LINE-1 preTa Elements in the Human Genome

Salem, Abdel Halim; Myers, Jeremy S.; Otieno, Anthony C.; Watkins, W. Scott; Jorde, Lynn B.; Batzer, Mark A.

doi:10.1016/s0022-2836(03)00032-9

Cited by 41 publications

(37 citation statements)

References 51 publications

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“…The observed proportion of inverted integrants exceeds the 8%-35% inversions in the human genome (Boissinot et al 2000;Goodier et al 2000;Myers et al 2002;Symer et al 2002;Szak et al 2002;Salem et al 2003), and 16%-30% in cultured cells (Gilbert et al , 2005Symer et al 2002). More frequent inversions in our study may be caused by the relative overrepresentation of shorter elements, the reduced ability to detect inverted L1s in the genome, or as yet unknown differences intrinsic to human and mouse hosts.…”

Section: De Novo Inserts Have Characteristic Features Of L1 Retrotrancontrasting

confidence: 52%

L1 integration in a transgenic mouse model

et al. 2005

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To study integration of the human LINE-1 retrotransposon (L1) in vivo, we developed a transgenic mouse model of L1 retrotransposition that displays de novo somatic L1 insertions at a high frequency, occasionally several insertions per mouse. We mapped 3Ј integration sites of 51 insertions by Thermal Asymmetric Interlaced PCR (TAIL-PCR). Analysis of integration locations revealed a broad genomic distribution with a modest preference for intergenic regions. We characterized the complete structures of 33 de novo retrotransposition events. Our results highlight the large number of highly truncated L1s, as over 52% (27/51) of total integrants were <1/3 the length of a full-length element. New integrants carry all structural characteristics typical of genomic L1s, including a number with inversions, deletions, and 5Ј-end microhomologies to the target DNA sequence. Notably, at least 13% (7/51) of all insertions contain a short stretch of extra nucleotides at their 5Ј end, which we postulate result from template-jumping by the L1-encoded reverse transcriptase. We propose a unified model of L1 integration that explains all of the characteristic features of L1 retrotransposition, such as 5Ј truncations, inversions, extra nucleotide additions, and 5Ј boundary and inversion point microhomologies.[Supplemental material is available online at www.genome.org.]The long interspersed nucleotide element-1 (L1) retrotransposon enjoyed tremendous evolutionary success in colonizing eukaryotic genomes (Kazazian Jr. 2004); its roughly 500,000 copies comprise ∼17% of human DNA (Lander et al. 2001). The full-length 6-kb L1 encodes a 5Ј UTR containing an internal promoter, two proteins-ORF1, a nucleic acid-binding protein with chaperone activity (Hohjoh andSinger 1996, 1997;Martin and Bushman 2001), and ORF2, a protein with endonuclease (EN) and reverse transcriptase (RT) activities (Mathias et al. 1991;Feng et al. 1996), and a 3Ј UTR ending with a poly(A) tail (Fig. 1A). Both ORF1 and ORF2 proteins are required for retrotransposition . Once transcribed and translated, L1 RNA is copied into the genome by target-primed reverse transcription (TPRT) (Luan et al. 1993;Cost et al. 2002). During TPRT, one strand of host DNA is cleaved by the EN to expose a free 3Ј-hydroxyl, which is then used by the RT as a primer in reverse transcription, copying the L1 RNA template directly into the host genome. To complete integration, the second strand of host DNA must be cleaved, RNA removed, the newly synthesized strand copied, and breaks resolved. The mechanism by which these later steps are accomplished is only beginning to be understood, with recent biochemical data from a related non-LTR retrotransposon R2 of the silkmoth, Bombyx mori, suggesting that a second R2 protein is involved in cleavage, RNA displacement, and synthesis of the second strand (Bibillo and Eickbush 2002a; Christensen and Eickbush 2005).Following essentially random integration, endogenous L1s are thought to be lost over time due to strong negative selection leading to their uneven ...

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Section: De Novo Inserts Have Characteristic Features Of L1 Retrotrancontrasting

confidence: 52%

L1 integration in a transgenic mouse model

et al. 2005

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“…Alu is ã 300 bp non-autonomous, non-LTR retroposon that represents another 11% of the human genome International Human Genome Sequence Consortium 2001). L1 and Alu are both non-site-specific and demonstrate a strong bias for insertion into a short, A+T-rich L1 endonuclease target site, as has been demonstrated for genomic L1 and Alu insertions (Boissinot et al 2000;Boissinot et al 2004;Feng et al 1996;Jurka 1997;Jurka and Klonowski 1996;Morrish et al 2002;Myers et al 2002;Ovchinnikov et al 2001;Salem et al 2003;Szak et al 2002), for L1 and Alu insertions from molecular assays (Dewannieux et al 2003;Feng et al 1996;Gilbert et al 2002;Gilbert et al 2005;Morrish et al 2002;Symer et al 2002), and for the L1 endonuclease in vitro (Cost and Boeke 1998;Feng et al 1996). Even though they both utilize the same endonuclease, L1 and Alu are distributed differently in the human genome.…”

