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At least 685 records · Page 38Linked to original sources
PubMed2001

Frequency of recent retrotransposition events in the human factor IX gene.

Two germline retrotransposition mutations of recent origin were observed in 727 independent mutations (0.28%) in the human factor IX gene (F9) of patients with hemophilia B: 1) a 279 bp insertion in exon H originating from an Alu family of short interspersed elements not previously known to be active and, 2) a 463 bp insertion in exon E of a LINE1 element originating in the maternal grandmother. If the rates of recent germline mutation in F9 are typical of the genome, a retrotransposition event is estimated to occur somewhere in the genome of about one in every 17 children born. Analysis of other estimates for retrotransposition frequency and overall mutation rates suggests that the actual rate of retrotransposition is likely to be in the range of one in every 2.4 to 28 live births.

Alu Elements↗
PubMed1995

Molecular etiology of factor VIII deficiency in hemophilia A.

Hemophilia is a common X-linked coagulation disorder due to deficiency of factor VIII. The factor VIII gene has been cloned in 1984 and a large number of mutations that cause hemophilia A have been identified in the last decade. The most common of the mutations is an inversion of factor VIII that accounts for nearly 45% of patients with severe hemophilia A. This review lists all the factor VIII mutations identified to date and briefly discusses their functional significance.

Amino Acid Sequence↗
PubMed2004

Characterization of a mutagenic B1 retrotransposon insertion in the jittery mouse.

B1 elements are an abundant class of short interspersed elements (SINEs) in the mouse genome and mobilize by a process known as retrotransposition. Here, we report the characterization of a mutagenic B1 insertion into exon 4 of the Atcay gene, which was previously shown to be responsible for the jittery mouse. Mutations in the human ortholog of this gene, ATCAY, are responsible for Cayman ataxia. The B1 insertion is approximately 150-bp long, ends in a 45-50-bp polyadenylic acid (poly A) tail, is flanked by a perfect 13-bp target-site duplication, and is inserted into a sequence that resembles a LINE-1 endonuclease consensus cleavage site. Computational analysis indicates that the mutagenic insertion is most closely related to elements of the B1-C subfamily, and we have identified two possible progenitor B1 sequences on mouse chromosome 19. Together, these data demonstrate that B1 retrotransposition is ongoing in the mouse genome and is consistent with the hypothesis that the reverse transcriptase and endonuclease encoded by LINE-1 elements mediate B1 mobility.

Animals↗
PubMed2005

Meta-analysis of gross insertions causing human genetic disease: novel mutational mechanisms and the role of replication slippage.

Although gross insertions (>20 bp) comprise <1% of disease-causing mutations, they nevertheless represent an important category of pathological lesion. In an attempt to study these insertions in a systematic way, 158 gross insertions ranging in size between 21 bp and approximately 10 kb were identified using the Human Gene Mutation Database (www.hgmd.org). A careful meta-analytical study revealed extensive diversity in terms of the nature of the inserted DNA sequence and has provided new insights into the underlying mutational mechanisms. Some 70% of gross insertions were found to represent sequence duplications of different types (tandem, partial tandem, or complex). Although most of the tandem duplications were explicable by simple replication slippage, the three complex duplications appear to result from multiple slippage events. Some 11% of gross insertions were attributable to nonpolyglutamine repeat expansions (including octapeptide repeat expansions in the prion protein gene [PRNP] and polyalanine tract expansions) and evidence is presented to support the contention that these mutations are also caused by replication slippage rather than by unequal crossing over. Some 17% of gross insertions, all >or=276 bp in length, were found to be due to LINE-1 (L1) retrotransposition involving different types of element (L1 trans-driven Alu, L1 direct, and L1 trans-driven SVA). A second example of pathological mitochondrial-nuclear sequence transfer was identified in the USH1C gene but appears to arise via a novel mechanism, trans-replication slippage. Finally, evidence for another novel mechanism of human genetic disease, involving the possible capture of DNA oligonucleotides, is presented in the context of a 26-bp insertion into the ERCC6 gene.

Base Sequence↗
PubMed2006

dbRIP: a highly integrated database of retrotransposon insertion polymorphisms in humans.

