Intragenic Deletions at Atp7a in Mouse Models for Menkes Disease

Cunliffe, Pamela; Reed, Vivienne; Boyd, Yvonne

doi:10.1006/geno.2001.6529

Cited by 22 publications

(15 citation statements)

References 39 publications

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“…1B; Supplemental Table S2). Analysis of their 5 ′ UTR monomers indicated that three of the tumor-specific L1 insertions were L1 T F elements, consistent with previous reports of spontaneous disease-causing L1 insertions in mice (Kingsmore et al 1994;Mulhardt et al 1994;Kohrman et al 1996;Takahara et al 1996;Perou et al 1997;Naas et al 1998;Yajima et al 1999;Cunliffe et al 2001). Unexpectedly, the fourth L1 insertion belonged to the L1 G F subfamily, representing the first instance in which an endogenous de novo L1 insertion has been definitively identified as an L1 G F subfamily element ( Fig.…”

Section: Resultssupporting

confidence: 89%

“…We also report the first example of a de novo L1 G F retrotransposition event in vivo. While some L1 G F elements are polymorphic among mouse strains, indicating recent germline mobilization, and L1 G F elements retain retrotransposition capability in cultured cell assays (Goodier et al 2001), all previously described disease-causing mouse L1 insertions where the subfamily could be determined were identified as T F elements (Kingsmore et al 1994;Mulhardt et al 1994;Kohrman et al 1996;Takahara et al 1996;Perou et al 1997;Naas et al 1998;Yajima et al 1999;Cunliffe et al 2001). Indeed, recent work from our laboratory identified 11 de novo L1 insertions occurring in the germline or early embryo in C57BL/6J mice, and all of these insertions belonged to the L1 T F subfamily (Richardson et al 2017).…”

Section: Discussionmentioning

confidence: 99%

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L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

et al. 2018

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The retrotransposon Long Interspersed Element 1 (LINE-1 or L1) is a continuing source of germline and somatic mutagenesis in mammals. Deregulated L1 activity is a hallmark of cancer, and L1 mutagenesis has been described in numerous human malignancies. We previously employed retrotransposon capture sequencing (RC-seq) to analyze hepatocellular carcinoma (HCC) samples from patients infected with hepatitis B or hepatitis C virus and identified L1 variants responsible for activating oncogenic pathways. Here, we have applied RC-seq and whole-genome sequencing (WGS) to an Abcb4 (Mdr2)−/− mouse model of hepatic carcinogenesis and demonstrated for the first time that L1 mobilization occurs in murine tumors. In 12 HCC nodules obtained from 10 animals, we validated four somatic L1 insertions by PCR and capillary sequencing, including T F subfamily elements, and one G F subfamily example. One of the T F insertions carried a 3 ′ transduction, allowing us to identify its donor L1 and to demonstrate that this full-length T F element retained retrotransposition capacity in cultured cancer cells. Using RC-seq, we also identified eight tumor-specific L1 insertions from 25 HCC patients with a history of alcohol abuse. Finally, we used RC-seq and WGS to identify three tumor-specific L1 insertions among 10 intra-hepatic cholangiocarcinoma (ICC) patients, including one insertion traced to a donor L1 on Chromosome 22 known to be highly active in other cancers. This study reveals L1 mobilization as a common feature of hepatocarcinogenesis in mammals, demonstrating that the phenomenon is not restricted to human viral HCC etiologies and is encountered in murine liver tumors.

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Section: Resultssupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

et al. 2018

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“…Using PCR and capillary sequencing, we validated 11 de novo L1 insertions (Table 1; Supplemental Table 2). All 11 were T F subfamily elements, consistent with previous reports of disease-causing L1 insertions in mice wherein all insertions for which sufficient L1 sequence was present for subfamily distinction were identified as T F elements (Kingsmore et al 1994;Mulhardt et al 1994;Kohrman et al 1996;Takahara et al 1996;Perou et al 1997;Naas et al 1998;Yajima et al 1999;Cunliffe et al 2001). De novo L1 insertions bore hallmarks of L1 retrotransposition by target-primed reverse transcription (TPRT), including insertion at sequences resembling the L1 endonuclease cleavage motif (5 ′ -TTTT/AA-3 ′ ), the presence of 13-to 17-bp target-site duplications (TSDs), and 3 ′ poly(A) tracts (Table 1; Supplemental Figs.…”

Section: Resultssupporting

confidence: 89%

Heritable L1 retrotransposition in the mouse primordial germline and early embryo

et al. 2017

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LINE-1 (L1) retrotransposons are a noted source of genetic diversity and disease in mammals. To expand its genomic footprint, L1 must mobilize in cells that will contribute their genetic material to subsequent generations. Heritable L1 insertions may therefore arise in germ cells and in pluripotent embryonic cells, prior to germline specification, yet the frequency and predominant developmental timing of such events remain unclear. Here, we applied mouse retrotransposon capture sequencing (mRC-seq) and whole-genome sequencing (WGS) to pedigrees of C57BL/6J animals, and uncovered an L1 insertion rate of ≥1 event per eight births. We traced heritable L1 insertions to pluripotent embryonic cells and, strikingly, to early primordial germ cells (PGCs). New L1 insertions bore structural hallmarks of target-site primed reverse transcription (TPRT) and mobilized efficiently in a cultured cell retrotransposition assay. Together, our results highlight the rate and evolutionary impact of heritable L1 retrotransposition and reveal retrotransposition-mediated genomic diversification as a fundamental property of pluripotent embryonic cells in vivo.

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“…The disabled gene L1 lacks a poly(A) tail, 3Ј end, and TSDs, and thus may not be a bona fide retrotransposition event. The remaining insertions into the sodium channel gene Scn8a (Kohrman et al 1996) and the copper-transporting ATPase gene Atp7a (Cunliffe et al 2001) are too short to assign to a subfamily (Kohrman et al 1996). However, the number of elements characterized to date is still small, and we expect that A and G F insertions will eventually be detected.…”

Section: Novel Active L1 Retrotransposon Subfamily In Mousementioning

confidence: 99%

A Novel Active L1 Retrotransposon Subfamily in the Mouse

Goodier¹,

Ostertag²,

Du³

et al. 2001

Genome Res.

213

249

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Unlike human L1 retrotransposons, the 5′ UTR of mouse L1 elements contains tandem repeats of ∼200 bp in length called monomers. Multiple L1 subfamilies exist in the mouse which are distinguished by their monomer sequences. We previously described a young subfamily, called the TF subfamily, which contains ∼1800 active elements among its 3000 full-length members. Here we characterize a novel subfamily of mouse L1 elements, GF, which has unique monomer sequence and unusual patterns of monomer organization. A majority of these GF elements also have a unique length polymorphism in ORF1. Polymorphism analysis of GF elements in various mouse subspecies and laboratory strains revealed that, like TF, the GF subfamily is young and expanding. About 1500 full-length GF elements exist in the diploid mouse genome and, based on the results of a cell culture assay, ∼400 GF elements are potentially capable of retrotransposition. We also tested 14 A-type subfamily elements in the assay and estimate that about 900 active A elements may be present in the mouse genome. Thus, it is now known that there are three large active subfamilies of mouse L1s; TF, A, and GF, and that in total ∼3000 full-length elements are potentially capable of active retrotransposition. This number is in great excess to the number of L1 elements thought to be active in the human genome

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Intragenic Deletions at Atp7a in Mouse Models for Menkes Disease

Cited by 22 publications

References 39 publications

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

Heritable L1 retrotransposition in the mouse primordial germline and early embryo

A Novel Active L1 Retrotransposon Subfamily in the Mouse

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