]  R. Maraia,et al.  The decline in human Alu retroposition was accompanied by an asymmetric decrease in SRP9/14 binding to dimeric Alu RNA and increased expression of small cytoplasmic Alu RNA , 1997, Molecular and cellular biology.

[88]  Daniel G. Miller,et al.  A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy , 2010, Science.

[89]  Oliver Weichenrieder,et al.  Non-LTR retrotransposons encode noncanonical RRM domains in their first open reading frame , 2009, Proceedings of the National Academy of Sciences.

[90]  W. Berger,et al.  Full-length human L1 insertions retain the capacity for high frequency retrotransposition in cultured cells. , 1999, Human molecular genetics.

[91]  Norbert Bannert,et al.  The evolutionary dynamics of human endogenous retroviral families. , 2006, Annual review of genomics and human genetics.

[92]  E. Eichler,et al.  A Human Genome Structural Variation Sequencing Resource Reveals Insights into Mutational Mechanisms , 2010, Cell.

[93]  R. Plasterk,et al.  Molecular Reconstruction of Sleeping Beauty , a Tc1-like Transposon from Fish, and Its Transposition in Human Cells , 1997, Cell.

[94]  Circe W. Tsui,et al.  Natural Genetic Variation Caused by Transposable Elements in Humans , 2004, Genetics.

[95]  David A Largaespada,et al.  Hopping around the tumor genome: transposons for cancer gene discovery. , 2005, Cancer research.

[96]  David J Griffiths,et al.  Insertional polymorphisms: a new lease of life for endogenous retroviruses in human disease. , 2007, Trends in genetics : TIG.

[97]  A. Buzdin,et al.  A new family of chimeric retrotranscripts formed by a full copy of U6 small nuclear RNA fused to the 3' terminus of l1. , 2002, Genomics.

[98]  N. Yang,et al.  An important role for RUNX3 in human L1 transcription and retrotransposition. , 2003, Nucleic acids research.

[99]  S. Martin,et al.  In vitro properties of the first ORF protein from mouse LINE-1 support its role in ribonucleoprotein particle formation during retrotransposition. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[100]  D. Haussler,et al.  A distal enhancer and an ultraconserved exon are derived from a novel retroposon , 2006, Nature.

[101]  L. Carrel,et al.  Genomic Environment Predicts Expression Patterns on the Human Inactive X Chromosome , 2006, PLoS genetics.

[102]  J. V. Moran,et al.  Exon shuffling by L1 retrotransposition. , 1999, Science.

[103]  Katsushi Tokunaga,et al.  Exon-trapping mediated by the human retrotransposon SVA. , 2009, Genome research.

[104]  D. Conrad,et al.  Global variation in copy number in the human genome , 2006, Nature.

[105]  M. Batzer,et al.  The impact of retrotransposons on human genome evolution , 2009, Nature Reviews Genetics.

[106]  T. Fanning,et al.  Differential methylation of human LINE-1 retrotransposons in malignant cells. , 1996, Gene.

[107]  M. Hattori,et al.  Identification of an internal cis-element essential for the human L1 transcription and a nuclear factor(s) binding to the element. , 1992, Nucleic acids research.

[108]  B. Mcclintock.  The origin and behavior of mutable loci in maize , 1950, Proceedings of the National Academy of Sciences.

[109]  J. V. Moran,et al.  Unconventional translation of mammalian LINE-1 retrotransposons. , 2006, Genes & development.

[110]  Dan Graur,et al.  Deletions in processed pseudogenes accumulate faster in rodents than in humans , 1989, Journal of Molecular Evolution.

[111]  D. Largaespada,et al.  Efficient Transposition of Tol2 in the Mouse Germline , 2009, Genetics.

[112]  D. Conrad,et al.  A high-resolution survey of deletion polymorphism in the human genome , 2006, Nature Genetics.

[113]  S. Boissinot,et al.  L1 (LINE-1) retrotransposon evolution and amplification in recent human history. , 2000, Molecular biology and evolution.

[114]  I. Georgiou,et al.  Retrotransposon RNA expression and evidence for retrotransposition events in human oocytes. , 2009, Human molecular genetics.