Retrotransposons constitute over 40% of the human genome and play important roles in the evolution of the genome. Since certain types of retrotransposons, particularly members of the Alu, L1, and SVA families, are still active, their recent and ongoing propagation generates a unique and important class of human genomic diversity/polymorphism (for the presence and absence of an insertion) with some elements known to cause genetic diseases. So far, over 2,300, 500, and 80 Alu, L1, and SVA insertions, respectively, have been reported to be polymorphic and many more are yet to be discovered. We present here the Database of Retrotransposon Insertion Polymorphisms (dbRIP; http://falcon.roswellpark.org:9090), a highly integrated and interactive database of human retrotransposon insertion polymorphisms (RIPs). dbRIP currently contains a nonredundant list of 1,625, 407, and 63 polymorphic Alu, L1, and SVA elements, respectively, or a total of 2,095 RIPs. In dbRIP, we deploy the utilities and annotated data of the genome browser developed at the University of California at Santa Cruz (UCSC) for user-friendly queries and integrative browsing of RIPs along with all other genome annotation information. Users can query the database by a variety of means and have access to the detailed information related to a RIP, including detailed insertion sequences and genotype data. dbRIP represents the first database providing comprehensive, integrative, and interactive compilation of RIP data, and it will be a useful resource for researchers working in the area of human genetics.

Databases, Genetic↗
PubMed2005

Two independent retrotransposon insertions at the same site within the coding region of BTK.

Insertion of endogenous retrotransposon sequences accounts for approximately 0.2% of disease causing mutations. These insertions are mediated by the reverse transcriptase and endonuclease activity of long interspersed nucleotide (LINE-1) elements. The factors that control the target site selection in insertional mutagenesis are not well understood. In our analysis of 199 unrelated families with proven mutations in BTK, the gene responsible for X-linked agammaglobulinemia, we identified two families with retrotransposon insertions at exactly the same nucleotide within the coding region of BTK. Both insertions, an SVA element and an AluY sequence, occurred 12 bp before the end of exon 9. Both had the typical hallmarks of a retrotransposon insertion including target site duplication and a long poly A tail. The insertion site is flanked by AluSx sequences 1 kb upstream and 1 kb downstream and an unusual 60 bp sequence consisting of only As and Ts is located in intron 9, 60 bp downstream of the insertion. The occurrence of two retrotransposon sequences at exactly the same site suggests that this site is vulnerable to insertional mutagenesis. A better understanding of the factors that make this site vulnerable will shed light on the mechanisms of LINE-1 mediated insertional mutagenesis.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2005

De novo Alu element insertions targeted to a sequence common to the BRCA1 and BRCA2 genes.

Linkage analysis suggests that mutations in the BRCA1 and BRCA2 genes are responsible for cancer predisposition in more than 80% of the families with high incidence of breast/ovarian cancer. However, pathogenic mutations in the BRCA1/2 genes are generally identified in much less than half of the families investigated in a diagnostic setting with the currently used PCR-based screening protocols. Here we report the identification of two different de novo Alu element insertions within the BRCA1/2 coding sequences in three out of the 50 families in which we found a cancer predisposing mutation, suggesting that this type of mutation is much more common than suggested by their occurrence in mutation databases. The Alu insertion in the BRCA2 gene resulted in the removal of the targeted exon from the corresponding mRNA molecule. Unexpectedly the Target Site Duplications generated by both Alu element insertions contained a specific 9 bp long segment, which might eventually serve as a recognition site for the transposition machinery. Finally, in contrast to the disease causing Alu insertions reported to date, the transposon identified in the BRCA1 gene does not belong to a "young" AluY but to an AluS subfamily, indicating that some of these "old" Alu elements, which are supposed to be non-functional fossil relics, are still able to retrotranspose in vivo.

Alu Elements↗
PubMed1990

Virus-like particle formation of Drosophila copia through autocatalytic processing.

Northern blot and nucleotide sequence analyses of copia RNA from a transfectant made by introducing a genomic copia into copia-free cells showed that the 2 kb RNA, one of the major transcripts of copia, is generated through splicing. Using the polymerase chain reaction (PCR), we have also found that the position of the splice sites used in Drosophila larvae and cultured cells originally containing copia is the same as that used in the transfectant. To investigate the function of the 2 kb RNA, we constructed mutant copias which harboured a single point mutation at the splice site or approximately 3 kb deletion of the internal region corresponding to the spliced out sequence. Analyses of transfectants made by introducing these mutant copias into copia-free cells demonstrated that the spliced 2 kb RNA contains sufficient information to make copia virus-like particles (VLPs). Furthermore, when copia RNA corresponding to the spliced RNA was translated in vitro, the major VLP protein was found to be released autocatalytically from its own precursor. A single amino acid substitution at the putative protease active site in the precursor prevented the processing, and resulted in accumulation of the mutant precursor in vitro. From these results, we conclude that copia VLPs are produced through autocatalytic processing of the precursor polyprotein encoded by the spliced copia RNA.

