L1-associated genomic regions are deleted in somatic cells of the healthy human brain

Erwin, Jennifer A.; Paquola, Apuã C.M.; Singer, Tatjana; Gallina, Iryna; Novotny, M. A.; Quayle, Carolina; Bedrosian, Tracy A.; Alves, Francisco I A; Butcher, Cheyenne R; Herdy, Joseph R.; Sarkar, Anindita; Lasken, Roger S.; Muotri, Alysson R.; Gage, Fred H.

doi:10.1038/nn.4388

Cited by 172 publications

(222 citation statements)

References 43 publications

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“…Furthermore, recent publications have implicated somatic retrotransposition in the brain as a feature of both normal neurobiology and neurological diseases (Muotri et al 2005(Muotri et al , 2010Coufal et al 2009Coufal et al , 2011Baillie et al 2011;Evrony et al 2012Evrony et al , 2015Bundo et al 2014;Upton et al 2015;Erwin et al 2016). Early embryonic insertions contributing broad mosaicism to tissues including the brain likewise represent a component of genetic neurodiversity, and the prevalence and potential functional consequences of such insertions compared to those occurring specifically in cells of the neuronal lineage remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

Heritable L1 retrotransposition in the mouse primordial germline and early embryo

et al. 2017

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“…The reference genome assembly captures fixed alleles and high-frequency alleles, but does not encompass many common variants (17). Targeted methods for recovering LINE-1 insertions for next-generation sequencing are new technologies, and include approaches developed by Rahbari and Badge (38), Devine and co-workers (15), Faulkner and coworkers (19,39,40), Kazazian and co-workers (16,41), Deininger and co-workers (42), and Gage and co-workers (43), as well as our own approaches. Collectively, their application has reinforced that LINE-1 is an important source of structural variation in humans and contributed to a growing database of LINE-1 insertion polymorphisms (44).…”

Section: Discussionmentioning

confidence: 99%

Human transposon insertion profiling: Analysis, visualization and identification of somatic LINE-1 insertions in ovarian cancer

Tang

Steranka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

111

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Mammalian genomes are replete with interspersed repeats reflecting the activity of transposable elements. These mobile DNAs are self-propagating, and their continued transposition is a source of both heritable structural variation as well as somatic mutation in human genomes. Tailored approaches to map these sequences are useful to identify insertion alleles. Here, we describe in detail a strategy to amplify and sequence long interspersed element-1 (LINE-1, L1) retrotransposon insertions selectively in the human genome, transposon insertion profiling by next-generation sequencing (TIPseq). We also report the development of a machine-learning-based computational pipeline, TIPseqHunter, to identify insertion sites with high precision and reliability. We demonstrate the utility of this approach to detect somatic retrotransposition events in highgrade ovarian serous carcinoma.retrotransposon | TIPseq | human | LINE-1 | ovarian cancer

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“…In the mammalian germline and early embryo, L1 escapes repression to mobilize and create heritable insertions to ensure its evolutionary success (Kano et al 2009;Faulkner and Garcia-Perez 2017;Richardson et al 2017). More recently, somatic L1 mobilization has been revealed as a characteristic of normal neuronal cells in rodents and humans, and L1 dysregulation has been associated with neurological diseases (Muotri et al 2005(Muotri et al , 2010Baillie et al 2011;Coufal et al 2011;Evrony et al 2012;Upton et al 2015;Erwin et al 2016;Hazen et al 2016).…”

mentioning

confidence: 99%

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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L1-associated genomic regions are deleted in somatic cells of the healthy human brain

Cited by 172 publications

References 43 publications

Heritable L1 retrotransposition in the mouse primordial germline and early embryo

Heritable L1 retrotransposition in the mouse primordial germline and early embryo

Human transposon insertion profiling: Analysis, visualization and identification of somatic LINE-1 insertions in ovarian cancer

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

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