[115]  Jie Zhang,et al.  Nuclear Receptor-Induced Chromosomal Proximity and DNA Breaks Underlie Specific Translocations in Cancer , 2009, Cell.

[116]  J. Connolly,et al.  Comparative expression of the LINE-1 p40 protein in human breast carcinomas and normal breast tissues. , 1996, Oncology research.

[117]  E. Eichler,et al.  An Alu transposition model for the origin and expansion of human segmental duplications. , 2003, American journal of human genetics.

[118]  M. Batzer,et al.  Recently integrated human Alu repeats: finding needles in the haystack , 2004, Genetica.

[119]  Dawei Li,et al.  The diploid genome sequence of an Asian individual , 2008, Nature.

[120]  E. Ostertag,et al.  Twin priming: a proposed mechanism for the creation of inversions in L1 retrotransposition. , 2001, Genome research.

[121]  Kenny Q. Ye,et al.  Mapping copy number variation by population scale genome sequencing , 2010, Nature.

[122]  C. Férec,et al.  A large genomic deletion in the PDHX gene caused by the retrotranspositional insertion of a full‐length LINE‐1 element , 2007, Human mutation.

[123]  P. Deininger,et al.  Diverse cis factors controlling Alu retrotransposition: what causes Alu elements to die? , 2009, Genome research.

[124]  Jef D Boeke,et al.  Human L1 Retrotransposon Encodes a Conserved Endonuclease Required for Retrotransposition , 1996, Cell.

[125]  E. Ostertag,et al.  SVA elements are nonautonomous retrotransposons that cause disease in humans. , 2003, American journal of human genetics.

[126]  M. Batzer,et al.  L1 recombination-associated deletions generate human genomic variation , 2008, Proceedings of the National Academy of Sciences.

[127]  T. Heidmann,et al.  Trex1 Prevents Cell-Intrinsic Initiation of Autoimmunity , 2008, Cell.

[128]  H. Hohjoh,et al.  Cytoplasmic ribonucleoprotein complexes containing human LINE‐1 protein and RNA. , 1996, The EMBO journal.

[129]  T. Heidmann,et al.  Role of poly(A) tail length in Alu retrotransposition. , 2005, Genomics.

[130]  Evan E. Eichler,et al.  LINE-1 Retrotransposition Activity in Human Genomes , 2010, Cell.

[131]  F. Gage,et al.  LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes? , 2010, Trends in Neurosciences.

[132]  H. Nishio,et al.  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. , 1993, The Journal of clinical investigation.

[133]  M. Davisson,et al.  Differential expression of a new dominant agouti allele (Aiapy) is correlated with methylation state and is influenced by parental lineage. , 1994, Genes & development.

[134]  K. Ohshima,et al.  Inference for the initial stage of domain shuffling: tracing the evolutionary fate of the PIPSL retrogene in hominoids. , 2010, Molecular biology and evolution.

[135]  Y. Yung,et al.  Neuronal DNA content variation (DCV) with regional and individual differences in the human brain , 2010, The Journal of comparative neurology.

[136]  A. Troxel,et al.  Genomic characterization of recent human LINE-1 insertions: evidence supporting random insertion. , 2001, Genome research.

[137]  Jef D Boeke,et al.  Human L1 element target‐primed reverse transcription in vitro , 2002, The EMBO journal.

[138]  G. Carmichael,et al.  Altered nuclear retention of mRNAs containing inverted repeats in human embryonic stem cells: functional role of a nuclear noncoding RNA. , 2009, Molecular cell.

[139]  L. Samuelson,et al.  Retrotransposons and the evolution of mammalian gene expression , 2004, Genetica.

[140]  J. Goodship,et al.  Long interspersed nuclear element‐1 (LINE1)‐mediated deletion of EVC, EVC2, C4orf6, and STK32B in Ellis–van Creveld syndrome with borderline intelligence , 2008, Human mutation.

[141]  S T Sherry,et al.  Reading between the LINEs: human genomic variation induced by LINE-1 retrotransposition. , 2000, Genome research.

[142]  E. Kirkness,et al.  Mobile elements create structural variation: analysis of a complete human genome. , 2009, Genome research.

[143]  P. Deininger,et al.  Somatic expression of LINE-1 elements in human tissues , 2010, Nucleic acids research.

