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PubMed1988

A semi-dominant allele, niv-525, acts in trans to inhibit expression of its wild-type homologue in Antirrhinum majus.

Niv-525 is a semi-dominant allele of the nivea locus, which encodes the enzyme chalcone synthase required for flower pigment biosynthesis in Antirrhinum majus. Plants heterozygous for niv-525 and wild-type (Niv+) allele, have flowers with a reduced intensity and novel spatial pattern of pigmentation compared with Niv+ homozygotes. In heterozygotes, niv-525 acts in trans to reduce the steady-state level of nivea transcript produced by its Niv+ homologue and hence the quantity of chalcone synthase protein. Niv-525 carries an inverted duplication of 207 bp in its promoter region which has arisen following excision of the transposable element Tam 3. This structure can be explained by a model of plant transposable element excision that involves resolution of two hairpin DNA molecules. Possible mechanisms for the trans-acting effect of niv-525 and its relationship to other examples of allelic interactions, such as transvection in Drosophila melanogaster, are discussed.

Acyltransferases↗
PubMed1997

P-element insertion alleles of essential genes on the third chromosome of Drosophila melanogaster: correlation of physical and cytogenetic maps in chromosomal region 86E-87F.

We have established a collection of 2460 lethal or semi-lethal mutant lines using a procedure thought to insert single P elements into vital genes on the third chromosome of Drosophila melanogaster. More than 1200 randomly selected lines were examined by in situ hybridization and 90% found to contain single insertions at sites that mark 89% of all lettered subdivisions of the Bridges' map. A set of chromosomal deficiencies that collectively uncover approximately 25% of the euchromatin of chromosome 3 reveal lethal mutations in 468 lines corresponding to 145 complementation groups. We undertook a detailed analysis of the cytogenetic interval 86E-87F and identified 87 P-element-induced mutations falling into 38 complementation groups, 16 of which correspond to previously known genes. Twenty-one of these 38 complementation groups have at least one allele that has a P-element insertion at a position consistent with the cytogenetics of the locus. We have rescued P elements and flanking chromosomal sequences from the 86E-87F region in 35 lines with either lethal or genetically silent P insertions, and used these as probes to identify cosmids and P1 clones from the Drosophila genome projects. This has tied together the physical and genetic maps and has linked 44 previously identified cosmid contigs into seven "super-contigs" that span the interval. STS data for sequences flanking one side of the P-element insertions in 49 lines has identified insertions in the alphagamma element at 87C, two known transposable elements, and the open reading frames of seven putative single copy genes. These correspond to five known genes in this interval, and two genes identified by the homology of their predicted products to known proteins from other organisms.

Alleles↗
PubMed1983

Evolution of hybrid dysgenesis determinants in Drosophila melanogaster.

Hybrid dysgenesis is manifested as a group of correlated aberrant genetic traits such as sterility, increased mutation rate, and male recombination. Previous work has shown that it appears when males of strains carrying either of two independent families of transposable elements called I and P factors are hybridized with females of susceptible strains called R and M, respectively. Here the results of an extensive survey for dysgenic potential in Drosophila melanogaster strains are reported. Striking temporal trends in the distribution of strains were observed with respect to the two transposable element systems; in particular, the frequency of R and M strains is positively correlated with laboratory age. In recent tests of strain samples, those collected from nature about 50 years ago were the earliest observed to possess I characteristics. The I type was increasingly frequent in samples from strains more recently originating in the wild. This type is apparently ubiquitous in present day natural populations. the P type was not found in strain samples collected before 1950, and collections made subsequently showed increasing frequencies of P-factor activity with decreasing laboratory age. Marked geographical patterns are documented in the contemporary worldwide distribution of variant strains within the P-M system. M strains are currently fairly common in natural populations from various parts of the world, except on the American continent where they are rare. The degree and distribution of quantitative variation within M and P strain categories is related to their time of origin in the wild. The implications of these results are discussed in relation to the hypothesis that hybrid dysgenesis determinants have evolved recently in natural populations and to an alternative hypothesis of laboratory evolution.

Animals↗
PubMed1988

Transposon-induced alterations in the promoter region affect transcription of the chalcone synthase gene of Antirrhinum majus.

