scholarly journals A Novel and Direct Metamobilome Approach improves the Detection of Larger-sized Circular Elements across Kingdoms

2019 ◽  
Author(s):  
Katrine Skov Alanin ◽  
Tue Sparholt Jørgensen ◽  
Patrick Browne ◽  
Bent Petersen ◽  
Leise Riber ◽  
...  
Keyword(s):  
Multiple Displacement Amplification ◽  
Bacterial Species ◽  
Human Health Risk ◽  
Prokaryotic Genome ◽  
Mobile Genetic Elements ◽  
Wastewater Sample ◽  
Mobile Dna ◽  
Complex Samples ◽  
Genetic Elements ◽  
Dna Elements

AbstractMobile genetic elements (MGEs) are instrumental in natural prokaryotic genome editing, permitting genome plasticity and allowing microbes to accumulate immense genetic diversity. MGEs include DNA elements such as plasmids, transposons and Insertion Sequences (IS-elements), as well as bacteriophages (phages), and they serve as a vast communal gene pool. These mobile DNA elements represent a human health risk as they can add new traits, such as antibiotic resistance or virulence, to a bacterial strain. Sequencing libraries targeting circular MGEs, referred to as mobilomes, allows the expansion of our current understanding of the mechanisms behind the mobility, prevalence and content of these elements. However, metamobilomes from bacterial communities are not studied to the same extent as metagenomics, partly because of methodological biases arising from multiple displacement amplification (MDA), often used in previous metamobilome publications. In this study, we show that MDA is detrimental to the detection of larger-sized plasmids if small plasmids are present by comparing the abundances of reads mapping to plasmids in a wastewater sample spiked with a mock community of selected plasmids with and without MDA. Furthermore, we show that it is possible to produce samples consisting almost exclusively of circular MGEs and obtain a catalog of larger, complete, circular MGEs from complex samples without the use of MDA.ImportanceMobile genetic elements (MGEs) can transport genetic information between genomes in different bacterial species, adding new traits, potentially generating dangerous multidrug-resistant pathogens. In fact, plasmids and circular MGEs can encode bacterial genetic specializations such as virulence, resistance to metals, antimicrobial compounds, and bacteriophages, as well as the degradation of xenobiotics. For this reason, circular MGEs are crucial to investigate, but they are often missed in metagenomics and ecological studies. In this study, we present, for the first time, an improved method, which reduces the bias towards small MGEs and we demonstrate that this method can unveil larger, complete circular MGEs from complex samples without the use of multiple displacement amplification. This method may result in the detection of larger-sized plasmids that have hitherto remained unnoticed and therefore has the potential to reveal novel accessory genes, acting as possible targets in the development of preventive strategies directed at pathogens.

scholarly journals Transmission of ESBL-producing Enterobacteriaceae and their mobile genetic elements—identification of sources by whole genome sequencing: study protocol for an observational study in Switzerland

BMJ Open ◽  
2018 ◽  
Vol 8 (2) ◽  
pp. e021823 ◽  
Author(s):  
Tanja Stadler ◽  
Dominik Meinel ◽  
Lisandra Aguilar-Bultet ◽  
Jana S Huisman ◽  
Ruth Schindler ◽  
...  
Keyword(s):  
Observational Study ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Bacterial Species ◽  
Mobile Genetic Elements ◽  
University Hospital ◽  
Whole Genome ◽  
Hospital Acquired Infections ◽  
Genetic Elements ◽  
Hospital Acquired