[144]  J. Luban,et al.  Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1 , 2004, Nature.

[145]  Liane Gagnier,et al.  Retroviral Elements and Their Hosts: Insertional Mutagenesis in the Mouse Germ Line , 2006, PLoS genetics.

[146]  L. Feuk,et al.  Detection of large-scale variation in the human genome , 2004, Nature Genetics.

[147]  H. Kazazian,et al.  High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes. , 2010, Genome research.

[148]  J. V. Moran,et al.  A YY1-binding site is required for accurate human LINE-1 transcription initiation. , 2004, Nucleic acids research.

[149]  J. V. Moran,et al.  ATLAS: a system to selectively identify human-specific L1 insertions. , 2003, American journal of human genetics.

[150]  Gene W. Yeo,et al.  Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis , 2009, Nature Neuroscience.

[151]  N. Yang,et al.  L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells , 2006, Nature Structural &Molecular Biology.

[152]  M. Batzer,et al.  Recently integrated Alu elements and human genomic diversity. , 2003, Molecular biology and evolution.

[153]  M. Lyon,et al.  X-Chromosome inactivation: a repeat hypothesis , 1998, Cytogenetic and Genome Research.

[154]  Kenny Q. Ye,et al.  Large-Scale Copy Number Polymorphism in the Human Genome , 2004, Science.

[155]  R. Maraia,et al.  Terminator-specific Recycling of a B1-AluTranscription Complex by RNA Polymerase III Is Mediated by the RNA Terminus-binding Protein La* , 1998, The Journal of Biological Chemistry.

[156]  J. Löwer,et al.  Analysis of 5' junctions of human LINE-1 and Alu retrotransposons suggests an alternative model for 5'-end attachment requiring microhomology-mediated end-joining. , 2005, Genome research.

[157]  J. V. Moran,et al.  Genomic Deletions Created upon LINE-1 Retrotransposition , 2002, Cell.

[158]  J. V. Moran,et al.  Allelic heterogeneity in LINE-1 retrotransposition activity. , 2003, American journal of human genetics.

[159]  Francis Harper,et al.  Identification of an infectious progenitor for the multiple-copy HERV-K human endogenous retroelements. , 2006, Genome research.

[160]  C. Feschotte.  Transposable elements and the evolution of regulatory networks , 2008, Nature Reviews Genetics.

[161]  Jef D. Boeke,et al.  Human L1 Retrotransposition: cisPreference versus trans Complementation , 2001, Molecular and Cellular Biology.

[162]  M. Gerstein,et al.  Identification and analysis of over 2000 ribosomal protein pseudogenes in the human genome. , 2002, Genome research.

[163]  Michel J. Weber,et al.  Mammalian Small Nucleolar RNAs Are Mobile Genetic Elements , 2006, PLoS genetics.

[164]  M. Emerman,et al.  Antiretroelement activity of APOBEC3H was lost twice in recent human evolution. , 2008, Cell host & microbe.

[165]  Fred H. Gage,et al.  Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition , 2005, Nature.

[166]  Francisco M. De La Vega,et al.  Sequence and structural variation in a human genome uncovered by short-read, massively parallel ligation sequencing using two-base encoding. , 2009, Genome research.

[167]  M. Ono,et al.  A novel human nonviral retroposon derived from an endogenous retrovirus. , 1987, Nucleic acids research.

[168]  A. Weiner,et al.  Abundant pseudogenes for small nuclear RNAs are dispersed in the human genome. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[169]  H. Kazazian,et al.  Retrotransposons Revisited: The Restraint and Rehabilitation of Parasites , 2008, Cell.

[170]  Sandra L. Martin,et al.  Developmental biology: Jumping-gene roulette , 2009, Nature.

[171]  J. V. Moran,et al.  DNA repair mediated by endonuclease-independent LINE-1 retrotransposition , 2002, Nature Genetics.

[172]  Alan M. Lambowitz,et al.  Mobile DNA III , 2002 .

[173]  H. Kazazian,et al.  LINE-1 ORF1 Protein Localizes in Stress Granules with Other RNA-Binding Proteins, Including Components of RNA Interference RNA-Induced Silencing Complex , 2007, Molecular and Cellular Biology.