Four solid-colour revertants were isolated from the highly variegated niv-53::Tam1 mutant, in which the transposable element Tam1 is integrated in the promoter region of the chalcone synthase (chs) gene. DNA sequence analysis revealed that in all four lines the Tam1 element was deleted together with flanking nucleotides of the chs promoter. In one case the TATA box of the chs gene was removed resulting in extremely low expression of the gene, and initiation of transcription occurring at a new position. The other three deletions defined a sequence motif (TAC-CAT) which is apparently required for maximal gene expression. Thus transposable elements seem to be useful for probing gene structure, in this case the signal structure in the promoter region, by virtue of imprecise excision.

Acyltransferases↗
PubMed2006

DNA hypomethylation and human diseases.

Changes in human DNA methylation patterns are an important feature of cancer development and progression and a potential role in other conditions such as atherosclerosis and autoimmune diseases (e.g., multiple sclerosis and lupus) is being recognised. The cancer genome is frequently characterised by hypermethylation of specific genes concurrently with an overall decrease in the level of 5 methyl cytosine. This hypomethylation of the genome largely affects the intergenic and intronic regions of the DNA, particularly repeat sequences and transposable elements, and is believed to result in chromosomal instability and increased mutation events. This review examines our understanding of the patterns of cancer-associated hypomethylation, and how recent advances in understanding of chromatin biology may help elucidate the mechanisms underlying repeat sequence demethylation. It also considers how global demethylation of repeat sequences including transposable elements and the site-specific hypomethylation of certain genes might contribute to the deleterious effects that ultimately result in the initiation and progression of cancer and other diseases. The use of hypomethylation of interspersed repeat sequences and genes as potential biomarkers in the early detection of tumors and their prognostic use in monitoring disease progression are also examined.

CpG Islands↗
PubMed1996

The y1 gene of maize codes for phytoene synthase.

The cloned y1 locus of maize was sequenced and found to encode phytoene synthase. Different "wild-type" alleles of the locus were found to differ by the insertion of transposable elements in their promoter and polyA addition regions, and by the length of a CCA tandem repeat series, without any obvious effect on function of the gene. A dominant Y1 ("wild-type") allele was observed to be expressed at highest levels in the seedling but also in the embryo and endosperm. The Mu3 transposable element insertion responsible for a pastel allele of y1, which gives lowered levels of carotenoids in the endosperm of kernels and seedlings grown at high temperatures, was located in the 5' end of the gene. Although the size of the transcript from this y1 mutation suggests that the Mu3 element provides the promoter for this allele, leaf tissue in this mutant line contained approximately normal amounts of y1 mRNA. A recessive allele of y1, which conditions normal levels of carotenoids in the embryo and seedling, but almost no carotenoids in the endosperm, was found to accumulate normal amounts of y1 mRNA in the seedling and embryo, while y1 transcripts were not detected in the endosperm.

Alkyl and Aryl Transferases↗
PubMed2005

The map-based sequence of the rice genome.

Rice, one of the world's most important food plants, has important syntenic relationships with the other cereal species and is a model plant for the grasses. Here we present a map-based, finished quality sequence that covers 95% of the 389 Mb genome, including virtually all of the euchromatin and two complete centromeres. A total of 37,544 non-transposable-element-related protein-coding genes were identified, of which 71% had a putative homologue in Arabidopsis. In a reciprocal analysis, 90% of the Arabidopsis proteins had a putative homologue in the predicted rice proteome. Twenty-nine per cent of the 37,544 predicted genes appear in clustered gene families. The number and classes of transposable elements found in the rice genome are consistent with the expansion of syntenic regions in the maize and sorghum genomes. We find evidence for widespread and recurrent gene transfer from the organelles to the nuclear chromosomes. The map-based sequence has proven useful for the identification of genes underlying agronomic traits. The additional single-nucleotide polymorphisms and simple sequence repeats identified in our study should accelerate improvements in rice production.

Cell Nucleus↗
PubMed2004

Development of hyperactive sleeping beauty transposon vectors by mutational analysis.