Amino Acid Sequence↗
PubMed1995

Effects of the su(Hw) insulator protein on the expression of the divergently transcribed Drosophila yolk protein genes.

The suppressor of Hairy-wing [su(Hw)] protein mediates the mutagenic effects of the gypsy retrotransposon by blocking enhancer activity. These repressive effects are general, can occur over long distances and require that the su(Hw) protein is bound between the affected enhancer and promoter. The effects of the su(Hw) binding region on yolk protein (yp) gene expression were determined. These genes are regulated by shared enhancers in the intergenic region, which provided a method to examine whether an enhancer blocked by the su(Hw) protein remained functional. We demonstrate that a blocked enhancer is completely active, supporting the proposal that the su(Hw) protein is an insulator protein that acts by forming a new boundary in a pre-existing chromatin domain, thereby preventing the interaction of regulatory elements located upstream of the insertion site with the promoter. In addition, we found that yp promoter function is not diminished by sharing enhancers, suggesting that these enhancers are not rate limiting for transcriptional activation. Lastly, our data indicate that yp promoter activity is interdependent, such that transcription from one promoter influences the level of activity of the linked promoter.

Alcohol Dehydrogenase↗
PubMed1995

mRNA retroposition in human cells: processed pseudogene formation.

Using a sensitive assay for detection of reverse transcription events, we demonstrate that human HeLa cells can 'retropose', i.e. reverse transcribe and integrate, the mRNA of a naive reporter gene, at a low but detectable frequency. Furthermore, we show that the retroposed copies have all the hallmarks of the processed pseudogenes naturally found in the mammalian genome: they lack intron and 5' promoter sequence, they have acquired a 3' poly(A) tail, and they are flanked by short repeats (< 15 bp) of target DNA sequence. These results demonstrate that human cells possess an endogenous reverse transcription activity, which is not restricted to transcripts of transposable elements, and which is likely to be involved in the formation, still ongoing, of a large fraction of the eukaryotic genome.

Base Sequence↗
PubMed2003

Structure and evolution of the teleost extraretinal rod-like opsin (errlo) and ocular rod opsin (rho) genes: is teleost rho a retrogene?

In Teleost fish examined to date the ocular rod opsin gene, rho, is intronless, unlike the rod opsin genes of other vertebrate classes which possess a five exon/four intron structure. We have examined in silico the structure of rho (which is expressed uniquely in the retina) and the closely related extraretinal rod-like opsin (exo-rhodopsin) gene, errlo (which is expressed uniquely in the pineal), in the puffer-fish, Fugu rubripes (Takifugu rubripes). Whilst the ocular rho is intronless in common with other Teleosts, the pineal errlo has the five exon/four intron structure common to the rod opsin gene of other vertebraes. A comparison of the sequence surrounding the errlo and rho loci indicates that the errlo locus is syntenic with RHO, the human rod opsin gene, rather than rho. We suggest that the intronless rho may have arisen through an ancient retrotransposition of a mature mRNA originating from errlo. This duplication event has occurred early in the evolution of the Actinopterygii (ray-finned fish) since the rho of the primitive Actinopterygians such as sturgeon, bowfin, and gar is also intronless. Since it appears that the intron containing errlo is the ancestral opsin gene that gave rise to the intronless rho in the Teleostei, errlo is therefore the true orthologue of the rod opsin gene in other vertebrate classes. We suggest that loss of expression of errlo in the retina could be related to the metabolic and physiological advantages, such as a reduction in splicing events during RNA processing, that may be conferred through possession of an additional, intronless rod opsin gene in the form of rho.

Animals↗
PubMed2005

NfCR1, the first non-LTR retrotransposon characterized in the Australian lungfish genome, Neoceratodus forsteri, shows similarities to CR1-like elements.

