L1Base 2: more retrotransposition-active LINE-1s, more mammalian genomes

Penzkofer, Tobias; Jäger, Marten; Figlerowicz, Marek; Badge, Richard M.; Mundlos, Stefan; Robinson, Peter N.; Żemojtel, Tomasz

doi:10.1093/nar/gkw925

Cited by 116 publications

(119 citation statements)

References 38 publications

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“…1A). Alu and LINE-1 gRNAs were respectively designed on the consensus sequences obtained from repeatmasker (25) (table S3) and on the 10 consensus of 146 full-length sequences that encodes both functional ORF1 and ORF2 proteins (26). Finally, gRNAs against HERV-W, one subfamily of HERV, were designed on the consensus of putatively active retro-viruses(27) (table S3).…”

Section: Grna Design and Copy Number Estimation Of Transposable Elementsmentioning

confidence: 99%

Enabling large-scale genome editing by reducing DNA nicking

Saïd

et al. 2019

Preprint

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To extend the frontier of genome editing and enable the radical redesign of mammalian genomes, we developed a set of dead-Cas9 base editor (dBE) variants that allow editing at tens of thousands of loci per cell by overcoming the cell death associated with DNA double-strand breaks (DSBs) and single-strand breaks (SSBs). We used a set of gRNAs targeting repetitive elementsranging in target copy number from about 31 to 124,000 per cell. dBEs enabled survival after 5 large-scale base editing, allowing targeted mutations at up to ~13,200 and ~2610 loci in 293T and human induced pluripotent stem cells (hiPSCs), respectively, three orders of magnitude greater than previously recorded. These dBEs can overcome current on-target mutation and toxicity barriers that prevent cell survival after large-scale genome engineering.One Sentence Summary: Base editing with reduced DNA nicking allows for the simultaneous 10

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Section: Grna Design and Copy Number Estimation Of Transposable Elementsmentioning

confidence: 99%

Enabling large-scale genome editing by reducing DNA nicking

Saïd

et al. 2019

Preprint

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“…Lineage-specificity, membership of different families, and their age and ability to transpose were ascertained for all 157 L1 repeats identified within the insertion (Supplemental Table S3). The L1Base 2 database (Penzkofer et al 2016) and the L1Xplorer program (Penzkofer et al 2005) were then used to identify fulllength L1s in the insertion. Nine putative full-length L1s were identified in the interval in L1Base 2 and one further full-length element by L1Xplorer (Supplemental Fig.…”

Section: Characterization Of Line-1 Repeat Array In the Dlk1-dio3 Impmentioning

confidence: 99%

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control

et al. 2018

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Approximately half the mammalian genome is composed of repetitive sequences, and accumulating evidence suggests that some may have an impact on genome function. Here, we characterized a large array class of repeats of long-interspersed elements (LINE-1). Although widely distributed in mammals, locations of such arrays are species specific. Using targeted deletion, we asked whether a 170-kb LINE-1 array located at a mouse imprinted domain might function as a modulator of local transcriptional control. The LINE-1 array is lamina associated in differentiated ES cells consistent with its AT-richness, and although imprinting occurs both proximally and distally to the array, active LINE-1 transcripts within the tract are biallelically expressed. Upon deletion of the array, no perturbation of imprinting was observed, and abnormal phenotypes were not detected in maternal or paternal heterozygous or homozygous mutant mice. The array does not shield nonimprinted genes in the vicinity from local imprinting control. Reduced neural expression of protein-coding genes observed upon paternal transmission of the deletion is likely due to the removal of a brain-specific enhancer embedded within the LINE array. Our findings suggest that presence of a 170-kb LINE-1 array reflects the tolerance of the site for repeat insertion rather than an important genomic function in normal development.

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“…The distal breakpoints of six deletions map within either L1PA2 (chr16:86,295,780‐86,301,803) (pt 153.3) or L1PA3 (chr16:86,266,902‐86,272,916) (pts 54.3, 155.3, 165.3, 177.3, and 179.3). These two full‐length L1s are located ∼22.9 kb apart, are directly‐oriented, contain PolII promoters at their 5′ end (Figure ; Table ; Supporting Information, Figure S1), and both are included in the L1Base2 database of ∼13,000 full‐length FLn1‐L1s; https://L1base.charite.de (Penzkofer et al., ).…”

Section: Resultsmentioning

confidence: 99%

LINE- andAlu-containing genomic instability hotspot at 16q24.1 associated with recurrent and nonrecurrent CNV deletions causative for ACDMPV

et al. 2018

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Transposable elements modify human genome by inserting into new loci or by mediating homology-, microhomology-, or homeology-driven DNA recombination or repair, resulting in genomic structural variation. Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare lethal neonatal developmental lung disorder caused by point mutations or copy-number variant (CNV) deletions of FOXF1 or its distant tissue-specific enhancer. Eighty-five percent of 45 ACDMPV-causative CNV deletions, of which junctions have been sequenced, had at least one of their two breakpoints located in a retrotransposon, with more than half of them being Alu elements. We describe a novel ∼35 kb-large genomic instability hotspot at 16q24.1, involving two evolutionarily young LINE-1 (L1) elements, L1PA2 and L1PA3, flanking AluY, two AluSx, AluSx1, and AluJr elements. The occurrence of L1s at this location coincided with the branching out of the Homo-Pan-Gorilla clade, and was preceded by the insertion of AluSx, AluSx1, and AluJr. Our data show that, in addition to mediating recurrent CNVs, L1 and Alu retrotransposons can predispose the human genome to formation of variably sized CNVs, both of clinical and evolutionary relevance. Nonetheless, epigenetic or other genomic features of this locus might also contribute to its increased instability.

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L1Base 2: more retrotransposition-active LINE-1s, more mammalian genomes

Cited by 116 publications

References 38 publications

Enabling large-scale genome editing by reducing DNA nicking

Enabling large-scale genome editing by reducing DNA nicking

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control

LINE- andAlu-containing genomic instability hotspot at 16q24.1 associated with recurrent and nonrecurrent CNV deletions causative for ACDMPV

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