Human L1 Retrotransposition Is Associated with Genetic Instability In Vivo

Symer, David E.; Connelly, Carla; Szak, Suzanne; Caputo, Emerita M.; Cost, Gregory J.; Parmigiani, Giovanni; Boeke, Jef D.

doi:10.1016/s0092-8674(02)00839-5

Cited by 427 publications

(513 citation statements)

References 31 publications

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“…Indeed, the factor IX gene has been shown to be targeted by one disease-causing LINE-1 insertion and two independent Alu insertions (Ostertag and Kazazian, 2001) suggesting that Alu and LINE-1 elements can share an insertion hotspot. The notion that Alu and LINE-1 elements have different insertion biases is also inconsistent with the finding that evolutionarily recent insertions of active Alu and LINE-1 subfamilies do not follow the non-random genomic distribution of the older elements (Feng et al, 1996;Ovchinnikov et al, 2001;Gilbert et al, 2002;Symer et al, 2002;Szak et al, 2002;Gilbert et al, 2005). Indeed, we show that all older (>2.4 myr) Alu subfamilies examined are significantly more abundant around housekeeping genes than tissue-specific genes while this trend is weaker or not evident among the youngest subfamilies.…”

Section: The Possibility That Non-random Insertion Patterns Contributmentioning

confidence: 90%

“…Regardless of whether Alu elements are beneficial or merely tolerated, the increased abundance of Alu elements around housekeeping genes stood in stark contrast to the scarcity of longer (>400-bp) repeats and repeat tracts (LINE-1 elements and various other repeats) in these same regions Although, the lower abundance of the TT|AAAA target sequence near housekeeping genes may very well contribute to LINE-1 scarcity (Jurka, 1997;Cost and Boeke, 1998;Lander et al, 2001;Graham and Boissinot, 2006) despite their otherwise random insertion pattern (Smit, 1999;Boissinot et al, 2001;Lander et al, 2001;Ovchinnikov et al, 2001;Gilbert et al, 2002;Myers et al, 2002;Symer et al, 2002;Szak et al, 2002;Jurka et al, 2004;Gilbert et al, 2005), at least one additional explanation is needed since long repeats in general were scarce. One reason why long repeats might be selected against near housekeeping genes is that an abundance of these repeats might reduce gene expression via heterochromatin spread.…”

Section: Long Repeats May Be Disadvantageous To Nearby Housekeeping Gmentioning

confidence: 99%

“…Alu transposons differ from other SINEs in that they are not derived from tRNA genes, but rather from the 7SL RNA gene (Ullu and Tschudi, 1984;Quentin, 1994;Smit, 1996;Okada and Hamada, 1997;Terai et al, 1998;Lander et al, 2001) which encodes the RNA component of the signal recognition particle that mediates the translocation of nascent secretory and membrane proteins (Wild et al, 2004). Aside from favoring TT|AAAA target sequences (Feng et al, 1996;Jurka, 1997;Cost and Boeke, 1998), human Alu and LINE-1 elements have been reported to insert at random positions in the genome (Smit, 1999;Boissinot et al, 2001;Lander et al, 2001;Ovchinnikov et al, 2001;Gilbert et al, 2002;Myers et al, 2002;Symer et al, 2002;Szak et al, 2002;Jurka et al, 2004;Gilbert et al, 2005). However, there is some evidence for insertional hot spots (Cost and Boeke, 1998;Myers et al, 2002;Graham and Boissinot, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Repetitive sequence environment distinguishes housekeeping genes

Eller¹,

Regelson²,

Merriman³

et al. 2007

Gene

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Housekeeping genes are expressed across a wide variety of tissues. Since repetitive sequences have been reported to influence the expression of individual genes, we employed a novel approach to determine whether housekeeping genes can be distinguished from tissue-specific genes their repetitive sequence context. We show that Alu elements are more highly concentrated around housekeeping genes while various longer (>400-bp) repetitive sequences ("repeats"), including Long Interspersed Nuclear Element 1 (LINE-1) elements, are excluded from these regions. We further show that isochore membership does not distinguish housekeeping genes from tissue-specific genes and that repetitive sequence environment distinguishes housekeeping genes from tissue-specific genes in every isochore. The distinct repetitive sequence environment, in combination with other previously published sequence properties of housekeeping genes, were used to develop a method of predicting housekeeping genes on the basis of DNA sequence alone. Using expression across tissue types as a measure of success, we demonstrate that repetitive sequence environment is by far the most important sequence feature identified to date for distinguishing housekeeping genes.