Section: Introductionmentioning

confidence: 85%

Characterization of pre-insertion loci of de novo L1 insertions

Gasior¹,

Preston²,

Hedges³

et al. 2007

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The human Long Interspersed Element-1 (LINE-1) and the Short Interspersed Element (SINE) Alu comprise 28% of the human genome. They share the same L1-encoded endonuclease for insertion, which recognizes an A+T-rich sequence. Under a simple model of insertion distribution, this nucleotide preference would lead to the prediction that the populations of both elements would be biased towards A+T-rich regions. Genomic L1 elements do show an A+T-rich bias. In contrast, Alu is biased towards G+C-rich regions when compared to the genome average. Several analyses have demonstrated that relatively recent insertions of both elements show less G+C content bias relative to older elements. We have analyzed the repetitive element and G+C composition of more than 100 pre-insertion loci derived from de novo L1 insertions in cultured human cancer cells, which should represent an evolutionarily unbiased set of insertions. An A+T-rich bias is observed in the 50 bp flanking the endonuclease target site, consistent with the known target site for the L1 endonuclease. The L1, Alu, and G+C content of 20 kb of the de novo pre-insertion loci show a different set of biases than those observed for fixed L1s in the human genome. In contrast to the insertion sites of genomic L1s, the de novo L1 pre-insertion loci are relatively L1-poor, Alu-rich and G+C-neutral. Finally, a statistically significant cluster of de novo L1 insertions was localized in the vicinity of the c-myc gene. These results suggest that the initial insertion preference of L1, while A+T-rich in the initial vicinity of the break site, can be influenced by the broader content of the flanking genomic region and have implications for understanding the dynamics of L1 and Alu distributions in the human genome.

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“…The recent availability of the human genome draft sequence, and additional diverse human genomic sequence data, have accelerated the process of identifying newly integrated retrotransposons. One strategy that has been very successfully used is to identify members belonging to the young subfamilies of retrotransposons from the reference genome sequence via computational analysis followed by determining their insertion polymorphism status through screening of DNA samples from diverse human populations [Callinan et al, 2003;Carroll et al, 2001;Carter et al, 2004;Myers et al, 2002;Otieno et al, 2004;Salem et al, 2003;2005b;Sheen et al, 2000;Vincent et al, 2003;Xing et al, 2003]. Furthermore, two recent studies, both employing in silico computational strategies that utilize the sequence data from sources representing different human individuals, have also shown great success.…”

Section: Introductionmentioning

confidence: 99%

dbRIP: A highly integrated database of retrotransposon insertion polymorphisms in humans

et al. 2006

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Communicated by Alastair BrownRetrotransposons constitute over 40% of the human genome and play important roles in the evolution of the genome. Since certain types of retrotransposons, particularly members of the Alu, L1, and SVA families, are still active, their recent and ongoing propagation generates a unique and important class of human genomic diversity/polymorphism (for the presence and absence of an insertion) with some elements known to cause genetic diseases. So far, over 2,300, 500, and 80 Alu, L1, and SVA insertions, respectively, have been reported to be polymorphic and many more are yet to be discovered. We present here the Database of Retrotransposon Insertion Polymorphisms (dbRIP; http://falcon.roswellpark.org:9090), a highly integrated and interactive database of human retrotransposon insertion polymorphisms (RIPs). dbRIP currently contains a nonredundant list of 1,625, 407, and 63 polymorphic Alu, L1, and SVA elements, respectively, or a total of 2,095 RIPs. In dbRIP, we deploy the utilities and annotated data of the genome browser developed at the University of California at Santa Cruz (UCSC) for user-friendly queries and integrative browsing of RIPs along with all other genome annotation information. Users can query the database by a variety of means and have access to the detailed information related to a RIP, including detailed insertion sequences and genotype data. dbRIP represents the first database providing comprehensive, integrative, and interactive compilation of RIP data, and it will be a useful resource for researchers working in the area of human genetics.

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LINE-1 preTa Elements in the Human Genome

Cited by 41 publications

References 51 publications

L1 integration in a transgenic mouse model

L1 integration in a transgenic mouse model

Characterization of pre-insertion loci of de novo L1 insertions

dbRIP: A highly integrated database of retrotransposon insertion polymorphisms in humans

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