[174]  Pawel Stankiewicz,et al.  Genomic Disorders: Molecular Mechanisms for Rearrangements and Conveyed Phenotypes , 2005, PLoS genetics.

[175]  S. Antonarakis,et al.  Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man , 1988, Nature.

[176]  Thierry Heidmann,et al.  Human LINE retrotransposons generate processed pseudogenes , 2000, Nature Genetics.

[177]  H. Kazazian,et al.  Whole-genome resequencing allows detection of many rare LINE-1 insertion alleles in humans. , 2011, Genome research.

[178]  T. Heidmann,et al.  mRNA retroposition in human cells: processed pseudogene formation. , 1995, The EMBO journal.

[179]  Ivan N. Shatsky,et al.  Efficient Translation Initiation Directed by the 900-Nucleotide-Long and GC-Rich 5′ Untranslated Region of the Human Retrotransposon LINE-1 mRNA Is Strictly Cap Dependent Rather than Internal Ribosome Entry Site Mediated , 2007, Molecular and Cellular Biology.

[180]  Matthew D. Dyer,et al.  Human genomic deletions mediated by recombination between Alu elements. , 2006, American journal of human genetics.

[181]  F. Bushman,et al.  Nucleic Acid Chaperone Activity of the ORF1 Protein from the Mouse LINE-1 Retrotransposon , 2001, Molecular and Cellular Biology.

[182]  E. Eichler,et al.  Population Stratification of a Common APOBEC Gene Deletion Polymorphism , 2007, PLoS genetics.

[183]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[184]  J. V. Moran,et al.  Endonuclease-independent LINE-1 retrotransposition at mammalian telomeres , 2007, Nature.

[185]  J. V. Moran,et al.  Hot L1s account for the bulk of retrotransposition in the human population , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[186]  M. Boguski,et al.  Frequent human genomic DNA transduction driven by LINE-1 retrotransposition. , 2000, Genome research.

[187]  G. Swergold,et al.  Tracing the LINEs of human evolution , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[188]  M. Batzer,et al.  Emergence of primate genes by retrotransposon-mediated sequence transduction , 2006, Proceedings of the National Academy of Sciences.

[189]  E. Ullu,et al.  Evolutionary conservation of the human 7 S RNA sequences. , 1982, Journal of molecular biology.

[190]  S. Dhanasekaran,et al.  Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer , 2007, Nature.

[191]  A. F. Scott,et al.  Isolation of an active human transposable element. , 1991, Science.

[192]  K. Kinzler,et al.  Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. , 1992, Cancer research.

[193]  E. Meese,et al.  Multiple human endogenous retrovirus (HERV-K) loci with gag open reading frames in the human genome. , 1997, Cytogenetics and cell genetics.

[194]  A. Weiner,et al.  Direct repeats flank three small nuclear RNA pseudogenes in the human genome , 1981, Cell.

[195]  P. Bieniasz,et al.  Reconstitution of an Infectious Human Endogenous Retrovirus , 2007, PLoS pathogens.

[196]  A. Weiner,et al.  Nonviral retroposons: genes, pseudogenes, and transposable elements generated by the reverse flow of genetic information. , 1986, Annual review of biochemistry.

[197]  M. Belfort,et al.  The beginning of the end: Links between ancient retroelements and modern telomerases , 2007, Proceedings of the National Academy of Sciences.

[198]  G. Swergold.  Identification, characterization, and cell specificity of a human LINE-1 promoter , 1990, Molecular and cellular biology.

[199]  M. Speek,et al.  Many human genes are transcribed from the antisense promoter of L1 retrotransposon. , 2002, Genomics.

[200]  S. Martin,et al.  Tightly regulated, developmentally specific expression of the first open reading frame from LINE-1 during mouse embryogenesis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[201]  E. Ostertag,et al.  L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. , 2009, Genes & development.

[202]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[203]  Gene W. Yeo,et al.  L1 retrotransposition in human neural progenitor cells , 2009, Nature.

[204]  Lichun Yang,et al.  Trans mobilization of genomic DNA as a mechanism for retrotransposon-mediated exon shuffling. , 2003, Human molecular genetics.

[205]  J. Jurka.  Conserved eukaryotic transposable elements and the evolution of gene regulation , 2007, Cellular and Molecular Life Sciences.

