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Cancer therapies that target epigenetic repressors can mediate their effects by activating retroelements within the human genome. Retroelement transcripts can form double-stranded RNA (dsRNA) that activates the MDA5 pattern recognition receptor 1 – 6 . This state of viral mimicry leads to loss of cancer cell fitness and stimulates innate and adaptive immune responses 7 , 8 . However, the clinical efficacy of epigenetic therapies has been limited. To find targets that would synergize with the viral mimicry response, we sought to identify the immunogenic retroelements that are activated by epigenetic therapies. Here we show that intronic and intergenic SINE elements, specifically inverted-repeat Alus, are the major source of drug-induced immunogenic dsRNA. These inverted-repeat Alus are frequently located downstream of ‘orphan’ CpG islands 9 . In mammals, the ADAR1 enzyme targets and destabilizes inverted-repeat Alu dsRNA 10 , which prevents activation of the MDA5 receptor 11 . We found that ADAR1 establishes a negative-feedback loop, restricting the viral mimicry response to epigenetic therapy. Depletion of ADAR1 in patient-derived cancer cells potentiates the efficacy of epigenetic therapy, restraining tumour growth and reducing cancer initiation. Therefore, epigenetic therapies trigger viral mimicry by inducing a subset of inverted-repeats Alus, leading to an ADAR1 dependency. Our findings suggest that combining epigenetic therapies with ADAR1 inhibitors represents a promising strategy for cancer treatment. Inverted-repeat Alu elements are the main source of drug-induced immunogenic double-stranded RNAs, which are destabilized by the RNA deaminase ADAR1, thereby limiting activation of the immune response.

For species with minor inverted repeat (IR) boundary changes in the plastid genome (plastome), nucleotide substitution rates were previously shown to be lower in the IR than the single copy regions (SC). However, the impact of large-scale IR expansion/contraction on plastid nucleotide substitution rates among closely related species remains unclear. We included plastomes from 22 Pelargonium species, including eight newly sequenced genomes, and used both pairwise and model-based comparisons to investigate the impact of the IR on sequence evolution in plastids. Ten types of plastome organization with different inversions or IR boundary changes were identified in Pelargonium. Inclusion in the IR was not sufficient to explain the variation of nucleotide substitution rates. Instead, the rate heterogeneity in Pelargonium plastomes was a mixture of locus-specific, lineage-specific and IR-dependent effects. Our study of Pelargonium plastomes that vary in IR length and gene content demonstrates that the evolutionary consequences of retaining these repeats are more complicated than previously suggested.

Rates of nucleotide substitution were previously shown to be several times slower in the plastid inverted repeat (IR) compared with single‐copy (SC) regions, suggesting that the IR provides enhanced copy‐correction activity. To examine the generality of this synonymous rate dependence on the IR, we compared plastomes from 69 pairs of closely related species representing 52 families of angiosperms, gymnosperms, and ferns. We explored the breadth of IR boundary shifts in land plants and demonstrate that synonymous substitution rates are, on average, 3.7 times slower in IR genes than in SC genes. In addition, genes moved from the SC into the IR exhibit lower synonymous rates consistent with other IR genes, while genes moved from the IR into the SC exhibit higher rates consistent with other SC genes. Surprisingly, however, several plastid genes from Pelargonium, Plantago, and Silene have highly accelerated synonymous rates despite their IR localization. Together, these results provide strong evidence that the duplicative nature of the IR reduces the substitution rate within this region. The anomalously fast‐evolving genes in Pelargonium, Plantago, and Silene indicate localized hypermutation, potentially induced by a higher level of error‐prone double‐strand break repair in these regions, which generates substitutional rate variation.

