Diverse cis factors controlling Alu retrotransposition: What causes Alu elements to die?

Comeaux, Matthew S.; Roy-Engel, Astrid M.; Hedges, Dale J.; Deininger, Prescott L.

doi:10.1101/gr.089789.108

Cited by 72 publications

(99 citation statements)

References 45 publications

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“…To obtain an unbiased overview of expressed Alu elements that contain an active core, we analyzed the activity of a randomly selected cohort of Alu elements expressed in hESCs, and determined that, on average, 60% of them have Ͼ10% of the activity of a reference hot Alu element (12,82). This result reflects the activity of the Alu cores and does not incorporate the influence of 5Ј and 3Ј flanking regions on the assayed Alu elements' activity (1,22,70). When combined with an in silico estimate of Alu activity, assuming that those elements with less than 10% variation with respect to the active core consensus represent active elements (12), approximately 40 to 50% of the core of Alu elements expressed in hESCs have a trans-retrotransposition potential of at least 10% of that of an active Alu element known to have caused a human disease (82).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Control of Retrotransposon Expression in Human Embryonic Stem Cells

Macia

Muñoz‐López

Cortés

et al. 2011

Molecular and Cellular Biology

128

130

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Long interspersed element 1s (LINE-1s or L1s) are a family of non-long-terminal-repeat retrotransposons that predominate in the human genome. Active LINE-1 elements encode proteins required for their mobilization. L1-encoded proteins also act in trans to mobilize short interspersed elements (SINEs), such as Alu elements. L1 and Alu insertions have been implicated in many human diseases, and their retrotransposition provides an ongoing source of human genetic diversity. L1/Alu elements are expected to ensure their transmission to subsequent generations by retrotransposing in germ cells or during early embryonic development. Here, we determined that several subfamilies of Alu elements are expressed in undifferentiated human embryonic stem cells (hESCs) and that most expressed Alu elements are active elements. We also exploited expression from the L1 antisense promoter to map expressed elements in hESCs. Remarkably, we found that expressed Alu elements are enriched in the youngest subfamily, Y, and that expressed L1s are mostly located within genes, suggesting an epigenetic control of retrotransposon expression in hESCs. Together, these data suggest that distinct subsets of active L1/Alu elements are expressed in hESCs and that the degree of somatic mosaicism attributable to L1 insertions during early development may be higher than previously anticipated.

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Section: Discussionmentioning

confidence: 99%

Epigenetic Control of Retrotransposon Expression in Human Embryonic Stem Cells

Macia

Muñoz‐López

Cortés

et al. 2011

Molecular and Cellular Biology

128

130

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“…To date, most L1 and L1 trans-mobilization assays have been carried out in HeLa cells (1,31,61,69,82), which exhibit low levels of endogenous L1 activity; this was, in part, one of the original reasons why the assays were carried out in those cells (61). Rare retrotransposition events have been observed in the absence of a driver, and this has been utilized most frequently for Alu assays in HeLa cells (14).…”

Section: Discussionmentioning

confidence: 99%

The Minimal Active Human SVA Retrotransposon Requires Only the 5′-Hexamer and Alu-Like Domains