The genomes of lungfish, together with those of some urodele amphibians, are the largest of all vertebrate genomes. It has been assumed that the bulk of the DNA making up these large genomes has been derived from repeat elements, like the noncoding DNA of those genomes that have been sequenced (e.g., human). In an attempt to characterize repeat sequences in the lungfish genome, we have isolated, by restriction enzyme digestion of genomic DNA, sequences of a repeat element in Neoceratodus forsteri, the most primitive of the living lungfishes. The fragments sequenced from the EcoRI and BglII digests were used to perform genome walking PCR in order to obtain the full sequence of the repeat element. This element shares homology with the non-LTR (LINE) element, Chicken Repeat 1 (CR1), described for several vertebrates and some invertebrates; we have called it N. forsteri CR1 (NfCR1). NfCR1 shares all the domains of other CR1 elements but it also has several unique features that suggest it may no longer be active in the lungfish genome. It occurs in both full-length and 5'-truncated versions and in its present "inactive" form represents approximately 0.05% of the lungfish genome.

Amino Acid Sequence↗
PubMed2026

Diving Deeper Into Mechanisms of Acrylamide-Induced Toxicity: RNA Sequencing Reveals Transcriptomic Alteration and Retrotransposon Expression in Drosophila melanogaster.

Given the inevitability of human and animal exposure to acrylamide, there is increasing concern regarding its potential health risks. While a number of molecular mechanisms have been proposed, the complexity of acrylamide toxicological pathways and interactions remains incompletely characterized. In this study, we employed a transcriptomic approach to investigate the transcriptional responses of Drosophila melanogaster following exposure to acrylamide (100&#x2009;mg/kg). Our analysis identified 634 differentially expressed genes (DEGs), with 362 upregulated and 272 downregulated. Functional analysis revealed these DEGs are enriched in pathways related to reproduction, detoxification, cellular and metabolic processes, signaling, synaptic formation and organization. Notably, acrylamide exposure upregulated the expression of tau and beta-amyloid protein precursor-like genes, both implicated in Alzheimer's disease pathology. An aversive memory test further demonstrated that acrylamide impaired the short-term memory of treated flies. Additionally, acrylamide-induced toxicity altered the expression of nine long terminal repeat retrotransposons, belonging to the gypsy and pao superfamilies. By exploring the potential role of transposable element activity in acrylamide-mediated toxicity, this study provides novel insights into the molecular mechanisms underlying its effects. Collectively, these findings offer a more comprehensive understanding of the mechanisms and pathways associated with the toxic action and detoxification of acrylamide in D. melanogaster.

Animals↗
PubMed2004

Analysis of a Ty1-less variant of Saccharomyces paradoxus: the gain and loss of Ty1 elements.

Because Ty elements transpose through an RNA intermediate, element accumulation through retrotransposition must be regulated or offset by element loss to avoid uncontrolled genome expansion. Here we examine the fate of Ty sequences in Saccharomyces strain 337, a strain that is reported to lack Ty1 and Ty2 elements, but contains remnant solo long terminal repeats (LTRs). Although strain 337 was initially classified as Saccharomyces cerevisiae, our work indicates that this strain is more closely related to S. paradoxus. Several degenerate Ty1 and Ty2 LTRs were mapped to the same insertion sites as full-length Ty1 and Ty2 elements in S. cerevisiae, suggesting that this strain lost Ty elements by LTR-LTR recombination. Southern analysis indicates that strain 337 also lacks Ty4 and Ty5 elements. We estimated the rates of element gain and loss in this strain by introducing a single transposition-competent Ty1 element. The results indicate that Ty1 retrotransposition occurs at a much higher rate than elimination, suggesting that copy-number-dependent co-factors or environmental conditions contribute to the loss of Ty elements in this genome.

Blotting, Southern↗
PubMed2005

Inferences of evolutionary relationships from a population survey of LTR-retrotransposons and telomeric-associated sequences in the Saccharomyces sensu stricto complex.

The Saccharomyces sensu stricto complex consists of six closely related species and one natural hybrid. Intra- and inter- species variability in repetitive elements can help elucidate the population structure and evolution of these close relatives. The chromosome positions of several telomeric associated sequences (TASs) and LTR-retrotransposons have been determined, using PFGE, in 112 isolates. Most of the repetitive elements studied are found in multiple copies in each strain, although in some subpopulations these elements are present in low copy number or are absent. Hybridization patterns and copy numbers of the repetitive elements correlate with geographic distribution. These patterns may yield interesting clues as to the origins and evolution of some TASs and retrotransposons, e.g. we can infer that Y' originated on the left end of chromosome XIV. There is strong evidence for horizontal transfer of Ty2 between S. cerevisiae and S. mikatae. Ty1 and Ty5 are either lost easily or frequently horizontally transferred. We have also found some gross chromosomal rearrangements in isolates within species and a few new natural hybrids between species, indicating that these processes occur in the wild and are not limited to conditions of human influence. DNA sequences have been deposited with the EMBL/GenBank database under Accession Nos AJ632279-AJ632293.