The subfamily Pothoideae belongs to the ecologically important plant family Araceae. Here, we report the chloroplast genomes of two species of the subfamily Pothoideae: Anthurium huixtlense (size: 163,116 bp) and Pothos scandens (size: 164,719 bp). The chloroplast genome of P. scandens showed unique contraction and expansion of inverted repeats (IRs), thereby increasing the size of the large single-copy region (LSC: 102,956 bp) and decreasing the size of the small single-copy region (SSC: 6779 bp). This led to duplication of many single-copy genes due to transfer to IR regions from the small single-copy (SSC) region, whereas some duplicate genes became single copy due to transfer to large single-copy regions. The rate of evolution of protein-coding genes was affected by the contraction and expansion of IRs; we found higher mutation rates for genes that exist in single-copy regions as compared to those in IRs. We found a 2.3-fold increase of oligonucleotide repeats in P. scandens when compared with A. huixtlense , whereas amino acid frequency and codon usage revealed similarities. The ratio of transition to transversion mutations was 2.26 in P. scandens and 2.12 in A. huixtlense . Transversion mutations mostly translated in non-synonymous substitutions. The phylogenetic inference of the limited species showed the monophyly of the Araceae subfamilies. Our study provides insight into the molecular evolution of chloroplast genomes in the subfamily Pothoideae and family Araceae.

Genomic instability is a hallmark of aging and cancer. A key contributor to genomic instability includes alternative DNA structures, such as cruciform‐forming inverted repeats (IRs). Short IRs (< 100 bps) are abundant in the human genome, mutagenic, and enriched at mutation hotspots in human cancer genomes. Using an innovative mutation‐reporter mouse model, we showed that short IRs are mutagenic in vivo. Further, we found that aging exacerbates IR‐induced genomic instability, as evidenced by increased mutation frequencies and altered spectra in the spleen and brain of mice harboring either a short IR or control B‐DNA sequence at 2 and 24 months of age. These findings establish a link between aging and enhanced mutagenesis at short IRs, providing a unique in vivo platform to investigate age‐related mechanisms of DNA structure‐mediated genomic instability. Aging amplifies the mutagenic potential of short, inverted repeats in mice. The increase in point mutations in the spleen and large deletions in the brain with age highlights distinct pathways across proliferative and post‐mitotic tissues.

Premise of the Study As more plastomes are assembled, it is evident that rearrangements, losses, intergenic spacer expansion and contraction, and syntenic breaks within otherwise functioning plastids are more common than was thought previously, and such changes have developed independently in disparate lineages. However, to date, the magnoliids remain characterized by their highly conserved plastid genomes (plastomes). Methods Illumina HiSeq and MiSeq platforms were used to sequence the plastomes of Saruma henryi and those of representative species from each of the six taxonomic sections of Asarum. Sequenced plastomes were compared in a phylogenetic context provided by maximum likelihood and parsimony inferences made using an additional 18 publicly available plastomes from early‐diverging angiosperm lineages. Key Results In contrast to previously published magnoliid plastomes and the newly sequenced Saruma henryi plastome published here, Asarum plastomes have undergone extensive disruption and contain extremely lengthy AT‐repeat regions. The entirety of the small single copy region (SSC) of A. canadense and A. sieboldii var. sieboldii has been incorporated into the inverted repeat regions (IR), and the SSC of A. delavayi is only 14 bp long. All sampled Asarum plastomes share an inversion of a large portion of the large single copy region (LSC) such that trnE‐UUC is adjacent to the LSC‐IR boundary. Conclusions Plastome divergence in Asarum appears to be consistent with trends seen in highly rearranged plastomes of the monocots and eudicots. We propose that plastome instability in Asarum is due to repetitive motifs that serve as recombinatory substrates and reduce genome stability.

Miniature inverted-repeat transposable elements (MITEs) are the most abundant group among class II mobile elements in plant genomes. They are frequently located in gene-rich regions, which may affect gene structure and expression, leading to functional diversity. Our research aimed to perform a comprehensive global annotation of MITEs in the sugar beet genome, which has been lacking to date. We also attempted to elucidate the association between the presence of MITE insertions and the regulation of gene expression. Analysis of the MITEs distribution in sugar beet revealed that MITEs cover about 3% of the genome, with the largest group comprising Stowaway -like elements. Approximately 60% of all identified MITEs were located within genic regions, indicating their potential impact on gene expression regulation. Stowaway and Tourist -like elements were frequently present in introns and downstream from genes. Tourists were also relatively more enriched in 3’UTRs than the other MITE groups. hAT -like MITEs were present mainly in introns and 5’UTRs, while Mutator -like elements were relatively more frequently located in 5’UTRs than in the other MITE groups. Our study also showed that a considerable portion of the differentially expressed genes in plants from two F2 sugar beet families was associated with MITEs, especially Stowaways and Tourists . We provided a comprehensive landscape of MITE distribution in the sugar beet genome and described examples of MITE insertions located in the regulatory regions of genes that show significant differential expression. These results will facilitate research into the role of MITEs in their potential impact on gene expression regulation.

