Mobile DNA最新文献

Nearly half of the human genome consists of transposable elements, among which endogenous retroviruses, remnants of ancient retroviral infections, represent some of the most evolutionarily intriguing due to their paradoxical functional duality. While research has documented functional ERV exaptation in key biological processes, these elements have also been associated with age-related diseases, particularly cancer. This apparent contradiction presents an evolutionary question: why would potentially disruptive elements persist in genomes over evolutionary time? Here we review the complex relationship between ERVs, aging and cancer to address this question. After reviewing the physiological roles of ERVs, we explore how the transcriptional activation of normally repressed ERVs may function as an evolutionary-conserved genomic surveillance system that, when triggered by cellular stressors, generates viral-like nucleic acids and proteins that activate pathways to potentially eliminate cancerous cells. Conversely, we discuss how cancer cells could appropriate ERV expression to distort cellular processes, promoting inflammation and senescence that ultimately facilitate tumor progression. Despite this duality, we advance a novel hypothesis that many ERVs have been exapted in mammalian genomes primarily as defense mechanisms against tumorigenesis. This evolutionary perspective provides a framework for understanding both the persistence of ERVs in our and other mammals' genomes and their intriguing roles in cancer biology. Moreover, even after tumor development, ERVs can be exploited by immunotherapy due to their canonical function as regulators of the immune response, positioning them as emerging central elements in cancer treatment strategies. This work offers new insights into these endogenous retroviruses' evolutionary significance and potential applications in cancer therapeutics and diagnostics.

Background: The recognition that transposable elements (TEs) play important roles in many biological processes has elicited growing interest in analyzing sequencing data derived from this 'dark genome'. This goal is complicated by the highly repetitive nature of these sequences in genomes, requiring the deployment of several problem-specific tools as well as the curation of appropriate genome annotations. This pipeline aims to make the analysis of TE sequences and their expression more generally accessible.

Results: The TE-Seq pipeline conducts an end-to-end analysis of RNA sequencing data, examining both genes and TEs, and is compatible with most eukaryotic species. It implements computational methods tailor-made for TEs, and produces a comprehensive analysis of TE expression at both the level of the individual element and at the TE clade level. Furthermore, if supplied with long-read DNA sequencing data, it is able to assess TE expression from non-reference (polymorphic) loci. As a demonstration, we analyzed proliferating, early senescent, and late senescent human lung fibroblast RNA-Seq data, and created a custom reference genome and annotations for this cell strain using Nanopore sequencing data. We found that several retrotransposable element clades were upregulated in senescence, which included non-reference, intact, and potentially active elements.

Conclusions: TE-Seq is made available as a Snakemake pipeline which can be obtained at https://github.com/maxfieldk/TE-Seq .

Transposable elements (TEs) are dynamic components of eukaryotic genomes, playing a crucial role in genome evolution and plasticity, particularly in unstable regions such as chromosome ends. In the globally significant fungal pathogen Fusarium oxysporum, we identified and characterized a novel family of non-LTR retrotransposons named FoTeRs (F. oxysporum Telomeric Retrotransposons). These elements are consistently and uniquely localized at chromosome ends, representing a rare example of site-specific TE integration. Phylogenetic analysis confirmed that FoTeRs form a distinct clade with other telomere-targeting retrotransposons, suggesting a shared evolutionary history and a convergent mechanism for telomeric integration. We found that individual FoTeR elements exhibit a duality in their evolutionary status. Putatively functional elements are under strong purifying selection, indicating that their protein-coding regions are highly conserved. This contrasts with the presence of other, non-functional copies that exhibit signs of mutational decay, a process accelerated by Repeat-Induced Point (RIP) mutations -a fungal-specific defense mechanism. The high density of upstream variable number tandem repeats (VNTRs) also contributes to their genomic plasticity. Furthermore, FoTeRs frequently co-localize with host Telomere-Linked Helicases (TLHs), suggesting a potential functional link in telomere maintenance. This study provides crucial insights into the role of TEs in shaping the genome architecture and adaptive potential of this important fungal pathogen.

Miniature inverted repeat transposable elements (MITEs) are short, non-autonomous transposable elements that have attracted considerable attention over the years due to their ubiquitous presence and functional roles in plant genomes. A growing body of evidence points to a complex and multifaceted interplay between MITEs and host genomes. This review aims to elucidate the diverse roles of MITEs in shaping plant genome architecture, gene expression and adaptability to environmental stresses through different molecular mechanisms such as accommodation of regulatory sequences, promotion of alternative splicing, generation of epialleles and small RNAs, and mediation of structural variation. These examples highlight the functional importance of MITEs in plant genomes and provide directions for future research.

Background: SINE variable number tandem repeat Alu elements (SVAs) are a unique group of hominid-specific composite retrotransposons with highly variable internal structure. They represent the youngest TE family in humans and contribute to genetic diversity, evolution, and disease. Recent findings indicate that SVA mobilization rates may exceed previous estimates, and many SVAs exhibit insertion polymorphism. SVAs facilitate transduction (TD) events when transcription initiates upstream of a source element, or when their internal termination signal is bypassed, mobilizing adjacent 5' and/or 3' sequence. To investigate features of non-reference SVA elements currently polymorphic in the human genome, we analyzed a structural variant callset built upon 35 diverse human genomes generated by the Human Genome Structural Variation Consortium.