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Section: The Possibility That Non-random Insertion Patterns Contributmentioning

confidence: 90%

Section: Long Repeats May Be Disadvantageous To Nearby Housekeeping Gmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Repetitive sequence environment distinguishes housekeeping genes

Eller¹,

Regelson²,

Merriman³

et al. 2007

Gene

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show abstract

“…The L1 sequence starts with a run of a variable number G residues, which I propose has accumulated through multiple rounds of cap reverse transcription. In support of this exotic idea, the majority of extra single nucleotides accumulated at the 5Ј junction of experimentally isolated new full-length L1 insertions are G residues, whereas truncated L1 elements do not prefer single-G insertions (Symer et al 2002; N. Gilbert, S.L. Lutz-Prigge, and J.V.…”

Section: Figurementioning

confidence: 94%

The Unusual Phylogenetic Distribution of Retrotransposons: A Hypothesis

Boeke¹

2003

Genome Res.

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Retrotransposons have proliferated extensively in eukaryotic lineages; the genomes of many animals and plants comprise 50% or more retrotransposon sequences by weight. There are several persuasive arguments that the enzymatic lynchpin of retrotransposon replication, reverse transcriptase (RT), is an ancient enzyme. Moreover, the direct progenitors of retrotransposons are thought to be mobile self-splicing introns that actively propagate themselves via reverse transcription, the group II introns, also known as retrointrons. Retrointrons are represented in modern genomes in very modest numbers, and thus far, only in certain eubacterial and organellar genomes. Archaeal genomes are nearly devoid of RT in any form. In this study, I propose a model to explain this unusual distribution, and rationalize it with the proposed ancient origin of the RT gene. A cap and tail hypothesis is proposed. By this hypothesis, the specialized terminal structures of eukaryotic mRNA provide the ideal molecular environment for the lengthening, evolution, and subsequent massive expansion of highly mobile retrotransposons, leading directly to the retrotransposon-cluttered structure that typifies modern metazoan genomes and the eventual emergence of retroviruses.

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“…That such events exist was first observed upon induction of retrotransposition in vitro. 2,3 Comparative analysis of the human and chimp genomes revealed that this kind of copy number alteration is also relevant on an evolutionary scale. The authors termed the phenomenon Alu retrotransposition-mediated deletion (AMD), and suggested that a novel, one-step mutational mechanism underlies AMD.…”

Section: Introductionmentioning

confidence: 99%

A polymorphic Alu insertion that mediates distinct disease-associated deletions

et al. 2016

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Large deletions that are associated with insertions of Alu-derived sequence represent a rare, but potentially unique class of alterations. Whether they form by a one-step mechanism or by a primary insertion step followed by an independent secondary deletion step is not clear. We resolved two disease-associated SPAST deletions, which involve distinct exons by long range PCR. Alu-derived sequence was observed between the breakpoints in both cases. The intronic regions that represent the targets of potentially involved Alu retrotransposition events overlapped. Microsatellite-and SNP-based haplotyping indicated that both deletions originated on one and the same founder allele. Our data suggest that the deletions are best explained by two-step insertion-deletion scenarios for which a single Alu retrotransposition event represents the shared primary step. This Alu then mediated one of the deletions by non-homologous end joining and the other by non-allelic homologous recombination. Our findings thus strongly argue for temporal separation of insertion and deletion in Alu insertion-associated deletions. They also suggest that certain Alu integrations confer a general increase in local genomic instability, and that this explains why they are usually not detected during the probably short time that precedes the rearrangements they mediate.

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Human L1 Retrotransposition Is Associated with Genetic Instability In Vivo

Cited by 427 publications

References 31 publications

Repetitive sequence environment distinguishes housekeeping genes

Repetitive sequence environment distinguishes housekeeping genes

The Unusual Phylogenetic Distribution of Retrotransposons: A Hypothesis

A polymorphic Alu insertion that mediates distinct disease-associated deletions

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