IntroductionExtended-spectrum beta-lactamases (ESBL)-producing Enterobacteriaceae were first described in relation with hospital-acquired infections. In the 2000s, the epidemiology of ESBL-producing organisms changed as especially ESBL-producingEscherichia coliwas increasingly described as an important cause of community-acquired infections, supporting the hypothesis that in more recent years ESBL-producing Enterobacteriaceae have probably been imported into hospitals rather than vice versa. Transmission of ESBL-producing Enterobacteriaceae is complicated by ESBL genes being encoded on self-transmissible plasmids, which can be exchanged among the same and different bacterial species. The aim of this research project is to quantify hospital-wide transmission of ESBL-producing Enterobacteriaceae on both the level of bacterial species and the mobile genetic elements and to determine if hospital-acquired infections caused by ESBL producers are related to strains and mobile genetic elements predominantly circulating in the community or in the healthcare setting. This distinction is critical in prevention since the former emphasises the urgent need to establish or reinforce antibiotic stewardship programmes, and the latter would call for more rigorous infection control.Methods and analysisThis protocol presents an observational study that will be performed at the University Hospital Basel and in the city of Basel, Switzerland. ESBL-producing Enterobacteriaceae will be collected from any specimens obtained by routine clinical practice or by active screening in both inpatient and outpatient settings, as well as from wastewater samples and foodstuffs, both collected monthly over a 12-month period for analyses by whole genome sequencing. Bacterial chromosomal, plasmid and ESBL-gene sequences will be compared within the cohort to determine genetic relatedness and migration between humans and their environment.Ethics and disseminationThis study has been approved by the local ethics committee (Ethikkommission Nordwest-und Zentralschweiz) as a quality control project (Project-ID 2017–00100). The results of this study will be published in peer-reviewed medical journals, communicated to participants, the general public and all relevant stakeholders.

scholarly journals Mobile genetic element insertions drive antibiotic resistance across pathogens

2019 ◽  
Author(s):  
Matthew G. Durrant ◽  
Michelle M. Li ◽  
Ben Siranosian ◽  
Ami S. Bhatt
Keyword(s):  
Antibiotic Resistance ◽  
De Novo ◽  
Bacterial Species ◽  
Mobile Element ◽  
Mobile Genetic Elements ◽  
Mobile Elements ◽  
Genetic Elements ◽  
Element Insertion ◽  
A Genome ◽  
Mobile Element Insertion

AbstractMobile genetic elements contribute to bacterial adaptation and evolution; however, detecting these elements in a high-throughput and unbiased manner remains challenging. Here, we demonstrate ade novoapproach to identify mobile elements from short-read sequencing data. The method identifies the precise site of mobile element insertion and infers the identity of the inserted sequence. This is an improvement over previous methods that either rely on curated databases of known mobile elements or rely on ‘split-read’ alignments that assume the inserted element exists within the reference genome. We apply our approach to 12,419 sequenced isolates of nine prevalent bacterial pathogens, and we identify hundreds of known and novel mobile genetic elements, including many candidate insertion sequences. We find that the mobile element repertoire and insertion rate vary considerably across species, and that many of the identified mobile elements are biased toward certain target sequences, several of them being highly specific. Mobile element insertion hotspots often cluster near genes involved in mechanisms of antibiotic resistance, and such insertions are associated with antibiotic resistance in laboratory experiments and clinical isolates. Finally, we demonstrate that mutagenesis caused by these mobile elements contributes to antibiotic resistance in a genome-wide association study of mobile element insertions in pathogenicEscherichia coli. In summary, by applying ade novoapproach to precisely identify mobile genetic elements and their insertion sites, we thoroughly characterize the mobile element repertoire and insertion spectrum of nine pathogenic bacterial species and find that mobile element insertions play a significant role in the evolution of clinically relevant phenotypes, such as antibiotic resistance.

scholarly journals Chromosomal Conjugative and Mobilizable Elements in Streptococcus suis: Major Actors in the Spreading of Antimicrobial Resistance and Bacteriocin Synthesis Genes

Pathogens ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 22 ◽  
Author(s):  
Virginie Libante ◽  
Yves Nombre ◽  
Charles Coluzzi ◽  
Johan Staub ◽  
Gérard Guédon ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
In Silico ◽  
Bacterial Species ◽  
Streptococcus Thermophilus ◽  
Streptococcus Suis ◽  
Mobile Genetic Elements ◽  
Zoonotic Pathogen ◽  
Genetic Elements ◽  
Integrative Conjugative Elements

