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Cellular and Molecular Life Sciences :... Mar 2024Over half of human genomic DNA is composed of repetitive sequences generated throughout evolution by prolific mobile genetic parasites called transposable elements... (Review)
Review
Over half of human genomic DNA is composed of repetitive sequences generated throughout evolution by prolific mobile genetic parasites called transposable elements (TEs). Long disregarded as "junk" or "selfish" DNA, TEs are increasingly recognized as formative elements in genome evolution, wired intimately into the structure and function of the human genome. Advances in sequencing technologies and computational methods have ushered in an era of unprecedented insight into how TE activity impacts human biology in health and disease. Here we discuss the current views on how TEs have shaped the regulatory landscape of the human genome, how TE activity is implicated in human cancers, and how recent findings motivate novel strategies to leverage TE activity for improved cancer therapy. Given the crucial role of methodological advances in TE biology, we pair our conceptual discussions with an in-depth review of the inherent technical challenges in studying repeats, specifically related to structural variation, expression analyses, and chromatin regulation. Lastly, we provide a catalog of existing and emerging assays and bioinformatic software that altogether are enabling the most sophisticated and comprehensive investigations yet into the regulation and function of interspersed repeats in cancer genomes.
Topics: Humans; DNA Transposable Elements; Computational Biology; Genome, Human; Neoplasms; Evolution, Molecular
PubMed: 38556602
DOI: 10.1007/s00018-024-05195-2 -
Genome Biology Feb 2024Centromeres are essential for faithful chromosome segregation during mitosis and meiosis. However, the organization of satellite DNA and chromatin at mouse centromeres...
BACKGROUND
Centromeres are essential for faithful chromosome segregation during mitosis and meiosis. However, the organization of satellite DNA and chromatin at mouse centromeres and pericentromeres is poorly understood due to the challenges of assembling repetitive genomic regions.
RESULTS
Using recently available PacBio long-read sequencing data from the C57BL/6 strain, we find that contrary to the previous reports of their homogeneous nature, both centromeric minor satellites and pericentromeric major satellites exhibit a high degree of variation in sequence and organization within and between arrays. While most arrays are continuous, a significant fraction is interspersed with non-satellite sequences, including transposable elements. Using chromatin immunoprecipitation sequencing (ChIP-seq), we find that the occupancy of CENP-A and H3K9me3 chromatin at centromeric and pericentric regions, respectively, is associated with increased sequence enrichment and homogeneity at these regions. The transposable elements at centromeric regions are not part of functional centromeres as they lack significant CENP-A enrichment. Furthermore, both CENP-A and H3K9me3 nucleosomes occupy minor and major satellites spanning centromeric-pericentric junctions and a low yet significant amount of CENP-A spreads locally at centromere junctions on both pericentric and telocentric sides. Finally, while H3K9me3 nucleosomes display a well-phased organization on major satellite arrays, CENP-A nucleosomes on minor satellite arrays are poorly phased. Interestingly, the homogeneous class of major satellites also phase CENP-A and H3K27me3 nucleosomes, indicating that the nucleosome phasing is an inherent property of homogeneous major satellites.
CONCLUSIONS
Our findings reveal that mouse centromeres and pericentromeres display a high diversity in satellite sequence, organization, and chromatin structure.
Topics: Mice; Animals; Nucleosomes; Centromere Protein A; DNA Transposable Elements; Mice, Inbred C57BL; Centromere; Chromatin; DNA, Satellite; Autoantigens
PubMed: 38378611
DOI: 10.1186/s13059-024-03184-z -
Microbial Genomics Jan 2022The rapid emergence of multidrug-resistant is being driven largely by the spread of specific clonal groups (CGs). Of these, CG147 includes 7-gene multilocus sequence...
