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International Journal of Molecular... Jul 2022The rapidly emerging phenomenon of antibiotic resistance threatens to substantially reduce the efficacy of available antibacterial therapies. Dissemination of... (Review)
Review
The rapidly emerging phenomenon of antibiotic resistance threatens to substantially reduce the efficacy of available antibacterial therapies. Dissemination of resistance, even between phylogenetically distant bacterial species, is mediated mainly by mobile genetic elements, considered to be natural vectors of horizontal gene transfer. Transposable elements (TEs) play a major role in this process-due to their highly recombinogenic nature they can mobilize adjacent genes and can introduce them into the pool of mobile DNA. Studies investigating this phenomenon usually focus on the genetic load of transposons and the molecular basis of their mobility. However, genes introduced into evolutionarily distant hosts are not necessarily expressed. As a result, bacterial genomes contain a reservoir of transcriptionally silent genetic information that can be activated by various transposon-related recombination events. The TEs themselves along with processes associated with their transposition can introduce promoters into random genomic locations. Thus, similarly to integrons, they have the potential to convert dormant genes into fully functional antibiotic resistance determinants. In this review, we describe the genetic basis of such events and by extension the mechanisms promoting the emergence of new drug-resistant bacterial strains.
Topics: Anti-Bacterial Agents; Bacteria; DNA Transposable Elements; Drug Resistance, Microbial; Gene Transfer, Horizontal; Integrons
PubMed: 35897639
DOI: 10.3390/ijms23158063 -
Nature Communications Oct 2019Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans...
Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 of which are likely causative of the patient's symptoms (0.04%), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we estimate genome-wide germline ME mutation rate and selective constraint and demonstrate that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies.
Topics: Developmental Disabilities; Genetic Variation; Humans; Mutation Rate; Retroelements
PubMed: 31604926
DOI: 10.1038/s41467-019-12520-y -
Genome Biology Jul 2020Mobile elements are a major source of structural variants in the human genome, and some mobile elements can regulate gene expression and transcript splicing. However,...
BACKGROUND
Mobile elements are a major source of structural variants in the human genome, and some mobile elements can regulate gene expression and transcript splicing. However, the impact of polymorphic mobile element insertions (pMEIs) on gene expression and splicing in diverse human tissues has not been thoroughly studied. The multi-tissue gene expression and whole genome sequencing data generated by the Genotype-Tissue Expression (GTEx) project provide a great opportunity to systematically evaluate the role of pMEIs in regulating gene expression in human tissues.
RESULTS
Using the GTEx whole genome sequencing data, we identify 20,545 high-quality pMEIs from 639 individuals. Coupling pMEI genotypes with gene expression profiles, we identify pMEI-associated expression quantitative trait loci (eQTLs) and splicing quantitative trait loci (sQTLs) in 48 tissues. Using joint analyses of pMEIs and other genomic variants, pMEIs are predicted to be the potential causal variant for 3522 eQTLs and 3717 sQTLs. The pMEI-associated eQTLs and sQTLs show a high level of tissue specificity, and these pMEIs are enriched in the proximity of affected genes and in regulatory elements. Using reporter assays, we confirm that several pMEIs associated with eQTLs and sQTLs can alter gene expression levels and isoform proportions, respectively.
CONCLUSION
Overall, our study shows that pMEIs are associated with thousands of gene expression and splicing variations, indicating that pMEIs could have a significant role in regulating tissue-specific gene expression and transcript splicing. Detailed mechanisms for the role of pMEIs in gene regulation in different tissues will be an important direction for future studies.
Topics: Alternative Splicing; Datasets as Topic; Gene Expression; Humans; Interspersed Repetitive Sequences; Quantitative Trait Loci
PubMed: 32718348
DOI: 10.1186/s13059-020-02101-4 -
Genetics Jul 2022Sequences derived from the Long INterspersed Element-1 (L1) family of retrotransposons occupy at least 17% of the human genome, with 67 distinct subfamilies representing...
Sequences derived from the Long INterspersed Element-1 (L1) family of retrotransposons occupy at least 17% of the human genome, with 67 distinct subfamilies representing successive waves of expansion and extinction in mammalian lineages. L1s contribute extensively to gene regulation, but their molecular history is difficult to trace, because most are present only as truncated and highly mutated fossils. Consequently, L1 entries in current databases of repeat sequences are composed mainly of short diagnostic subsequences, rather than full functional progenitor sequences for each subfamily. Here, we have coupled 2 levels of sequence reconstruction (at the level of whole genomes and L1 subfamilies) to reconstruct progenitor sequences for all human L1 subfamilies that are more functionally and phylogenetically plausible than existing models. Most of the reconstructed sequences are at or near the canonical length of L1s and encode uninterrupted ORFs with expected protein domains. We also show that the presence or absence of binding sites for KRAB-C2H2 Zinc Finger Proteins, even in ancient-reconstructed progenitor L1s, mirrors binding observed in human ChIP-exo experiments, thus extending the arms race and domestication model. RepeatMasker searches of the modern human genome suggest that the new models may be able to assign subfamily resolution identities to previously ambiguous L1 instances. The reconstructed L1 sequences will be useful for genome annotation and functional study of both L1 evolution and L1 contributions to host regulatory networks.