Streptococcus suis is a zoonotic pathogen suspected to be a reservoir of antimicrobial resistance (AMR) genes. The genomes of 214 strains of 27 serotypes were screened for AMR genes and chromosomal Mobile Genetic Elements (MGEs), in particular Integrative Conjugative Elements (ICEs) and Integrative Mobilizable Elements (IMEs). The functionality of two ICEs that host IMEs carrying AMR genes was investigated by excision tests and conjugation experiments. In silico search revealed 416 ICE-related and 457 IME-related elements. These MGEs exhibit an impressive diversity and plasticity with tandem accretions, integration of ICEs or IMEs inside ICEs and recombination between the elements. All of the detected 393 AMR genes are carried by MGEs. As previously described, ICEs are major vehicles of AMR genes in S. suis. Tn5252-related ICEs also appear to carry bacteriocin clusters. Furthermore, whereas the association of IME-AMR genes has never been described in S. suis, we found that most AMR genes are actually carried by IMEs. The autonomous transfer of an ICE to another bacterial species (Streptococcus thermophilus)—leading to the cis-mobilization of an IME carrying tet(O)—was obtained. These results show that besides ICEs, IMEs likely play a major role in the dissemination of AMR genes in S. suis.

scholarly journals Conservation of Restriction Sites in Isolates ofStreptococcus pneumoniae with Diverse Restriction Fragment Patterns

1998 ◽  
Vol 36 (6) ◽  
pp. 1805-1807 ◽  
Author(s):  
Lucinda M. C. Hall ◽  
Brigid Duke
Keyword(s):  
Restriction Fragment ◽  
Fragment Length Polymorphism ◽  
Bacterial Species ◽  
Point Mutations ◽  
Pulsed Field Gel Electrophoresis ◽  
Mobile Dna ◽  
Epidemiological Typing ◽  
Genetic Changes ◽  
Restriction Sites ◽  
Dna Elements

Separation of large restriction fragments by pulsed-field gel electrophoresis is a commonly used method for epidemiological typing ofStreptococcus pneumoniae and many other bacterial species. Information on the genetic changes underlying the restriction fragment polymorphisms that allow discrimination between isolates is scarce. In this study fragments adjacent to ApaI sites in a clinical isolate of S. pneumoniae were cloned and used to probeHindIII and HindIII-plus-ApaI genomic DNA digests from other isolates with very differentApaI fragment patterns. If for a given isolate theHindIII fragment detected by the probe was reduced in size on digestion with ApaI, it was deduced that theApaI site was conserved in that isolate. The results demonstrate that of six ApaI sites in PN93/908 examined, five were retained in 11 genetically different isolates and one was retained in 2 isolates but lost in 9 others. It was concluded that point mutations at restriction sites are unlikely to account for the restriction fragment length polymorphism observed and that much of the polymorphism may be due to DNA rearrangements, possibly resulting from the insertion or deletion of mobile DNA elements.

scholarly journals Genetic diversity, mobilisation and spread of the yersiniabactin-encoding mobile element ICEKp inKlebsiella pneumoniaepopulations

2017 ◽  
Author(s):  
Margaret M. C. Lam ◽  
Ryan R. Wick ◽  
Kelly L. Wyres ◽  
Claire L. Gorrie ◽  
Louise M. Judd ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Population Genomics ◽  
Bacterial Species ◽  
Critical Role ◽  
Mobile Element ◽  
Mobile Genetic Elements ◽  
Virulence Determinants ◽  
Genome Sequences ◽  
Genetic Elements ◽  
Resistant Strains

