1,063 research outputs found

    The Impact of CpG Island on Defining Transcriptional Activation of the Mouse L1 Retrotransposable Elements

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    BACKGROUND: L1 retrotransposable elements are potent insertional mutagens responsible for the generation of genomic variation and diversification of mammalian genomes, but reliable estimates of the numbers of actively transposing L1 elements are mostly nonexistent. While the human and mouse genomes contain comparable numbers of L1 elements, several phylogenetic and L1Xplore analyses in the mouse genome suggest that 1,500-3,000 active L1 elements currently exist and that they are still expanding in the genome. Conversely, the human genome contains only 150 active L1 elements. In addition, there is a discrepancy among the nature and number of mouse L1 elements in L1Xplore and the mouse genome browser at the UCSC and in the literature. To date, the reason why a high copy number of active L1 elements exist in the mouse genome but not in the human genome is unknown, as are the potential mechanisms that are responsible for transcriptional activation of mouse L1 elements. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the promoter sequences of the 1,501 potentially active mouse L1 elements retrieved from the GenBank and L1Xplore databases and evaluated their transcription factors binding sites and CpG content. To this end, we found that a substantial number of mouse L1 elements contain altered transcription factor YY1 binding sites on their promoter sequences that are required for transcriptional initiation, suggesting that only a half of L1 elements are capable of being transcriptionally active. Furthermore, we present experimental evidence that previously unreported CpG islands exist in the promoters of the most active T(F) family of mouse L1 elements. The presence of sequence variations and polymorphisms in CpG islands of L1 promoters that arise from transition mutations indicates that CpG methylation could play a significant role in determining the activity of L1 elements in the mouse genome. CONCLUSIONS: A comprehensive analysis of mouse L1 promoters suggests that the number of transcriptionally active elements is significantly lower than the total number of full-length copies from the three active mouse L1 families. Like human L1 elements, the CpG islands and potentially the transcription factor YY1 binding sites are likely to be required for transcriptional initiation of mouse L1 elements

    The Genomic Distribution of L1 Elements: The Role of Insertion Bias and Natural Selection

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    LINE-1 (L1) retrotransposons constitute the most successful family of retroelements in mammals and account for as much as 20% of mammalian DNA. L1 elements can be found in all genomic regions but they are far more abundant in AT-rich, gene-poor, and low-recombining regions of the genome. In addition, the sex chromosomes and some genes seem disproportionately enriched in L1 elements. Insertion bias and selective processes can both account for this biased distribution of L1 elements. L1 elements do not appear to insert randomly in the genome and this insertion bias can at least partially explain the genomic distribution of L1. The contrasted distribution of L1 and Alu elements suggests that postinsertional processes play a major role in shaping L1 distribution. The most likely mechanism is the loss of recently integrated L1 elements that are deleterious (negative selection) either because of disruption of gene function or their ability to mediate ectopic recombination. By comparison, the retention of L1 elements because of some positive effect is limited to a small fraction of the genome. Understanding the respective importance of insertion bias and selection will require a better knowledge of insertion mechanisms and the dynamics of L1 inserts in populations

    The Role of Retrotransposons in Gene Family Expansions: Insights from the Mouse \u3ci\u3eAbp\u3c/i\u3e Gene Family

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    Background: Retrotransposons have been suggested to provide a substrate for non-allelic homologous recombination (NAHR) and thereby promote gene family expansion. Their precise role, however, is controversial. Here we ask whether retrotransposons contributed to the recent expansions of the Androgen-binding protein (Abp) gene families that occurred independently in the mouse and rat genomes. Results: Using dot plot analysis, we found that the most recent duplication in the Abp region of the mouse genome is flanked by L1Md_T elements. Analysis of the sequence of these elements revealed breakpoints that are the relicts of the recombination that caused the duplication, confirming that the duplication arose as a result of NAHR using L1 elements as substrates. L1 and ERVII retrotransposons are considerably denser in the Abp regions than in one Mb flanking regions, while other repeat types are depleted in the Abp regions compared to flanking regions. L1 retrotransposons preferentially accumulated in the Abp gene regions after lineage separation and roughly followed the pattern of Abp gene expansion. By contrast, the proportion of shared vs. lineage-specific ERVII repeats in the Abp region resembles the rest of the genome. Conclusions: We confirmed the role of L1 repeats in Abp gene duplication with the identification of recombinant L1Md_T elements at the edges of the most recent mouse Abp gene duplication. High densities of L1 and ERVII repeats were found in the Abp gene region with abrupt transitions at the region boundaries, suggesting that their higher densities are tightly associated with Abp gene duplication. We observed that the major accumulation of L1 elements occurred after the split of the mouse and rat lineages and that there is a striking overlap between the timing of L1 accumulation and expansion of the Abp gene family in the mouse genome. Establishing a link between the accumulation of L1 elements and the expansion of the Abp gene family and identification of an NAHR-related breakpoint in the most recent duplication are the main contributions of our study