Background Miniature inverted-repeat transposable elements (MITEs) and long terminal repeat (LTR) retrotransposons are ubiquitous in plants genomes, and highly important in their evolution and diversity. However, their mechanisms of insertion/amplification and roles in Citrus genome’s evolution/diversity are still poorly understood. Results To address this knowledge gap, we developed different computational pipelines to analyze, annotate and classify MITEs and LTR retrotransposons in six different sequenced Citrus species. We identified 62,010 full-length MITEs from 110 distinguished families. We observed MITEs tend to insert in gene related regions and enriched in promoters. We found that DTM63 is possibly an active Mutator -like MITE family in the traceable past and may still be active in Citrus . The insertion of MITEs resulted in massive polymorphisms and played an important role in Citrus genome diversity and gene structure variations. In addition, 6630 complete LTR retrotransposons and 13,371 solo-LTRs were identified. Among them, 12 LTR lineages separated before the differentiation of mono- and dicotyledonous plants. We observed insertion and deletion of LTR retrotransposons was accomplished with a dynamic balance, and their half-life in Citrus was ~ 1.8 million years. Conclusions These findings provide insights into MITEs and LTR retrotransposons and their roles in genome diversity in different Citrus genomes.

Miniature inverted repeat transposable elements (MITEs) are prevalent in eukaryotic genomes, including plants and animals. Classified as a type of non-autonomous DNA transposable elements, they play important roles in genome organization and evolution. Comprehensive and accurate genome-wide detection of MITEs in various eukaryotic genomes can improve our understanding of their origins, transposition processes, regulatory mechanisms and biological relevance with regard to gene structures, expression and regulation. In this paper, we present a new MATLAB-based program called detectMITE that employs a novel numeric calculation algorithm to replace conventional string matching algorithms in MITE detection, adopts the Lempel-Ziv complexity algorithm to filter out MITE candidates with low complexity and utilizes the powerful clustering program CD-HIT to cluster similar MITEs into MITE families. Using the rice genome as test data, we found that detectMITE can more accurately, comprehensively and efficiently detect MITEs on a genome-wide scale than other popular MITE detection tools. Through comparison with the potential MITEs annotated in Repbase, the widely used eukaryotic repeat database, detectMITE has been shown to find known and novel MITEs with a complete structure and full-length copies in the genome. detectMITE is an open source tool ( https://sourceforge.net/projects/detectmite ).

Commiphora gileadensis and C. foliacea (family Burseraceae) are pantropical in nature and known for producing fragrant resin (myrrh). Both the tree species are economically and medicinally important however, least genomic understanding is available for this genus. Herein, we report the complete chloroplast genome sequences of C. gileadensis and C. foliacea and comparative analysis with related species (C. wightii and Boswellia sacra). A modified chloroplast DNA extraction method was adopted, followed with next generation sequencing, detailed bioinformatics and PCR analyses. The results revealed that the cp genome sizes of C. gileadensis and C. foliacea, are 160,268 and 160,249 bp, respectively, with classic quadripartite structures that comprises of inverted repeat's pair. Overall, the organization of these cp genomes, GC contents, gene order, and codon usage were comparable to other cp genomes in angiosperm. Approximately, 198 and 175 perfect simple sequence repeats were detected in C. gileadensis and C. foliacea genomes, respectively. Similarly, 30 and 25 palindromic, 15 and 25 forward, and 20 and 25 tandem repeats were determined in both the cp genomes, respectively. Comparison of these complete cp genomes with C. wightii and B. sacra revealed significant sequence resemblance and comparatively highest deviation in intergenic spacers. The phylo-genomic comparison showed that C. gileadensis and C. foliacea form a single clade with previously reported C. wightii and B. sacra from family Burseraceae. Current study reports for the first time the cp genomics of species from Commiphora, which could be helpful in understanding genetic diversity and phylogeny of this myrrh producing species.