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PubMed1991

Retrotransposable elements R1 and R2 interrupt the rRNA genes of most insects.

A large number of insect species have been screened for the presence of the retrotransposable elements R1 and R2. These elements integrate independently at specific sites in the 28S rRNA genes. Genomic blots indicated that 43 of 47 insect species from nine orders contained insertions, ranging in frequency from a few percent to greater than 50% of the 28S genes. Sequence analysis of these insertions from 8 species revealed 22 elements, 21 of which corresponded to R1 or R2 elements. Surprisingly, many species appeared to contain highly divergent copies of R1 and R2 elements. For example, a parasitic wasp contained at least four families of R1 elements; the Japanese beetle contained at least five families of R2 elements. The presence of these retrotransposable elements throughout Insecta and the observation that single species can harbor divergent families within its rRNA-encoding DNA loci present interesting questions concerning the age of these elements and the possibility of cross-species transfer.

Amino Acid Sequence↗

PubMed1990

Type I (R1) and type II (R2) ribosomal DNA insertions of Drosophila melanogaster are retrotransposable elements closely related to those of Bombyx mori.

Approximately 50% of the ribosomal DNA (rDNA) units of Drosophila melanogaster are inactivated by two different 28 S RNA ribosomal gene insertions (type I and type II). We present here the nucleotide sequence of complete type I and type II elements. Conceptual translation of these sequences revealed open reading frames (ORFs) encoding amino acid residues conserved in all retrotransposable elements. Full-length type I elements are 5.35 x 10(3) base-pairs in length and contain two overlapping ORFs. The smaller ORF (471 amino acid residues) has similarity to gag genes, while the larger ORF (1021 residues) has similarity to pol genes. Full-length type II elements are 3.6 x 10(3) base-pairs and contain one large ORF (1056 residues) that appears to represent a gag-pol fusion. Type I and type II elements are similar in structure, in the proteins they encode, and in insertion specificity to the R1Bm and R2Bm retrotransposable elements of Bombyx mori. We suggest that the D. melanogaster elements be called R1Dm and R2Dm, to reflect their structure as retrotransposons. Comparison of the R1 and R2 elements from these two widely different species revealed regions of the ORF that are likely to play an important role in the propagation of the elements. Four distinct regions of sequence conservation separated by regions of little or no sequence similarity were detected for both the R1 and R2 elements: (1) cysteine motifs of the gag gene, with three such motifs for R1 and one motif for R2; (2) a reverse transcriptase domain; (3) an integrase domain located carboxyl terminal to the reverse transcriptase region; and (4) a small region amino terminal to the reverse transcriptase domain, whose function is not known. The level of identity of the amino acid residues for these segments is 28 to 34% between the R1 elements, and 34 to 39% for the R2 elements. Finally, it may be predicted that the mechanism of unequal crossover might eventually eliminate R1 and R2 from the rDNA locus. The long history of selection at the protein level exhibited by these elements indicates that it is their active transposition that maintains them in the locus. The high level of sequence homogeneity between copies of each element within the same species is consistent with the high turnover rate expected to result from these processes.

Amino Acid Sequence↗

PubMed1990

The structure, distribution and evolution of the Ta1 retrotransposable element family of Arabidopsis thaliana.

The Ta1 elements are a low copy number, copia-like retrotransposable element family of Arabidopsis thaliana. Six Ta1 insertions comprise all of the Ta1 element copies found in three geographically diverse A. thaliana races. These six elements occupy three distinct target sites: Ta1-1 is located on chromosome 5 and is common to all three races (Col-0, Kas-1 and La-0). Ta1-2 is present in two races on chromosome 4 (Kas-1 and La-0), and Ta1-3, also located on chromosome 4, is present only in one race (La-0). The six Ta1 insertions share greater than 96% nucleotide identity, yet are likely to be incapable of further transposition due to deletions or nucleotide changes that alter either the coding capacity of the elements or conserved protein domains required for retrotransposition. Nucleotide sequence comparisons of these elements and the distribution of Ta1 among 12 additional A. thaliana geographical races suggest that Ta1-1 predated the global dispersal of A. thaliana. As the species spread throughout the world, two additional transposition events occurred which gave rise first to Ta1-2 and finally to Ta1-3.

Acyltransferases↗

PubMed1992

Turnover of R1 (type I) and R2 (type II) retrotransposable elements in the ribosomal DNA of Drosophila melanogaster.

R1 and R2 are distantly related non-long terminal repeat retrotransposable elements each of which inserts into a specific site in the 28S rRNA genes of most insects. We have analyzed aspects of R1 and R2 abundance and sequence variation in 27 geographical isolates of Drosophila melanogaster. The fraction of 28S rRNA genes containing these elements varied greatly between strains, 17-67% for R1 elements and 2-28% for R2 elements. The total percentage of the rDNA repeats inserted ranged from 32 to 77%. The fraction of the rDNA repeats that contained both of these elements suggested that R1 and R2 exhibit neither an inhibition of nor preference for insertion into a 28S gene already containing the other type of element. Based on the conservation of restriction sites in the elements of all strains, and sequence analysis of individual elements from three strains, nucleotide divergence is very low for R1 and R2 elements within or between strains (less than 0.6%). This sequence uniformity is the expected result of the forces of concerted evolution (unequal crossovers and gene conversion) which act on the rRNA genes themselves. Evidence for the role of retrotransposition in the turnover of R1 and R2 was obtained by using naturally occurring 5' length polymorphisms of the elements as markers for independent transposition events. The pattern of these different length 5' truncations of R1 and R2 was found to be diverse and unique to most strains analyzed. Because recombination can only, with time, amplify or eliminate those length variants already present, the diversity found in each strain suggests that retrotransposition has played a critical role in maintaining these elements in the rDNA repeats of D. melanogaster.