ABSTRACTMobile genetic elements (MGEs) that frequently transfer within and between bacterial species play a critical role in bacterial evolution, and often carry key accessory genes that associate with a bacteria’s ability to cause disease. MGEs carrying antimicrobial resistance (AMR) and/or virulence determinants are common in opportunistic pathogenKlebsiella pneumoniae, which are a leading cause of highly drug-resistant infections in hospitals. Well-characterised virulence determinants inK. pneumoniaeinclude the polyketide synthesis lociybtandclb(also known aspks), encoding the iron-scavenging siderophore yersiniabactin and genotoxin colibactin respectively. These loci are located within an MGE called ICEKp, which is the most common virulence-associated MGE ofK. pneumoniae,providing a mechanism for these virulence factors to spread within the population.Here we apply population genomics to investigate the prevalence, evolution and mobility ofybtandclbinK. pneumoniaepopulations through comparative analysis of 2,498 whole genome sequences. Theybtlocus was detected in 40% ofK. pneumoniaegenomes, particularly amongst those associated with invasive infections. We identified 17 distinctybtlineages and 3clblineages, each associated with one of 14 different structural variants of ICEKp. Comparison with the wider Enterobacteriaceae population showed occasional ICEKpacquisition by other members. Theclblocus was present in 14% of allK. pneumoniaeand 38.4% ofybt+ genomes. Hundreds of independent ICEKpintegration events were detected affecting hundreds of phylogenetically distinctK. pneumoniaelineages, including ≥19 in the globally-disseminated carbapenem-resistant clone CG258. A novel plasmid-encoded form ofybtwas also identified, representing a new mechanism forybtdispersal inK. pneumoniaepopulations. These data show that MGEs carryingybtandclbcirculate freely in theK. pneumoniaepopulation, including among multidrug-resistant strains, and should be considered a target for genomic surveillance along with AMR determinants.AUTHOR SUMMARYKlebsiella pneumoniaeinfections are becoming increasingly difficult to treat with antibiotics. SomeK. pneumoniaestrains also carry extra genes that allow them to synthesise yersiniabactin, an iron-scavenging molecule, which enhances their ability to cause disease. These genes are located on a genetic element that can easily transfer between strains. Here, we screened 2498K. pneumoniaegenome sequences and found substantial diversity in the yersiniabactin genes and the associated genetic elements, including a novel mechanism of transfer, and detected hundreds of distinct yersiniabactin acquisition events betweenK. pneumoniaestrains. We show that these yersiniabactin mobile genetic elements are specifically adapted to theK. pneumoniaepopulation but also occasionally acquired by other bacterial members belonging to the Enterobacteriaceae family such asE. coli.These insights into the movement and genetics of yersiniabactin genes allow tracking of the evolution and spread of yersiniabactin in globalK. pneumoniaepopulations and monitoring for acquisition of yersiniabactin in antibiotic-resistant strains.

The use of aminoglycosides in animals within the EU: development of resistance in animals and possible impact on human and animal health: a review

2019 ◽  
Vol 74 (9) ◽  
pp. 2480-2496 ◽  
Author(s):  
Engeline van Duijkeren ◽  
Christine Schwarz ◽  
Damien Bouchard ◽  
Boudewijn Catry ◽  
Constança Pomba ◽  
...  
Keyword(s):  
Veterinary Medicine ◽  
Resistance Genes ◽  
Bacterial Species ◽  
Animal Health ◽  
Acquired Resistance ◽  
Companion Animals ◽  
Mobile Genetic Elements ◽  
Salmonella Spp ◽  
Genetic Elements ◽  
Animal Pathogens

AbstractAminoglycosides (AGs) are important antibacterial agents for the treatment of various infections in humans and animals. Following extensive use of AGs in humans, food-producing animals and companion animals, acquired resistance among human and animal pathogens and commensal bacteria has emerged. Acquired resistance occurs through several mechanisms, but enzymatic inactivation of AGs is the most common one. Resistance genes are often located on mobile genetic elements, facilitating their spread between different bacterial species and between animals and humans. AG resistance has been found in many different bacterial species, including those with zoonotic potential such as Salmonella spp., Campylobacter spp. and livestock-associated MRSA. The highest risk is anticipated from transfer of resistant enterococci or coliforms (Escherichia coli) since infections with these pathogens in humans would potentially be treated with AGs. There is evidence that the use of AGs in human and veterinary medicine is associated with the increased prevalence of resistance. The same resistance genes have been found in isolates from humans and animals. Evaluation of risk factors indicates that the probability of transmission of AG resistance from animals to humans through transfer of zoonotic or commensal foodborne bacteria and/or their mobile genetic elements can be regarded as high, although there are no quantitative data on the actual contribution of animals to AG resistance in human pathogens. Responsible use of AGs is of great importance in order to safeguard their clinical efficacy for human and veterinary medicine.

scholarly journals Omics-based comparative analysis of putative mobile genetic elements in Lactococcus lactis

2019 ◽  
Vol 366 (Supplement_1) ◽  
pp. i105-i113
Author(s):  
Joakim Mark Andersen ◽  
Christine Møller Pedersen ◽  
Claus Heiner Bang-Berthelsen
Keyword(s):  
Genetic Variation ◽  
Lactococcus Lactis ◽  
Mobile Genetic Elements ◽  
Chromosome Size ◽  
Chromosomal Variation ◽  
Mobile Dna ◽  
Important Species ◽  
Genetic Elements ◽  
Gene Functions ◽  
Transcriptomics Data