Base Sequence↗
PubMed2005

Impact of ionizing radiation on the life cycle of Saccharomyces cerevisiae Ty1 retrotransposon.

Ty1 elements, LTR-retrotransposons of Saccharomyces cerevisiae, are known to be activated by genetic and environmental stress. Several DNA-damaging agents have been shown to increase both Ty1 transcription and retrotransposition. To explore further the relationship between Ty1 mobility and DNA damage, we have studied the impact of ionizing radiation at different steps of the Ty1 life cycle. We have shown that Ty1 transposition is strongly activated by gamma-irradiation and we have analysed its effect on Ty1 transcription, TyA1 protein and Ty1 cDNA levels. The activation of transposition rises with increasing doses of gamma-rays and is stronger for Ty1 elements than for the related Ty2 elements. Ty1 RNA levels are markedly elevated upon irradiation; however, no significant increase of TyA1 protein was detected as measured by TYA1-lacZ fusions and by Western blot. A moderate increase in Ty1 cDNA levels was also observed, indicating that ionizing radiation can induce the synthesis of Ty1 cDNA. In diploid cells and ste12 mutants, where both Ty1 transcription and transposition are repressed, gamma-irradiation is able to activate Ty1 transposition and increases Ty1 RNA levels. These results suggest the existence of a specific regulatory pathway involved in Ty1 response to the gamma-irradiation that would be independent of Ste12 and mating-type factors. Our findings also indicate that ionizing radiation acts on several steps of the Ty1 life cycle.

Blotting, Northern↗
PubMed2005

Tyl6, a novel Ty3/gypsy-like retrotransposon in the genome of the dimorphic fungus Yarrowia lipolytica.

The novel LTR retrotransposon Tyl6 was detected in the genome of the dimorphic fungus Yarrowia lipolytica. Sequence analysis revealed that this element is related to the well-known Ty3 element of Saccharomyces cerevisiae and, especially, to the recently described Tse3 retrotransposon of Saccharomyces exiguus and to the del1-like plant retrotransposons. Tyl6 is 5108 bp long, is flanked by two identical long terminal repeats (LTR), each of 276 bp, and its ORFs are separated by a -1 frameshift. Both ORFs are intact and deduced translation products display a significant similarity with those of previously described Ty3/gypsy retrotransposons. Distribution of Tyl6 among Y. lipolytica strains of different origins was also analysed. A single copy of the novel retrotransposon is present in some commonly used laboratory strains, which are derivatives of the wild-type isolate YB423-12, whereas other strains of independent origin are devoid of Ty16. No solo LTR of Tyl6 was detected in the analysed strains.

Amino Acid Sequence↗
PubMed1995

Sequence analysis of a 44 kb DNA fragment of yeast chromosome XV including the Tyl-H3 retrotransposon, the suf1(+) frameshift suppressor gene for tRNA-Gly, the yeast transfer RNA-Thr-1a and a delta element.

We have sequenced on both strands a 44,019 bp fragment located on the left arm of Saccharomyces cerevisiae chromosome XV. The sequenced segment contains 22 open reading frames (ORFs) of at least 100 amino acids long, one of which probably contains an intron. Six of the 22 ORFs correspond to known proteins: the multicopy suppressor of Snf1 protein 1, the two Tyl-H3 transposon proteins TyA and TyB, the myo-inositol transporter 2, the transcription factor protein Ino4 and the 3,4-dihydroxy-5-hexaprenylbenzoate methyltransferase. Of the 16 remaining ORFs, two show highest homologies with the yeast serine/threonine protein kinase Ste20 and the human tryptophanyl-tRNA synthetase. Eight ORFs show slight similarities with protein sequences described in data banks. DNA sequence comparison reveals also the presence of three known sequences: the Tyl-H3 transposable element, the yeast suf1(+) frameshift suppressor gene for tRNA-Gly and the yeast transfer RNA-Thr-1a. A fourth DNA sequence shows striking identities with the yeast delta elements.

Amino Acid Sequence↗