Topics: Animals; Evolution, Molecular; Genome, Human; Humans; Long Interspersed Nucleotide Elements; Mammals; Open Reading Frames; Phylogeny; Repetitive Sequences, Nucleic Acid; Retroelements
PubMed: 35552404
DOI: 10.1093/genetics/iyac074 -
Nature Biotechnology Oct 2023Most short sequences can be precisely written into a selected genomic target using prime editing; however, it remains unclear what factors govern insertion. We design a...
Most short sequences can be precisely written into a selected genomic target using prime editing; however, it remains unclear what factors govern insertion. We design a library of 3,604 sequences of various lengths and measure the frequency of their insertion into four genomic sites in three human cell lines, using different prime editor systems in varying DNA repair contexts. We find that length, nucleotide composition and secondary structure of the insertion sequence all affect insertion rates. We also discover that the 3' flap nucleases TREX1 and TREX2 suppress the insertion of longer sequences. Combining the sequence and repair features into a machine learning model, we can predict relative frequency of insertions into a site with R = 0.70. Finally, we demonstrate how our accurate prediction and user-friendly software help choose codon variants of common fusion tags that insert at high efficiency, and provide a catalog of empirically determined insertion rates for over a hundred useful sequences.
Topics: Humans; DNA Repair; DNA Transposable Elements; Gene Editing; CRISPR-Cas Systems
PubMed: 36797492
DOI: 10.1038/s41587-023-01678-y -
Philosophical Transactions of the Royal... Mar 2020Primate-specific Alu short interspersed nuclear elements (SINEs) and rodent-specific B and ID (B/ID) SINEs are non-autonomous and generally non-coding retrotransposons... (Review)
Review
Primate-specific Alu short interspersed nuclear elements (SINEs) and rodent-specific B and ID (B/ID) SINEs are non-autonomous and generally non-coding retrotransposons that have been copied and pasted into the respective genomes so as to constitute what is estimated to be a remarkable 13% and 8% of those genomes. In the context of messenger RNAs (mRNAs), those residing within 3'-untranslated regions (3'UTRs) can influence mRNA export from the nucleus to the cytoplasm, mRNA translation and/or mRNA decay via proteins with which they associate either individually or base-paired in or in with a partially complementary SINE. Each of these influences impinges on the primary function of mRNA, which is to serve as a template for protein synthesis. This review describes how human cells have used 3'UTR Alu elements to mediate post-transcriptional gene regulation and also describes examples of convergent evolution between human and mouse 3'UTR SINEs. This article is part of a discussion meeting issue 'Crossroads between transposons and gene regulation'.
Topics: 3' Untranslated Regions; Alu Elements; Animals; Gene Expression Regulation; Humans; Mice; RNA Stability; Retroelements; Short Interspersed Nucleotide Elements; Transcription, Genetic
PubMed: 32075563
DOI: 10.1098/rstb.2019.0344 -
Genes Jun 2021Transposable elements (TEs) are nearly ubiquitous in eukaryotes. The increase in genomic data, as well as progress in genome annotation and molecular biology techniques,... (Review)
Review
Transposable elements (TEs) are nearly ubiquitous in eukaryotes. The increase in genomic data, as well as progress in genome annotation and molecular biology techniques, have revealed the vast number of ways mobile elements have impacted the evolution of eukaryotes. In addition to being the main cause of difference in haploid genome size, TEs have affected the overall organization of genomes by accumulating preferentially in some genomic regions, by causing structural rearrangements or by modifying the recombination rate. Although the vast majority of insertions is neutral or deleterious, TEs have been an important source of evolutionary novelties and have played a determinant role in the evolution of fundamental biological processes. TEs have been recruited in the regulation of host genes and are implicated in the evolution of regulatory networks. They have also served as a source of protein-coding sequences or even entire genes. The impact of TEs on eukaryotic evolution is only now being fully appreciated and the role they may play in a number of biological processes, such as speciation and adaptation, remains to be deciphered.
Topics: Animals; DNA Transposable Elements; Evolution, Molecular; Humans; Plants
PubMed: 34203645
DOI: 10.3390/genes12060918 -
Journal of Hazardous Materials Jun 2024Aquatic microplastics (MPs) act as reservoirs for microbial communities, fostering the formation of a mobile resistome encompassing diverse antibiotic (ARGs) and...