The Sleeping Beauty (SB) transposable element is a promising vector for transgenesis in vertebrates and is being developed as a novel, nonviral system for gene therapeutic purposes. A mutagenesis approach was undertaken to improve various aspects of the transposon, including safety and overall efficiency of gene transfer in human cells. Deletional analysis of transposon sequences within first-generation SB vectors showed that the inverted repeats of the element are necessary and sufficient to mediate high-efficiency transposition. We constructed a "sandwich" transposon, in which the DNA to be mobilized is flanked by two complete SB elements arranged in an inverted orientation. The sandwich element has superior ability to transpose >10-kb transgenes, thereby extending the cloning capacity of SB-based vectors. We derived hyperactive versions of the SB transposase by single-amino-acid substitutions. These mutations act synergistically and result in an almost fourfold enhancement of activity compared to the wild-type transposase. When combined with hyperactive transposons and transiently overexpressed HMGB1, a cellular cofactor of SB transposition, hyperactive transposases elevate transposition by almost an order of magnitude compared to the first-generation transposon system. The improved vector system should prove useful for efficient gene transfer in vertebrates.

Amino Acid Sequence↗
PubMed2001

DNA-binding activity and subunit interaction of the mariner transposase.

Mos1 is a member of the mariner/Tc1 family of transposable elements originally identified in Drosophila mauritiana. It has 28 bp terminal inverted repeats and like other elements of this type it transposes by a cut and paste mechanism, inserts at TA dinucleotides and codes for a transposase. This is the only protein required for transposition in vitro. We have investigated the DNA binding properties of Mos1 transposase and the role of transposase-transposase interactions in transposition. Purified transposase recognises the terminal inverted repeats of Mos1 due to a DNA-binding domain in the N-terminal 120 amino acids. This requires a putative helix-turn-helix motif between residues 88 and 108. Binding is preferentially to the right hand end, which differs at four positions from the repeat at the left end. Cleavage of Mos1 by transposase is also preferentially at the right hand end. Wild-type transposase monomers interact with each other in a yeast two-hybrid assay and we have used this to isolate mutations resulting in reduced interaction. These mutations lie along the length of the protein, indicating that transposase-transposase interactions are not due to a single interaction domain. One such mutation which retains both DNA-binding and catalytic activity has greatly reduced ability to excise Mos1 from plasmid DNA through coordinate cleavage of the two ends and transposition in vitro is lowered to a level 20-fold below that of the wild-type. This suggests that transposase-transposase interaction is required to form a synaptic complex necessary for coordinate cleavage at the ends of Mos1 during transposition. This mutant enzyme allows insertion at dinucleotides other than TA, including sequences with GC base pairs. This is the first example of a mariner/Tc1 transposase with altered target specificity.

Amino Acid Sequence↗
PubMed1991

Evidence for retrotransposition of the I factor, a LINE element of Drosophila melanogaster.

LINEs are transposable elements found in various eukaryotes such as plants, protists, insects, and mammals. Their transposition is usually difficult to study, particularly in humans, where some diseases have been shown to result from LINE insertion mutations. This is due to the fact that most copies of any particular family of elements are defective and that their transposition frequency is low. By contrast, the I factor of Drosophila melanogaster transposes at high frequency during I-R hybrid dysgenesis and is a good model for studying the LINE element superfamily. LINEs encode putative polypeptides showing similarities with viral reverse transcriptases but, unlike viral retrotransposons, they do not have terminal repeats and their ability to transpose by reverse transcription has previously only been inferred from structural analysis. Here we present direct evidence for LINE retrotransposition. Transposition of an I factor marked by an intron resulted in accurate removal of the intron.

Animals↗
PubMed2006

Transposons for gene therapy!

Gene therapy is a promising strategy for the treatment of several inherited and acquired human diseases. Several vector platforms exist for the delivery of therapeutic nucleic acids into cells. Vectors based on viruses are very efficient at introducing gene constructs into cells, but their use has been associated with genotoxic effects of vector integration or immunological complications due to repeated administration in vivo. Non-viral vectors are easier to engineer and manufacture, but their efficient delivery into cells is a major challenge, and the lack of their chromosomal integration precludes long-term therapeutic effects. Transposable elements are non-viral gene delivery vehicles found ubiquitously in nature. Transposon-based vectors have the capacity of stable genomic integration and long-lasting expression of transgene constructs in cells. Molecular reconstruction of Sleeping Beauty, an ancient transposon in fish, represents a cornerstone in applying transposition-mediated gene delivery in vertebrate species, including humans. This review summarizes the state-of-the-art in the application of transposable elements for therapeutic gene transfer, and identifies key targets for the development of transposon-based gene vectors with enhanced efficacy and safety for human applications.