The rapid emergence of multidrug-resistant is being driven largely by the spread of specific clonal groups (CGs). Of these, CG147 includes 7-gene multilocus sequence typing (MLST) sequence types (STs) ST147, ST273 and ST392. CG147 has caused nosocomial outbreaks across the world, but its global population dynamics remain unknown. Here, we report a pandrug-resistant ST147 clinical isolate from India (strain DJ) and define the evolution and global emergence of CG147. Antimicrobial-susceptibility testing following European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines and genome sequencing (Illumina and Oxford Nanopore Technologies, Unicycler assembly) were performed on strain DJ. Additionally, we collated 217 publicly available CG147 genomes [National Center for Biotechnology Information (NCBI), May 2019]. CG147 evolution was inferred within a temporal phylogenetic framework (beast) based on a recombination-free sequence alignment (Roary/Gubbins). Comparative genomic analyses focused on resistance and virulence genes and other genetic elements (BIGSdb, Kleborate, PlasmidFinder, phaster, ICEfinder and CRISPRCasFinder). Strain DJ had a pandrug-resistance phenotype. Its genome comprised the chromosome, seven plasmids and one linear phage-plasmid. Four carbapenemase genes were detected: and two copies of in the chromosome, and a second copy of on an 84 kb IncFII plasmid. CG147 genomes carried a mean of 13 acquired resistance genes or mutations; 63 % carried a carbapenemase gene and 83 % harboured . All CG147 genomes presented GyrA and ParC mutations and a common subtype I-E CRISPR-Cas system. ST392 and ST273 emerged in 2005 and 1995, respectively. ST147, the most represented phylogenetic branch, was itself divided into two main clades with distinct capsular loci: KL64 (74 %, DJ included, emerged in 1994 and disseminated worldwide, with carbapenemases varying among world regions) and KL10 (20 %, emerged in 2002, predominantly found in Asian countries, associated with carbapenemases NDM and OXA-48-like). Furthermore, subclades within ST147-KL64 differed at the yersiniabactin locus, OmpK35/K36 mutations, plasmid replicons and prophages. The absence of IncF plasmids in some subclades was associated with a possible activity of a CRISPR-Cas system. CG147 comprises pandrug-resistant or extensively resistant isolates, and carries multiple and diverse resistance genes and mobile genetic elements, including chromosomal . Its emergence is being driven by the spread of several phylogenetic clades marked by their own genomic features and specific temporo-spatial dynamics. These findings highlight the need for precision surveillance strategies to limit the spread of particularly concerning CG147 subsets.
Topics: Drug Resistance, Multiple, Bacterial; Evolution, Molecular; Genome, Bacterial; Genomics; India; Interspersed Repetitive Sequences; Klebsiella pneumoniae; Microbial Sensitivity Tests; Multigene Family; Phylogeny; Plasmids; Prophages; Virulence Factors; Whole Genome Sequencing
PubMed: 35019836
DOI: 10.1099/mgen.0.000737 -
Molecular Biology and Evolution Jun 2020Mobile genetic elements (MGEs) often encode integrases which catalyze the site-specific insertion of their genetic information into the host genome and the reverse...
Mobile genetic elements (MGEs) often encode integrases which catalyze the site-specific insertion of their genetic information into the host genome and the reverse reaction of excision. Hyperthermophilic archaea harbor integrases belonging to the SSV-family which carry the MGE recombination site within their open reading frame. Upon integration into the host genome, SSV integrases disrupt their own gene into two inactive pseudogenes and are termed suicidal for this reason. The evolutionary maintenance of suicidal integrases, concurring with the high prevalence and multiples recruitments of these recombinases by archaeal MGEs, is highly paradoxical. To elucidate this phenomenon, we analyzed the wide phylogenomic distribution of a prominent class of suicidal integrases which revealed a highly variable integration site specificity. Our results highlighted the remarkable hybrid nature of these enzymes encoded from the assembly of inactive pseudogenes of different origins. The characterization of the biological properties of one of these integrases, IntpT26-2 showed that this enzyme was active over a wide range of temperatures up to 99 °C and displayed a less-stringent site specificity requirement than comparable integrases. These observations concurred in explaining the pervasiveness of these suicidal integrases in the most hyperthermophilic organisms. The biochemical and phylogenomic data presented here revealed a target site switching system operating on highly thermostable integrases and suggested a new model for split gene reconstitution. By generating fast-evolving pseudogenes at high frequency, suicidal integrases constitute a powerful model to approach the molecular mechanisms involved in the generation of active genes variants by the recombination of proto-genes.
Topics: Evolution, Molecular; Hydrothermal Vents; Integrases; Interspersed Repetitive Sequences; Pseudogenes; Thermococcus
PubMed: 32068866
DOI: 10.1093/molbev/msaa041 -
Nature Dec 2023Indigenous Australians harbour rich and unique genomic diversity. However, Aboriginal and Torres Strait Islander ancestries are historically under-represented in...