    LINE-1 RNA splicing and influences on mammalian gene expression

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    Long interspersed element-1 elements compose on average one-fifth of mammalian genomes. The expression and retrotransposition of L1 is restricted by a number of cellular mechanisms in order to limit their damage in both germ-line and somatic cells. L1 transcription is largely suppressed in most tissues, but L1 mRNA and/or proteins are still detectable in testes, a number of specific somatic cell types, and malignancies. Down-regulation of L1 expression via premature polyadenylation has been found to be a secondary mechanism of limiting L1 expression. We demonstrate that mammalian L1 elements contain numerous functional splice donor and acceptor sites. Efficient usage of some of these sites results in extensive and complex splicing of L1. Several splice variants of both the human and mouse L1 elements undergo retrotransposition. Some of the spliced L1 mRNAs can potentially contribute to expression ofopen reading frame 2-related products and therefore have implications for the mobility of SINEs even if they are incompetent for L1 retrotransposition. Analysis of the human EST database revealed that L1 elements also participate in splicing events with other genes. Such contribution of functional splice sites by L1 may result in disruption of normal gene expression or formation of alternative mRNA transcripts

    A comprehensive analysis of recently integrated human LINE-1 mobile elements

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    Long INterspersed Elements (LINE or L1) have had an enormous influence on human genomic structure, comprising about 20% of the mass of the human genome. In this analysis the most recent L1 insertions in the human genome belonging to L1Hs Ta and preTa subfamilies were examined to further understand the impact L1 elements have had on human genomic structure and diversity. Collectively, over 800 human specific L1 elements from the draft sequence of the human genome were characterized. Estimates suggest that human specific L1 mobilization alone is responsible for increasing the size of the human genome by roughly 1.4 million bases, and that over 70 human specific L1 elements may still possess the ability to retrotranspose within human cells. Interestingly, over 35 L1 insertions were found adjacent to exons, though the majority of insertions showed general preference for gene poor regions of the genomes with low GC content. Analysis of over 500 L1 insertions by PCR on a diverse panel of humans representing geographically distinct human populations revealed that 115 (45%) of the Ta and 33 (14%) of the preTa human specific L1 insertions were variable in the human population with respect to insertion presence or absence. Sequence analysis of L1Hs Ta and preTa subfamily members yielded estimated average ages of 1.99 and 2.34 million years respectively. The 148 newly identified L1 insertion polymorphisms will serve as useful genetic markers for the study of human population genetics

    Endonuclease-independent insertion provides an alternative pathway for L1 retrotransposition in the human genome

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    LINE-1 elements (L1s) are a family of highly successful retrotransposons comprising ∼ 17% of the human genome, the majority of which have inserted through an endonuclease-dependent mechanism termed target-primed reverse transcription. Recent in vitro analyses suggest that in the absence of non-homologous end joining proteins, L1 elements may utilize an alternative, endonuclease-independent pathway for insertion. However, it remains unknown whether this pathway operates in vivo or in cell lines where all DNA repair mechanisms are functional. Here, we have analyzed the human genome to demonstrate that this alternative pathway for L1 insertion has been active in recent human evolution and characterized 21 loci where L1 elements have integrated without signs of endonuclease-related activity. The structural features of these loci suggest a role for this process in DNA double-strand break repair. We show that endonuclease-independent L1 insertions are structurally distinguishable from classical L1 insertion loci, and that they are associated with inter-chromosomal translocations and deletions of target genomic DNA. © 2007 The Author(s)

    Silencing of LINE-1 retrotransposons contributes to variation in small noncoding RNA expression in human cancer cells

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    Noncoding RNAs are key players in the maintenance of genomic integrity, particularly in silencing the expression of repetitive elements, some of which are retrotransposable and capable of causing genomic instability. Recent computational studies suggest an association between L1 expression and the generation of small RNAs. However, whether L1 expression has a role in the activation of small RNA expression has yet to be determined experimentally. Here we report a global analysis of small RNAs in deep sequencing from L1-active and L1-silenced breast cancer cells. We found that cells in which L1 expression was silenced exhibited greatly increased expression of a number of miRNAs and in particular, members of the let-7 family. In addition, we found differential expression of a few piRNAs that might potentially regulate gene expression. We also report the identification of several repeat RNAs against LTRs, LINEs and SINE elements. Although most of the repeat RNAs mapped to L1 elements, in general we found no significant differences in the expression levels of repeat RNAs in the presence or absence of L1 expression except for a few RNAs targeting subclasses of L1 elements. These differentially expressed small RNAs may function in human genome defence responses
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