L1 Retrotransposons and Somatic Mosaicism in the Brain

Richardson, Sandra R.; Morell, Santiago; Faulkner, Geoffrey J.

doi:10.1146/annurev-genet-120213-092412

Cited by 152 publications

(161 citation statements)

References 137 publications

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“…While very few LINE-1s are actively mobile, mobility can result in human disease and is a significant source of genome variation (45). LINE-1 retrotransposition is initiated by a DNA nick targeted to a consensus 5′-TTTT/A-3′ site, and the 3′ end of the nick then anneals to the polyA at the 3′ end of the LINE-1 mRNA which serves as a template for DNA synthesis [reviewed in (46)]. Nicking, annealing and DNA synthesis (reverse transcription) are performed in a concerted manner by the LINE-1 encoded ORF2 protein.…”

Section: Discussionmentioning

confidence: 99%

Initiation of homologous recombination at DNA nicks

Maizels

Davis

2018

Nucleic Acids Research

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Discontinuities in only a single strand of the DNA duplex occur frequently, as a result of DNA damage or as intermediates in essential nuclear processes and DNA repair. Nicks are the simplest of these lesions: they carry clean ends bearing 3′-hydroxyl groups that can undergo ligation or prime new DNA synthesis. In contrast, single-strand breaks also interrupt only one DNA strand, but they carry damaged ends that require clean-up before subsequent steps in repair. Despite their apparent simplicity, nicks can have significant consequences for genome stability. The availability of enzymes that can introduce a nick almost anywhere in a large genome now makes it possible to systematically analyze repair of nicks. Recent experiments demonstrate that nicks can initiate recombination via pathways distinct from those active at double-strand breaks (DSBs). Recombination at targeted DNA nicks can be very efficient, and because nicks are intrinsically less mutagenic than DSBs, nick-initiated gene correction is useful for genome engineering and gene therapy. This review revisits some physiological examples of recombination at nicks, and outlines experiments that have demonstrated that nicks initiate homology-directed repair by distinctive pathways, emphasizing research that has contributed to our current mechanistic understanding of recombination at nicks in mammalian cells.

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Section: Discussionmentioning

confidence: 99%

Initiation of homologous recombination at DNA nicks

Maizels

Davis

2018

Nucleic Acids Research

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“…There were very few changes located in transcription start sites or in exons. Interestingly, many changes occurred in long interspersed elements, 39 with the smaller number of changes occurring in the SSvsCT comparison (27.9% against 56.2% and 55.6% for SRvsCT and SRvsSS, respectively) (Figure 2c). Changes in DNA hydroxymethylation also occurred in short interspersed elements, with peak counts being similar across the three comparisons.…”

Section: Dna Hydroxymethylationmentioning

confidence: 99%

Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

et al. 2016

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Epigenetic consequences of exposure to psychostimulants are substantial but the relationship of these changes to compulsive drug taking and abstinence is not clear. Here, we used a paradigm that helped to segregate rats that reduce or stop their methamphetamine (METH) intake (nonaddicted) from those that continue to take the drug compulsively (addicted) in the presence of footshocks. We used that model to investigate potential alterations in global DNA hydroxymethylation in the nucleus accumbens (NAc) because neuroplastic changes in the NAc may participate in the development and maintenance of drug-taking behaviors. We found that METH-addicted rats did indeed show differential DNA hydroxymethylation in comparison with both control and nonaddicted rats. Nonaddicted rats also showed differences from control rats. Differential DNA hydroxymethylation observed in addicted rats occurred mostly at intergenic sites located on long and short interspersed elements. Interestingly, differentially hydroxymethylated regions in genes encoding voltage (Kv1.1, Kv1.2, Kvb1 and Kv2.2)-and calcium (Kcnma1, Kcnn1 and Kcnn2)-gated potassium channels observed in the NAc of nonaddicted rats were accompanied by increased mRNA levels of these potassium channels when compared with mRNA expression in METH-addicted rats. These observations indicate that changes in differentially hydroxymethylated regions and increased expression of specific potassium channels in the NAc may promote abstinence from drug-taking behaviors. Thus, activation of specific subclasses of voltage-and/or calcium-gated potassium channels may provide an important approach to the beneficial treatment for METH addiction.

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“…The presence of a TTTT/AA endonuclease cleavage site has been shown to not be reliable (Richardson et al 2014). We inferred the boundary between retrocopies and flanking regions by BLAT.…”

Section: Analysis Of Hallmark Sequences Of L1-mediated Retropositionmentioning

confidence: 99%

“…L1-mediated retrocopies harbor several hallmark sequences in their flanking regions: a TTTT/AA endonuclease cleavage site, a poly(A) tail priming the reverse transcription, target site duplications (TSDs) generated when fixing the insertion nick overhang, and a bias favoring truncation of the 5 ′ rather than the 3 ′ end (Kaessmann et al 2009;Richardson et al 2014). …”

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confidence: 99%

LTR-mediated retroposition as a mechanism of RNA-based duplication in metazoans

et al. 2016

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In a broad range of taxa, genes can duplicate through an RNA intermediate in a process mediated by retrotransposons (retroposition). In mammals, L1 retrotransposons drive retroposition, but the elements responsible for retroposition in other animals have yet to be identified. Here, we examined young retrocopies from various animals that still retain the sequence features indicative of the underlying retroposition mechanism. In Drosophila melanogaster, we identified and de novo assembled 15 polymorphic retrocopies and found that all retroposed loci are chimeras of internal retrocopies flanked by discontinuous LTR retrotransposons. At the fusion points between the mRNAs and the LTR retrotransposons, we identified shared short similar sequences that suggest the involvement of microsimilarity-dependent template switches. By expanding our approach to mosquito, zebrafish, chicken, and mammals, we identified in all these species recently originated retrocopies with a similar chimeric structure and shared microsimilarities at the fusion points. We also identified several retrocopies that combine the sequences of two or more parental genes, demonstrating LTR-retroposition as a novel mechanism of exon shuffling. Finally, we found that LTR-mediated retrocopies are immediately cotranscribed with their flanking LTR retrotransposons. Transcriptional profiling coupled with sequence analyses revealed that the sense-strand transcription of the retrocopies often lead to the origination of in-frame proteins relative to the parental genes. Overall, our data show that LTR-mediated retroposition is highly conserved across a wide range of animal taxa; combined with previous work from plants and yeast, it represents an ancient and ongoing mechanism continuously shaping gene content evolution in eukaryotes.

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L1 Retrotransposons and Somatic Mosaicism in the Brain

Cited by 152 publications

References 137 publications

Initiation of homologous recombination at DNA nicks

Initiation of homologous recombination at DNA nicks

Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

LTR-mediated retroposition as a mechanism of RNA-based duplication in metazoans

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