ABSTRACT Lactococcus lactis is globally used in food fermentation. Genomics is useful to investigate speciation and differential occurrence of (un)desired gene functions, often related to mobile DNA. This study investigates L. lactis for putative chromosomal mobile genetic elements through comparative genomics, and analyses how they contribute to chromosomal variation at strain level. Our work identified 95 loci that may range over 10% of the chromosome size when including prophages, and the loci display a marked differential occurrence in the analysed strains. Analysis of differential transcriptomics data revealed how mobile genetic elements may impact the host physiology in response to conditional changes. This insight in the genetic variation of mobile genetic elements in L. lactis holds potential to further identify important functions related to food and biotechnology applications within this important species.

scholarly journals In SilicoIdentification of Three Types of Integrative and Conjugative Elements (ICEs) inElizabethkingia anophelisStrains Isolated from Around the World

2018 ◽  
Author(s):  
Jiannong Xu ◽  
Dong Pei ◽  
Ainsley Nicholson ◽  
Yuhao Lan ◽  
Qing Xia
Keyword(s):  
Bacterial Species ◽  
Temporal Patterns ◽  
Mobile Genetic Elements ◽  
Ecological Niches ◽  
Trna Genes ◽  
Type I ◽  
Genetic Elements ◽  
Integrative And Conjugative Elements ◽  
The World ◽  
Integration Sites

ABSTRACTElizabethkingia anophelisis an emerging global multidrug-resistant opportunistic pathogen. We assessed the diversity among 13 complete genomes and 23 draft genomes ofE. anophelisderived from various environmental settings and human infections from different geographic regions around the world over past decades from 1950s. Thirty-one of these 36 strains harbor integrative and conjugative elements (ICEs). A total of 52 ICEs were identified, and categorized into three ICE types based on the architecture of signature genes in the conjugation module. The type II and III ICEs were found to integrate into regions adjacent to tRNA genes, while type I ICEs used a variety of integration sites, inserting into intergenic regions or even directly into a gene, sometimes disrupting gene function. Integrases such as tyrosine recombinases, serine recombinases and DDE transposases were found in most ICEs. The ICEs carry various cargo genes including transcription regulators and those involved in antibiotic resistance. The CRISPR-Cas system was found in nine strains, including four strains in which CRISPR-Cas machinery and ICEs co-exist. ICE distribution in the strains showed no geographic or temporal patterns. The ICEs inE. anophelisdiffer in gene structure and sequence from CTnDOT, a well-studied ICE prevalent inBacteroidesspp. This is the first set of ICEs identified in the family Flavobacteriaceae. As a prevalent type of mobile genetic elements in various strains ofE. anophelisaround the world, the categorization of ICEs will facilitate further investigations such as virulence, genome epidemiology and adaptation genomics ofE. anophelis.ImportanceElizabethkingia anophelisis an opportunistic human pathogen, and the genetic diversity between strains from around the world becomes apparent as more genomes are sequenced. The Integrative Conjugative Element (ICE), found in many bacterial species, contains genes for transfer via conjugation and integration into the chromosome, along with various cargo genes. ICEs are identified in 31 of 36 strains and categorized into three types based on architecture of modular genes, integrases, and integration sites. ICE distribution in different strains displays no spatial and temporal patterns. Several ICE-containing strains also possessed CRISPR-Cas units, considered to be the bacterial adaptive immune system providing protection against phage and predatory mobile genetic elements. This co-existence suggests that ICEs are beneficial or at least not harmful to the bacterial cells they inhabit. ICEs as a component of the mobile genetic repertoire enable recipients to resist antibiotics, survive disinfecting agents, and adapt to various ecological niches.

scholarly journals A novel anti-dipteran Bacillus thuringiensis strain: Unusual Cry toxin genes in a highly dynamic plasmid environment

2020 ◽  
Author(s):  
Nancy Fayad ◽  
Zakaria Kambris ◽  
Laure El Chamy ◽  
Jacques Mahillon ◽  
Mireille Kallassy Awad
Keyword(s):  
Bacillus Thuringiensis ◽  
Mobile Genetic Elements ◽  
Global Market ◽  
Mobile Dna ◽  
Parasporal Crystal ◽  
Genetic Elements ◽  
Toxin Genes ◽  
Cry Toxin ◽  
Large Plasmids ◽  
Thuringiensis Strain