Indigenous Australians harbour rich and unique genomic diversity. However, Aboriginal and Torres Strait Islander ancestries are historically under-represented in genomics research and almost completely missing from reference datasets. Addressing this representation gap is critical, both to advance our understanding of global human genomic diversity and as a prerequisite for ensuring equitable outcomes in genomic medicine. Here we apply population-scale whole-genome long-read sequencing to profile genomic structural variation across four remote Indigenous communities. We uncover an abundance of large insertion-deletion variants (20-49 bp; n = 136,797), structural variants (50 b-50 kb; n = 159,912) and regions of variable copy number (>50 kb; n = 156). The majority of variants are composed of tandem repeat or interspersed mobile element sequences (up to 90%) and have not been previously annotated (up to 62%). A large fraction of structural variants appear to be exclusive to Indigenous Australians (12% lower-bound estimate) and most of these are found in only a single community, underscoring the need for broad and deep sampling to achieve a comprehensive catalogue of genomic structural variation across the Australian continent. Finally, we explore short tandem repeats throughout the genome to characterize allelic diversity at 50 known disease loci, uncover hundreds of novel repeat expansion sites within protein-coding genes, and identify unique patterns of diversity and constraint among short tandem repeat sequences. Our study sheds new light on the dimensions and dynamics of genomic structural variation within and beyond Australia.
Topics: Humans; Alleles; Australia; Australian Aboriginal and Torres Strait Islander Peoples; Datasets as Topic; DNA Copy Number Variations; Genetic Loci; Genetics, Medical; Genomic Structural Variation; Genomics; INDEL Mutation; Interspersed Repetitive Sequences; Microsatellite Repeats; Genome, Human
PubMed: 38093003
DOI: 10.1038/s41586-023-06842-7 -
International Journal of Molecular... Jan 2021Transposable elements (TEs) represent a considerable fraction of eukaryotic genomes, thereby contributing to genome size, chromosomal rearrangements, and to the...
Transposable elements (TEs) represent a considerable fraction of eukaryotic genomes, thereby contributing to genome size, chromosomal rearrangements, and to the generation of new coding genes or regulatory elements. An increasing number of works have reported a link between the genomic abundance of TEs and the adaptation to specific environmental conditions. Diadromy represents a fascinating feature of fish, protagonists of migratory routes between marine and freshwater for reproduction. In this work, we investigated the genomes of 24 fish species, including 15 teleosts with a migratory behaviour. The expected higher relative abundance of DNA transposons in ray-finned fish compared with the other fish groups was not confirmed by the analysis of the dataset considered. The relative contribution of different TE types in migratory ray-finned species did not show clear differences between oceanodromous and potamodromous fish. On the contrary, a remarkable relationship between migratory behaviour and the quantitative difference reported for short interspersed nuclear (retro)elements (SINEs) emerged from the comparison between anadromous and catadromous species, independently from their phylogenetic position. This aspect is likely due to the substantial environmental changes faced by diadromous species during their migratory routes.
Topics: Animal Migration; Animals; DNA Transposable Elements; Evolution, Molecular; Fishes; Genome Size; Phylogeny; Short Interspersed Nucleotide Elements
PubMed: 33435333
DOI: 10.3390/ijms22020602 -
Current Opinion in Microbiology Jun 2023Horizontal gene transfer is central to bacterial adaptation and is facilitated by mobile genetic elements (MGEs). Increasingly, MGEs are being studied as agents with... (Review)
Review
Horizontal gene transfer is central to bacterial adaptation and is facilitated by mobile genetic elements (MGEs). Increasingly, MGEs are being studied as agents with their own interests and adaptations, and the interactions MGEs have with one another are recognised as having a powerful effect on the flow of traits between microbes. Collaborations and conflicts between MGEs are nuanced and can both promote and inhibit the acquisition of new genetic material, shaping the maintenance of newly acquired genes and the dissemination of important adaptive traits through microbiomes. We review recent studies that shed light on this dynamic and oftentimes interlaced interplay, highlighting the importance of genome defence systems in mediating MGE-MGE conflicts, and outlining the consequences for evolutionary change, that resonate from the molecular to microbiome and ecosystem levels.
Topics: Gene Transfer, Horizontal; Interspersed Repetitive Sequences; Bacteria; Biological Evolution; Microbiota
PubMed: 36863168
DOI: 10.1016/j.mib.2023.102282 -
ELife Mar 2021Horizontal gene transfer is a major force in bacterial evolution. Mobile genetic elements are responsible for much of horizontal gene transfer and also carry beneficial...