Aquatic microplastics (MPs) act as reservoirs for microbial communities, fostering the formation of a mobile resistome encompassing diverse antibiotic (ARGs) and biocide/metal resistance genes (BMRGs), and mobile genetic elements (MGEs). This collective genetic repertoire, referred to as the "plastiome," can potentially perpetuate environmental antimicrobial resistance (AMR). Our study examining two Japanese rivers near Tokyo revealed that waterborne MPs are primarily composed of polyethylene and polypropylene fibers and sheets of diverse origin. Clinically important genera like Exiguobacterium and Eubacterium were notably enriched on MPs. Metagenomic analysis uncovered a 3.46-fold higher enrichment of ARGs on MPs than those in water, with multidrug resistance genes (MDRGs) and BMRGs prevailing, particularly within MPs. Specific ARG and BMRG subtypes linked to resistance to vancomycin, beta-lactams, biocides, arsenic, and mercury showed selective enrichment on MPs. Network analysis revealed intense associations between host genera with ARGs, BMRGs, and MGEs on MPs, emphasizing their role in coselection. In contrast, river water exhibited weaker associations. This study underscores the complex interactions shaping the mobile plastiome in aquatic environments and emphasizes the global imperative for research to comprehend and effectively control AMR within the One Health framework.
Topics: Rivers; Microplastics; Anti-Bacterial Agents; Water Pollutants, Chemical; Bacteria; Water Microbiology; Interspersed Repetitive Sequences; Genes, Bacterial; Drug Resistance, Bacterial; Disinfectants; Microbiota; Drug Resistance, Microbial
PubMed: 38678707
DOI: 10.1016/j.jhazmat.2024.134353 -
Anaerobe Jun 2023Five human clinical multidrug-resistant (MDR) Bacteroides fragilis isolates, including resistance to meropenem and metronidazole, were recovered at different hospitals...
OBJECTIVES
Five human clinical multidrug-resistant (MDR) Bacteroides fragilis isolates, including resistance to meropenem and metronidazole, were recovered at different hospitals in the Netherlands between 2014 and 2020 and sent to the anaerobic reference laboratory for full characterization.
METHODS
Isolates were recovered from a variety of clinical specimens from patients with unrelated backgrounds. Long- and short-read sequencing was performed, followed by a hybrid assembly to study the presence of mobile genetic elements (MGEs) and antimicrobial resistance genes (ARGs).
RESULTS
A cfxA gene was present on a transposon (Tn) similar to Tn4555 in two isolates. In two isolates a novel Tn was present with the cfxA gene. Four isolates harbored a nimE gene, located on a pBFS01_2 plasmid. One isolate contained a novel plasmid carrying a nimA gene with IS1168. The tetQ gene was present on novel conjugative transposons (CTns) belonging to the CTnDOT family. Two isolates harbored a novel plasmid with tetQ. Other ARGs in these isolates, but not on an MGE, were: cfiA, ermF, mef(EN2), and sul2. ARGs harboured differed between isolates and corresponded with the observed phenotypic resistance.
CONCLUSIONS
Novel CTns, Tns, and plasmids were encountered in the five MDR B. fragilis isolates, complementing our knowledge on MDR and horizontal gene transfer in anaerobic bacteria.
Topics: Humans; Bacteroides fragilis; Genes, Bacterial; Netherlands; Bacterial Infections; Interspersed Repetitive Sequences; Anti-Bacterial Agents; Bacteroides Infections; Microbial Sensitivity Tests
PubMed: 37001724
DOI: 10.1016/j.anaerobe.2023.102722 -
Genetics Apr 2021Compared to their eukaryotic counterparts, bacterial genomes are small and contain extremely tightly packed genes. Repetitive sequences are rare but not completely...
Compared to their eukaryotic counterparts, bacterial genomes are small and contain extremely tightly packed genes. Repetitive sequences are rare but not completely absent. One of the most common repeat families is REPINs. REPINs can replicate in the host genome and form populations that persist for millions of years. Here, we model the interactions of these intragenomic sequence populations with the bacterial host. We first confirm well-established results, in the presence and absence of horizontal gene transfer (hgt) sequence populations either expand until they drive the host to extinction or the sequence population gets purged from the genome. We then show that a sequence population can be stably maintained, when each individual sequence provides a benefit that decreases with increasing sequence population size. Maintaining a sequence population of stable size also requires the replication of the sequence population to be costly to the host, otherwise the sequence population size will increase indefinitely. Surprisingly, in regimes with high hgt rates, the benefit conferred by the sequence population does not have to exceed the damage it causes to its host. Our analyses provide a plausible scenario for the persistence of sequence populations in bacterial genomes. We also hypothesize a limited biologically relevant parameter range for the provided benefit, which can be tested in future experiments.
Topics: DNA Replication; DNA Transposable Elements; Escherichia coli; Evolution, Molecular; Gene Transfer, Horizontal; Genome, Bacterial; Models, Genetic
PubMed: 33724360
DOI: 10.1093/genetics/iyab027