Animals↗
PubMed1998

Evolution of bacterial resistance to antibiotics during the last three decades.

Bacterial resistance to antibiotics is often plasmid-mediated and the associated genes encoded by transposable elements. These elements play a central role in evolution by providing mechanisms for the generation of diversity and, in conjunction with DNA transfer systems, for the dissemination of resistances to other bacteria. At the University Hospital of Zaragoza, extensive efforts have been made to define both the dissemination and evolution of antibiotic resistance by studying the transferable R plasmids and transposable elements. Here we describe the research on bacterial resistance to antibiotics in which many authors listed in the references have participated. The aspects of bacterial resistance dealt with are: (i) transferable resistance mediated by R plasmids in Gram-negative bacteria, (ii) R plasmid-mediated resistance to apramycin and hygromycin in clinical strains, (iii) the transposon Tn1696 and the integron In4, (iv) expression of Escherichia coli resistance genes in Haemophilus influenzae, (v) aminoglycoside-modifying-enzymes in the genus Mycobacterium with no relation to resistance, and (vi) macrolide-resistance and new mechanisms developed by Gram-positive bacteria.

Anti-Bacterial Agents↗
PubMed1991

Chlorobenzoate catabolic transposon Tn5271 is a composite class I element with flanking class II insertion sequences.

The structure of a transposon specifying the biodegradation of chlorobenzoate contaminants is described. Tn5271 is a 17-kilobase (kb) transposon that resides in the plasmid or chromosome of Alcaligenes sp. strain BR60 and allows this organism to grow on 3- and 4-chlorobenzoate. The transposon is flanked by a directly repeated sequence of 3201 base pairs (bp), which in turn is flanked by 110-bp inverted repeats. The 3.2-kb repeated sequence, designated IS1071, exists in multiple copies in the genome of Alcaligenes sp. strain BR60 and is involved in recombination of the catabolic genes into the chromosome of this strain. Sequence analysis revealed that the inverted repeat of IS1071 and the derived amino acid sequence of the single open reading frame within IS1071 are related to the inverted repeats and transposase (TnpA) proteins of the class II (Tn3 family) transposable elements. The absence of a resolvase gene within IS1071 suggests that this element is capable of determining the first step in class II transposition only. This was confirmed by observations on the IS1071-dependent formation of stable cointegrates in a recombination-deficient Escherichia coli. These results support an evolutionary scheme in which the class II transposable elements descended from simple insertion sequences.

Alcaligenes↗
PubMed2002

piggyBac-mediated germline transformation of the malaria mosquito Anopheles stephensi using the red fluorescent protein dsRED as a selectable marker.

It is estimated that every year malaria infects approximately 300 million people and accounts for the death of 2 million individuals. The Plasmodium parasites that cause malaria in humans are transmitted exclusively by mosquito species belonging to the Anopheles genus. The recent development of a gene transfer technology for Anopheles stephensi mosquitoes, using the Minos transposable element marked with the enhanced green fluorescent protein EGFP (Catteruccia, F., Nolan, T., Loukeris, T. G., Blass, C., Savakis, C., Kafatos, F. C., and Crisanti, A. (2000) Nature 405, 959--962), provides now a powerful tool to investigate the role of mosquito molecules involved in the interaction with the malaria parasite. Such technology, when further developed with additional markers and transposable elements, will be invaluable for analyzing the biology of the vector and for developing malaria-resistant mosquitoes to be used as a tool to control malaria transmission in the field. We report here the germline transformation of A. stephensi mosquitoes using a piggyBac-based transposon to drive integration of the gene encoding for the red fluorescent protein dsRED. A. stephensi embryos were injected with transformation vector pPBRED containing the dsRED marker cloned within the arms of piggyBac. Microscopic analysis of G(1) larvae revealed the presence of seven fluorescent phenotypes whose different molecular origins were confirmed by Southern blotting analysis. Sequencing of the insertion sites in two lines demonstrated that integrations had occurred at TTAA nucleotides in accordance with piggyBac-mediated transpositions.

Animals↗
PubMed1996

Drosophila IRBP/Ku p70 corresponds to the mutagen-sensitive mus309 gene and is involved in P-element excision in vivo.