Horizontal gene transfer is a major force in bacterial evolution. Mobile genetic elements are responsible for much of horizontal gene transfer and also carry beneficial cargo genes. Uncovering strategies used by mobile genetic elements to benefit host cells is crucial for understanding their stability and spread in populations. We describe a benefit that ICE, an integrative and conjugative element of , provides to its host cells. Activation of ICE conferred a frequency-dependent selective advantage to host cells during two different developmental processes: biofilm formation and sporulation. These benefits were due to inhibition of biofilm-associated gene expression and delayed sporulation by ICE-containing cells, enabling them to exploit their neighbors and grow more prior to development. A single ICE gene, (formerly ), was both necessary and sufficient for inhibition of development. Manipulation of host developmental programs allows ICE to increase host fitness, thereby increasing propagation of the element.
Topics: Bacillus subtilis; DNA, Bacterial; Gene Transfer, Horizontal; Genetic Fitness; Host Microbial Interactions; Interspersed Repetitive Sequences
PubMed: 33655883
DOI: 10.7554/eLife.65924 -
BioEssays : News and Reviews in... Feb 2023Integrative mobile genetic elements (MGEs), such as transposons and insertion sequences, propagate within bacterial genomes, but persistence times in individual lineages...
Integrative mobile genetic elements (MGEs), such as transposons and insertion sequences, propagate within bacterial genomes, but persistence times in individual lineages are short. For long-term survival, MGEs must continuously invade new hosts by horizontal transfer. Theoretically, MGEs that persist for millions of years in single lineages, and are thus subject to vertical inheritance, should not exist. Here we draw attention to an exception - a class of MGE termed REPIN. REPINs are non-autonomous MGEs whose duplication depends on non-jumping RAYT transposases. Comparisons of REPINs and typical MGEs show that replication rates of REPINs are orders of magnitude lower, REPIN population size fluctuations correlate with changes in available genome space, REPIN conservation depends on RAYT function, and REPIN diversity accumulates within host lineages. These data lead to the hypothesis that REPINs form enduring, beneficial associations with eubacterial chromosomes. Given replicative nesting, our hypothesis predicts conflicts arising from the diverging effects of selection acting simultaneously on REPINs and host genomes. Evidence in support comes from patterns of REPIN abundance and diversity in two distantly related bacterial species. Together this bolsters the conclusion that REPINs are the genetic counterpart of mutualistic endosymbiotic bacteria.
Topics: Bacteria; DNA Transposable Elements; Genome, Bacterial; Interspersed Repetitive Sequences
PubMed: 36456469
DOI: 10.1002/bies.202200085 -
Frontiers in Immunology 2020More than 200 human disorders include various manifestations of autoimmunity. The molecular events that lead to these diseases are still incompletely understood and... (Review)
Review
More than 200 human disorders include various manifestations of autoimmunity. The molecular events that lead to these diseases are still incompletely understood and their causes remain largely unknown. Numerous potential triggers of autoimmunity have been proposed over the years, but very few of them have been conclusively confirmed or firmly refuted. Viruses have topped the lists of suspects for decades, and it seems that many viruses, including those of the Herpesviridae family, indeed can influence disease initiation and/or promote exacerbations by a number of mechanisms that include prolonged anti-viral immunity, immune subverting factors, and mechanisms, and perhaps "molecular mimicry". However, no specific virus has yet been established as being truly causative. Here, we discuss a different, but perhaps mechanistically related possibility, namely that retrotransposons or retroviruses that infected us in the past and left a lasting copy of themselves in our genome still can provoke an escalating immune response that leads to autoimmune disease. Many of these loci still encode for retroviral proteins that have retained some, or all, of their original functions. Importantly, these endogenous proviruses cannot be eliminated by the immune system the way it can eliminate exogenous viruses. Hence, if not properly controlled, they may drive a frustrated and escalating chronic, or episodic, immune response to the point of a frank autoimmune disorder. Here, we discuss the evidence and the proposed mechanisms, and assess the therapeutic options that emerge from the current understanding of this field.
Topics: Alu Elements; Animals; Autoimmune Diseases; Autoimmunity; Disease Susceptibility; Endogenous Retroviruses; Genome, Human; Humans; Immunity; Long Interspersed Nucleotide Elements; Proviruses; Retroelements; Rheumatic Diseases
PubMed: 33281822
DOI: 10.3389/fimmu.2020.593891