Bacillus thuringiensis emerged as a major bioinsecticide on the global market. It offers a valuable alternative to chemical products classically utilized to control pest insects. Despite the efficiency of several strains and products available on the market, the scientific community is always on the lookout for novel toxins that can replace or supplement the existing products. In this study, H3, a novel B. thuringiensis strain showing mosquitocidal activity, was isolated from Lebanese soil and characterized at an in vivo, genomic and proteomic levels. H3 parasporal crystal is toxic on its own but displays an unusual killing profile with a higher LC50 than the reference B. thuringiensis serovar israelensis crystal proteins. In addition, H3 has a different toxicity order: it is more toxic to Aedes albopictus and Anopheles gambiae than to Culex pipiens. Whole genome sequencing and crystal analysis revealed that H3 can produce eleven novel Cry proteins, eight of which are assembled in genes with an orf1-gap-orf2 organization, where orf2 is a potential Cry4-type crystallization domain. Moreover, pH3-180, the toxin-carrying plasmid, holds a wide repertoire of mobile genetic elements that amount to ca. 22% of its size., including novel insertion sequences and class II transposable elements Two other large plasmids present in H3 carry genetic determinants for the production of many interesting molecules - such as chitinase, cellulase and bacitracin - that may add up to H3 bioactive properties. This study therefore reports a novel mosquitocidal Bacillus thuringiensis strain with unusual Cry toxin genes in a rich mobile DNA environment. IMPORTANCE Bacillus thuringiensis, a soil entomopathogenic bacteria, is at the base of many sustainable eco-friendly bio-insecticides. Hence stems the need to continually characterize insecticidal toxins. H3 is an anti-dipteran B. thuringiensis strain, isolated from Lebanese soil, whose parasporal crystal contains eleven novel Cry toxins and no Cyt toxins. In addition to its individual activity, H3 showed potential as a co-formulant with classic commercialized B. thuringiensis products, to delay the emergence of resistance and to shorten the time required for killing. On a genomic level, H3 holds three large plasmids, one of which carries the toxin-coding genes, with four occurrences of the distinct orf1-gap-orf2 organization. Moreover, this plasmid is extremely rich in mobile genetic elements, unlike its two co-residents. This highlights the important underlying evolutionary traits between toxin-carrying plasmids and the adaptation of a B. thuringiensis strain to its environment and insect host spectrum.

scholarly journals Identification and analysis of mobile genetic elements in Gibbon genome

2017 ◽  
Author(s):  
Kamal Rawal ◽  
Jaisri Jagannadham ◽  
Chahat Kubba ◽  
Tanya Sharma
Keyword(s):  
Mobile Genetic Elements ◽  
Wide Distribution ◽  
Alu Elements ◽  
Genetic Elements ◽  
Genome Wide ◽  
Nomascus Leucogenys ◽  
Dna Elements ◽  
Insertion Mechanism ◽  
Insertion Sites

AbstractRecent sequencing of genome of northern white-cheeked gibbon (Nomascus leucogenys) has provided important insight into fast evolution of gibbons and signatures relevant to gibbon biology. It was revealed that mobile genetic elements (MGE) seems to play major role in gibbon evolution. Here we report that most of the gibbon genome is occupied by the MGEs such as ALUs, MIRs, LINE1, LINE 2, LINE 3, ERVL, ERV-class1, ERV-class II and other DNA elements which include hAT Charlie and TcMar tigger. We provide detailed description and genome wide distribution of all the MGEs present in gibbon genome. Previously, it was reported that gibbon-specific retrotransposon (LAVA) tend to insert into chromosome segregation genes and alter transcription by providing a premature termination site, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage. We show that insertion sites of LAVA elements present atypical signals/patterns which are different from typical signals present at insertion sites of Alu elements. This suggests possibility of distinct insertion mechanism used by LAVA elements for their insertions. We also find similarity in signals of LAVA elements insertion sites with atypical signals present at Alus /L1s insertion sites disrupting the genes leading to diseases such as cancer and Duchenne muscular dystrophy. This suggest role of LAVA in premature transcription termination.

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