The P family of transposable elements in Drosophila transpose by a cut-and-paste mechanism involving double-strand gap repair. We report here that a Drosophila mutagen-sensitive mutant, mus3O9, contains a mutation in IRBP (inverted repeat binding protein), the Drosophila homolog of the mammalian Ku p70 gene. We show that the repair of double-strand DNA breaks after P-element excision is severely reduced in mus3O9 mutants using an in vivo assay for P-element transposase activity. In addition, excision products recovered from mus3O9 mutant embryos by use of a plasmid-based P-element mobility assay contain large deletions, suggesting that IRBP is involved in the repair of double-strand DNA breaks. Our findings provide the first demonstration that a mutation in the IRBP gene affects double-strand DNA break repair and suggest that DNA repair functions are conserved between Drosophila and mammals.

Animals↗
PubMed1991

Retrotransposon-induced overexpression of a homeobox gene causes defects in eye morphogenesis in Drosophila.

Insertion of the tom transposable element into various Drosophila ananassae genes results in dominant phenotypes that affect eye morphology. One of these genes encoded by the Om(1D) locus was isolated by transposon tagging. The Om(1D) gene encodes a 2.7 kb transcript that is expressed in every stage of development. The deduced Om(1D) protein is 606 amino acids long and contains two glutamine/histidine, two alanine-rich and one histidine/proline repeats, as well as a homeodomain located near the carboxy terminus. Tom-induced alleles of Om(1D) show a 1.7-fold increased accumulation of Om(1D) RNA in whole individuals during late larval--early pupal stages of development, whereas expression of this transcript is 7-fold higher in the eye--antenna imaginal disc of mutant versus wild-type flies. D. melanogaster flies transformed with the Om(1D) coding region under the control of the hsp70 promoter display an eye phenotype similar to that of Om(1D) when expression of the homeobox protein encoded by the chimeric gene is induced by temperature elevation at the end of the third instar period. These results suggest that the eye-specific mutant phenotype caused by the insertion of the tom retrotransposon in the Om(1D) locus may be a consequence of the tissue-specific induction of the expression of this gene by sequences present in the transposable element.

Amino Acid Sequence↗
PubMed2003

Polymerase chain reaction assay for Cydia pomonella granulovirus detection in Cydia pomonella population.

The polymerase chain reaction (PCR) assay was successfully used to identify Cydia pomonella granulovirus (CpGV) in larvae of Cydia pomonella L. (codling moth). PCR with the primers CpGV-2A/CpGV-2B and CpGV-3A/CpGV-3B was found suitable for detection of CpGV. The primers Cp-I/Cp-II and Cp-III/Cp-IV were able to identify the transposable element TCp3.2 in C. pomonella larvae. The presence of CpGV in the larvae from orchards,which had been infected with CpGV was tested during 2 years post infection. (p.i.). CpGV was found in as many as 15% of the surviving larvae 1 year p.i. in one location. The virus was not detected in CpGV-infected orchards 2 years p.i. or in natural C. pomonella populations. This result suggests a poor persistence of CpGV in surviving C. pomonella individuals and its slow spread in a natural host population. One the other hand, the presence of a transposable element, transposon TCp3.2 may correlate with virus redistribution in this insect population.

Animals↗
PubMed2003

Identification of essential genes in the human fungal pathogen Aspergillus fumigatus by transposon mutagenesis.

The opportunistic pathogen Aspergillus fumigatus is the most frequent cause of deadly airborne fungal infections in developed countries. In order to identify novel antifungal-drug targets, we investigated the genome of A. fumigatus for genes that are necessary for efficient fungal growth. An artificial A. fumigatus diploid strain with one copy of an engineered impala160 transposon from Fusarium oxysporum integrated into its genome was used to generate a library of diploid strains by random in vivo transposon mutagenesis. Among 2,386 heterozygous diploid strains screened by parasexual genetics, 1.2% had a copy of the transposable element integrated into a locus essential for A. fumigatus growth. Comparison of genomic sequences flanking impala160 in these mutants with that of the genome of A. fumigatus allowed the characterization of 20 previously uncharacterized A. fumigatus genes. Among these, homologues of genes essential for Saccharomyces cerevisiae growth have been identified, as well as genes that do not have homologues in other fungal species. These results confirm that heterologous transposition using the transposable element impala is a powerful tool for functional genomics in ascomycota, and they pave the way for defining the complete set of essential genes in A. fumigatus, the first step toward target-based development of new antifungal drugs.

Antifungal Agents↗