[206]  Joshua M. Korn,et al.  Mapping and sequencing of structural variation from eight human genomes , 2008, Nature.

[207]  J. Skowroński,et al.  Unit-length line-1 transcripts in human teratocarcinoma cells , 1988, Molecular and cellular biology.

[208]  Nancy F. Hansen,et al.  Accurate Whole Human Genome Sequencing using Reversible Terminator Chemistry , 2008, Nature.

[209]  J. V. Moran,et al.  A comprehensive analysis of recently integrated human Ta L1 elements. , 2002, American journal of human genetics.

[210]  T. Hayakawa,et al.  Alu-mediated inactivation of the human CMP- N-acetylneuraminic acid hydroxylase gene , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[211]  Robert Belshaw,et al.  Genomewide Screening Reveals High Levels of Insertional Polymorphism in the Human Endogenous Retrovirus Family HERV-K(HML2): Implications for Present-Day Activity , 2005, Journal of Virology.

[212]  M. Gerstein,et al.  Transcribed processed pseudogenes in the human genome: an intermediate form of expressed retrosequence lacking protein-coding ability , 2005, Nucleic acids research.

[213]  Deepak Grover,et al.  dbRIP: A highly integrated database of retrotransposon insertion polymorphisms in humans , 2006, Human mutation.

[214]  Deniz Yorukoglu,et al.  Alu repeat discovery and characterization within human genomes. , 2011, Genome research.

[215]  P. Simmonds,et al.  Allelic Variation of HERV-K(HML-2) Endogenous Retroviral Elements in Human Populations , 2004, Journal of Molecular Evolution.

[216]  C. Schmid,et al.  Proposed roles for DNA methylation in Alu transcriptional repression and mutational inactivation. , 1993, Nucleic acids research.

[217]  Noam Shomron,et al.  The Birth of an Alternatively Spliced Exon: 3' Splice-Site Selection in Alu Exons , 2003, Science.

[218]  D. Valle,et al.  Mobile Interspersed Repeats Are Major Structural Variants in the Human Genome , 2010, Cell.

[219]  M. Batzer,et al.  5'-Transducing SVA retrotransposon groups spread efficiently throughout the human genome. , 2009, Genome research.

[220]  D. Keller,et al.  Trimeric structure for an essential protein in L1 retrotransposition , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[221]  H. Lauke,et al.  Cell Type-specific Expression of LINE-1 Open Reading Frames 1 and 2 in Fetal and Adult Human Tissues* , 2004, Journal of Biological Chemistry.

[222]  A. Smit,et al.  Ancestral, mammalian-wide subfamilies of LINE-1 repetitive sequences. , 1995, Journal of molecular biology.

[223]  Philip M. Kim,et al.  Paired-End Mapping Reveals Extensive Structural Variation in the Human Genome , 2007, Science.

[224]  A. Weiner,et al.  Upstream sequences modulate the internal promoter of the human 7SL RNA gene , 1985, Nature.

[225]  E. Vanin,et al.  Processed pseudogenes: characteristics and evolution. , 1984, Annual review of genetics.

[226]  Daniel G. Miller,et al.  Facioscapulohumeral Dystrophy: Incomplete Suppression of a Retrotransposed Gene , 2010, PLoS genetics.

[227]  J. Mccoy,et al.  Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis , 2000, Nature.

[228]  M. Batzer,et al.  Endonuclease-independent insertion provides an alternative pathway for L1 retrotransposition in the human genome , 2007, Nucleic acids research.

[229]  C. Tufarelli,et al.  Isolation of cancer-specific chimeric transcripts induced by hypomethylation of the LINE-1 antisense promoter. , 2009, Genomics.

[230]  S. Boissinot,et al.  The insertional history of an active family of L1 retrotransposons in humans. , 2004, Genome research.

[231]  Jeffrey S. Han,et al.  Gene-breaking: a new paradigm for human retrotransposon-mediated gene evolution. , 2005, Genome research.

[232]  J. L. Cortés,et al.  Epigenetic Control of Retrotransposon Expression in Human Embryonic Stem Cells , 2010, Molecular and Cellular Biology.