Hancks

Mandal

Cheung

et al. 2012

Molecular and Cellular Biology

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RNA-based duplication mediated by reverse transcriptase (RT), a process termed retrotransposition, is ongoing in humans and is a source of significant inter-and perhaps intraindividual genomic variation. The long interspersed element 1 (LINE-1 or L1) ORF2 protein is the genomic source for RT activity required for mobilization of its own RNA in cis and other RNAs, such as SINE/variable-number tandem-repeat (VNTR)/Alu (SVA) elements, in trans. SVA elements are ϳ2-kb hominid-specific noncoding RNAs that have resulted in single-gene disease in humans through insertional mutagenesis or aberrant mRNA splicing. Here, using an SVA retrotransposition cell culture assay in U2OS cells, we investigated SVA domains important in L1-mediated SVA retrotransposition. Partial-and whole-domain deletions revealed that removal of either the Alu-like or SINE-R domain in the context of a full-length SVA has little to no effect, whereas removal of the CT hexamer or the VNTR domain can result in a 75% decrease in activity. Additional experiments demonstrate that the Alu-like fragment alone can retrotranspose at low levels while the addition of the CT hexamer can enhance activity as much as 2-fold compared to that of the full-length SVA. These results suggest that no SVA domain is essential for retrotransposition in U2OS cells and that the 5= end of SVA (hexamer and Alu-like domain) is sufficient for retrotransposition.A pproximately one-third of the human genome (52) is derived from the direct (cis) or indirect (trans) reverse transcriptase (RT) activity of the long interspersed element 1 (LINE-1 or L1). A full-length active L1 (6.0 kb) (70) is the only autonomous retrotransposon in humans. It contains two nonoverlapping open reading frames (ORFs) (70), an ϳ900-bp 5= untranslated region (UTR), with promoter activity (75), and a short 3=-UTR. ORF1 encodes a 40-kDa RNA binding protein (ORF1p) (40) with chaperone activity in vitro (56), whereas ORF2 encodes a 150-kDa protein with demonstrated endonuclease (EN) (25) and RT (57) activities. Both ORF1p and ORF2p are required for retrotransposition (20, 61) of their encoding RNA, a phenomenon termed cis preference (20,23,61,82).Most human L1s are inactive due to 5= truncations, point mutations, or internal rearrangements; however, a subset, ϳ80 to 100 in any given individual, remain active (4, 8). These active L1 loci are the source for new L1 insertions and can provide the L1 proteins required to mobilize other RNAs (Alu [7,19], SVA elements [37,65,67], U6 [9,27,31], and processed pseudogenes [23,82]) in trans. Retrotransposition is ongoing in the human population (4,6,24,(41)(42)(43)46), with almost 100 cases of single-gene disease (5,11,39,83) caused by L1 (47), Alu (80), SVA (50, 65), or poly(A) insertions. L1-mediated insertions may be deleterious by disrupting mRNA expression (32, 76) of a specific gene (ϳ25 examples [39,78]) or mitigating nonallelic homologous recombination (18,35,71). New insertions may also contribute to somatic mosaicism (28,45,62,77), in particular, neuronal diversi...

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“…Cold Spring Harbor Laboratory Press on May 12, 2018 -Published by genome.cshlp.org Downloaded from activity of Alu (Roy-Engel et al 2002;Bennett et al 2008;Comeaux et al 2009); this is likely true for Platy-1 as well. Based on this and the analysis of 427 elements, we estimate that ∼8% of elements have a higher chance of being retrotranspositionally active (pristine A-tail and length >20 bp).…”

Section: Wwwgenomeorgmentioning

confidence: 99%

“…Of these, more than half contained a Pol III termination signal downstream within 100 bp and 28% within 25 bp. The latter elements have the highest probability of being source elements, as a Pol III termination signal immediately downstream from an Alu element has been positively correlated with Alu retrotransposition efficiency in vitro (Comeaux et al 2009). On the other hand, more than one-third of the inspected Platy-1 A-tails harbored nucleotide substitutions, with many of them containing microsatellites.…”

Section: Wwwgenomeorgmentioning

confidence: 99%

Discovery of a new repeat family in the Callithrix jacchus genome

et al. 2016

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We identified a novel repeat family, termed Platy-1, in the Callithrix jacchus (common marmoset) genome that arose around the time of the divergence of platyrrhines and catarrhines and established itself as a repeat family in New World monkeys (NWMs). A full-length Platy-1 element is ∼100 bp in length, making it the shortest known short interspersed element (SINE) in primates, and harbors features characteristic of non-LTR retrotransposons. We identified 2268 full-length Platy-1 elements across 62 subfamilies in the common marmoset genome. Our subfamily reconstruction and phylogenetic analyses support Platy-1 propagation throughout the evolution of NWMs in the lineage leading to C. jacchus. Platy-1 appears to have reached its amplification peak in the common ancestor of current day marmosets and has since moderately declined. However, identification of more than 200 Platy-1 elements identical to their respective consensus sequence, and the presence of polymorphic elements within common marmoset populations, suggests ongoing retrotransposition activity. Platy-1, a SINE, appears to have originated from an Alu element, and hence is likely derived from 7SL RNA. Our analyses illustrate the birth of a new repeat family and its propagation dynamics in the lineage leading to the common marmoset over the last 40 million years.

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Diverse cis factors controlling Alu retrotransposition: What causes Alu elements to die?

Cited by 72 publications

References 45 publications

Epigenetic Control of Retrotransposon Expression in Human Embryonic Stem Cells

Epigenetic Control of Retrotransposon Expression in Human Embryonic Stem Cells

The Minimal Active Human SVA Retrotransposon Requires Only the 5′-Hexamer and Alu-Like Domains

Discovery of a new repeat family in the Callithrix jacchus genome

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