Results: In our curated dataset of 543 polymorphic, non-reference SVAs, we identify insertions representing the three youngest subfamilies: D (7%), E (38%), and F (55%). Of the latter, we determine that at least 47% are actually SVA_F₁, a more recently discovered human-specific subfamily, indicating that F₁ is a major contributor to SVA expansion in the human population. We further uncover that 40% of non-reference SVAs carry a TD on their 5' and/or 3' ends. Of these, the majority (69%) harbor sequence originating in a gene, including 14 exonic events and the mobilization of a processed pseudogene, supporting the role of SVA in exon shuffling. In addition, we identified a so-called "orphan" TD, defined by the absence of SVA sequence at the insertion site. Leveraging TD origin coordinates, we identify 55 active source elements, including nine non-reference and 46 across GRCh38 and T2T-CHM13, giving rise to 84% of TD-carrying SVAs.

Conclusions: Our analyses indicate that SVA_F₁ is more active than previously described and is a main driver of SVA expansion. We find two-fold more TD events compared to previous estimates, with an unexpected bias toward 3' events. Finally, we postulate that the discrepant SVA mobilization rate may be attributed to inter-individual variation in the presence/absence of source elements, a recent uptick in mobilization supported by overall low allele frequencies, and/or negative selection against deleterious insertions.

Mobile group II introns are site-specific retrotransposons composed of a large self-splicing ribozyme and an intron-encoded reverse transcriptase that are widespread in bacterial and organellar genomes. Sequence and structural variations of the ribozyme and the associated reverse transcriptase define several lineages of bacterial group II introns. Interestingly, some of these intron families evolved different mobility strategies while others colonize particular genetic contexts. Here, we have investigated the mobility activity of an Escherichia coli group II intron that is inserted into the stop codon of the stress-response gene groEL. Using mobility assays based on over-expression from a donor plasmid, we demonstrate that this intron is a highly efficient and site-specific retrotransposon, capable of colonizing the groEL gene of an E. coli host strain according to the insertion pattern observed in natural genomes. Furthermore, we provide evidence that a chromosomal copy of the full-length retrotransposon can be expressed from its native genetic locus to yield mobile retroelement particles. This intron constitutes a novel model system that could help reveal original mobility strategies used by some group II intron retrotransposons to colonize bacterial genomes.

Long Interspersed Nuclear Elements-1 (LINE-1 or L1) make up approximately 21% of the human genome, with some L1 loci containing intact open reading frames (ORFs) that facilitate retrotransposition. Because retrotransposition can have deleterious effects leading to mutations and genomic instability, L1 activity is typically suppressed in somatic cells through transcriptional and post-transcriptional mechanisms. However, L1 elements are derepressed in senescent cells causing age-associated inflammation. Despite the recognition of L1 activity as a hallmark of aging, the underlying molecular mechanisms governing L1 derepression in these cells are not fully understood. In this study, we employed high throughput sequencing datasets and validated our findings through independent experiments to investigate the regulation of L1 elements in senescent cells. Our results reveal that both replicative and oncogene-induced senescence are associated with reduced expression of the cytidine deaminase APOBEC3B, a known suppressor of L1 retrotransposition. Consequently, senescent cells exhibited diminished levels of C-to-U editing of full-length L1 elements. Moreover, Ribo-seq profiling indicated that progression to senescence is not only associated with increased L1 transcription, but also translation of L1 ORFs. In summary, our results suggest that the depletion of APOBEC3B contributes to enhanced activity of L1 in senescent cells and promotion of L1-induced DNA damage and aging.

Background: Retroelements are repetitive sequences that comprise 42% of the human genome and are strictly regulated through various epigenetic mechanisms. Examining retroelement expression on a locus-specific level in relation to cancer can uncover distinct disease signatures.

Results: Using over 5000 RNA-sequencing samples, we assessed retroelement transcription across 23 tissue systems, 159 cell types, 1019 cancer cell lines, and cells isolated from various stages of embryogenesis using the specialized software tool, Telescope. In healthy individuals, 11,388 retroelements were found to be actively transcribed and dynamically regulated in a tissue- and cell type-dependent manner. Using the adult human body as a reference, we observed that 94% of cancer cell lines displayed elevated transcription of at least one cancer-specific retroelement, providing a three-fold larger reservoir of cancer biomarkers (1182) than our comparable analysis of annotated protein-coding genes (338). The precise retroelements that were transcribed following tumorigenesis were influenced by the originating location, with cancers of the blood, lungs, and soft tissue displaying the highest origin-specific activation. Moreover, nearly half of the cancer-specific retroelement loci, mostly from the HERV-H family, were found to be expressed during early embryonic development.

Conclusions: Our data demonstrate that elevated transcription of certain tissue-specific and embryonic retroelements can be considered as a hallmark of tumorigenesis.