[233]  Jef D Boeke,et al.  High Frequency Retrotransposition in Cultured Mammalian Cells , 1996, Cell.

[234]  Ryan E. Mills,et al.  Active Alu retrotransposons in the human genome. , 2008, Genome research.

[235]  J. Nathans,et al.  Effects of L1 retrotransposon insertion on transcript processing, localization and accumulation: lessons from the retinal degeneration 7 mouse and implications for the genomic ecology of L1 elements. , 2006, Human molecular genetics.

[236]  H H Kazazian,et al.  HUGO—a midlife crisis? , 1998, Nature Genetics.

[237]  M F Singer,et al.  Translation of the human LINE-1 element, L1Hs. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[238]  A. Smit,et al.  The origin of interspersed repeats in the human genome. , 1996, Current opinion in genetics & development.

[239]  J. Chun,et al.  Chromosomal mosaicism in neural stem cells. , 2008, Methods in molecular biology.

[240]  P. D. de Jong,et al.  L1 retrotransposition can occur early in human embryonic development. , 2007, Human molecular genetics.

[241]  J. Jurka,et al.  RAG1 Core and V(D)J Recombination Signal Sequences Were Derived from Transib Transposons , 2005, PLoS biology.

[242]  Lisa Z. Scheifele,et al.  Transposon insertion site profiling chip (TIP-chip) , 2006, Proceedings of the National Academy of Sciences.

[243]  A. F. Scott,et al.  Origin of the human L1 elements: Proposed progenitor genes deduced from a consensus DNA sequence☆ , 1987, Genomics.

[244]  G. Grimaldi,et al.  Defining the beginning and end of KpnI family segments. , 1984, The EMBO journal.

[245]  A. Buzdin,et al.  Genome-wide targeted search for human specific and polymorphic L1 integrations , 2003, Human Genetics.

[246]  S. Boissinot,et al.  The structures of mouse and human L1 elements reflect their insertion mechanism , 2005, Cytogenetic and Genome Research.

[247]  J. V. Moran,et al.  Ribonucleoprotein particle formation is necessary but not sufficient for LINE-1 retrotransposition. , 2005, Human molecular genetics.

[248]  J. V. Moran,et al.  Multiple Fates of L1 Retrotransposition Intermediates in Cultured Human Cells , 2005, Molecular and Cellular Biology.

[249]  S. Martin,et al.  Ribonucleoprotein particles with LINE-1 RNA in mouse embryonal carcinoma cells , 1991, Molecular and cellular biology.

[250]  E. Ostertag,et al.  L1 integration in a transgenic mouse model. , 2005, Genome research.

[251]  J. Feigon,et al.  Identification and Solution Structure of a Highly Conserved C-terminal Domain within ORF1p Required for Retrotransposition of Long Interspersed Nuclear Element-1* , 2007, Journal of Biological Chemistry.

[252]  Giovanni Parmigiani,et al.  Human L1 Retrotransposition Is Associated with Genetic Instability In Vivo , 2002, Cell.

[253]  C. Hutchison,et al.  Dispersal process associated with the L1 family of interspersed repetitive DNA sequences. , 1984, Journal of molecular biology.

[254]  J. Lupski,et al.  The complete genome of an individual by massively parallel DNA sequencing , 2008, Nature.

[255]  E. Ostertag,et al.  Biology of mammalian L1 retrotransposons. , 2001, Annual review of genetics.

[256]  Michel J. Weber,et al.  Correction: Mammalian Small Nucleolar RNAs Are Mobile Genetic Elements , 2007, PLoS Genetics.

[257]  J. Weber,et al.  Alu repeats: a source for the genesis of primate microsatellites. , 1995, Genomics.

[258]  Anton Buzdin,et al.  The human genome contains many types of chimeric retrogenes generated through in vivo RNA recombination. , 2003, Nucleic acids research.

[259]  E. Ostertag,et al.  A novel testis ubiquitin-binding protein gene arose by exon shuffling in hominoids. , 2007, Genome research.

[260]  J. V. Moran,et al.  L1 retrotransposition in nondividing and primary human somatic cells. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[261]  J A Bailey,et al.  Molecular evidence for a relationship between LINE-1 elements and X chromosome inactivation: the Lyon repeat hypothesis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.