Animals↗

PubMed2026

Retrotransposable element derepression distinguishes DNMT3A-mutant from TET2-mutant clonal haematopoiesis.

Clonal haematopoiesis (CH) is driven by somatic mutations in haematopoietic stem cells that generate clonal populations detectable in peripheral blood and is present in 10-20% of individuals over the age of 65. Mutations in DNMT3A and TET2 are the most common drivers and have been linked to inflammatory phenotypes and increased risk of haematologic and cardiovascular disease. However, the cell-intrinsic mechanisms connecting these mutations to inflammatory signalling remain incompletely understood. Because retrotransposable elements (RTEs) are epigenetically regulated and can activate innate immune pathways when derepressed, we hypothesised that RTE reactivation may represent a mutation-specific mechanism linking clonal haematopoiesis driver mutations to inflammatory pathways. We analysed RTE expression and clonal burden in peripheral blood mononuclear cell (PBMC) samples from 56 individuals with CH and 12 non-CH controls using integrated genomic and transcriptomic approaches, with complementary validation by TARGET-seq across haematopoietic lineages. High variant allele frequency (VAF; > 10%) DNMT3A-mutant clones exhibited widespread derepression of RTEs, particularly LINE and LTR families, whereas TET2-mutant clones showed a trend towards reduced RTE expression relative to controls. Transcriptomic analyses revealed that DNMT3A high-variant allele frequency clones with elevated RTE expression were enriched for inflammatory signalling pathways, including TNF-α/NF-κB signalling, interferon responses, and senescence-associated signatures. In contrast, TET2-mutant clones lacked these RTE-associated inflammatory signatures and instead showed enrichment of oxidative phosphorylation, reactive oxygen species signalling, and a mechanistic target of rapamycin complex 1 pathway. These findings were reproduced in an independent cohort. Collectively, our results highlight mutation-specific inflammatory mechanisms in clonal haematopoiesis and provide a foundation for future functional and preclinical studies to determine whether modulation of RTE activity can influence the inflammatory phenotype of DNMT3A-mutant CH and represent a potential therapeutic strategy.

DNMT3A↗

PubMed1992

Structure of DRE, a retrotransposable element which integrates with position specificity upstream of Dictyostelium discoideum tRNA genes.

Different Dictyostelium discoideum strains contain between 2 and 200 copies of a retrotransposable element termed DRE (Dictyostelium repetitive element). From the analysis of more than 50 elements, it can be concluded that DRE elements always occur 50 +/- 3 nucleotides upstream of tRNA genes. All analyzed clones contain DRE in a constant orientation relative to the tRNA gene, implying orientation specificity as well as position specificity. DRE contains two open reading frames which are flanked by nonidentical terminal repeats. Long terminal repeats (LTRs) are composed of three distinct modules, called A, B, and C. The tRNA gene-proximal LTR is characterized by one or multiple A modules followed by a single B module (AnB). With respect to the distal LTR, two different subforms of DRE have been isolated. The majority of isolated clones contains a distal LTR composed of a B module followed by a C module (BC), whereas the distal LTR of the other subform contains a consecutive array of a B module, a C module, a slightly altered A module, another B module, and another C module (BC.ABC). Full-length as well as smaller transcripts from DRE elements have been detected, but in comparison with the high copy number in D. discoideum strains derived from the wild-type strain NC4, transcription is rather poor.

Amino Acid Sequence↗

PubMed1990

A retrotransposable element from the mosquito Anopheles gambiae .

A family of middle repetitive elements from the African malaria vector Anopheles gambiae is described. Approximately 100 copies of the element, designated T1Ag, are dispersed in the genome. Full-length elements are 4.6 kilobase pairs in length, but truncation of the 5' end is common. Nucleotide sequences of one full-length, two 5'-truncated, and two 5' ends of T1Ag elements were determined and aligned to define a consensus sequence. Sequence analysis revealed two long, overlapping open reading frames followed by a polyadenylation signal, AATAAA, and a tail consisting of tandem repetitions of the motif TGAAA. No direct or inverted long terminal repeats (LTRs) were detected. The first open reading frame, 442 amino acids in length, includes a domain resembling that of nucleic acid-binding proteins. The second open reading frame, 975 amino acids long, resembles the reverse transcriptases of a category of retrotransposable elements without LTRs, variously termed class II retrotransposons, class III elements or non-LTR retrotransposons. Similarity at the sequence and structural levels places T1Ag in this category.

Amino Acid Sequence↗

PubMed1992

Transposing without ends: the non-LTR retrotransposable elements.

Transposable elements have been discovered in animals, plants, fungi, and protozoans which contain open reading frames similar to the gag and pol genes of retroviruses and retrotransposons but which lack long terminal repeats (LTRs). Recent experiments have shown that these non-LTR elements [also called poly(A) type and LINE-like elements] encode functional reverse transcriptase and replicate via an RNA intermediate. Based on phylogenetic analysis of their encoded reverse transcriptase sequences, the non-LTR retrotransposons are the likely progenitors of retroviruses and LTR retrotransposons. Because retroviruses and LTR retrotransposons depend upon their LTRs for key steps in both transcription and integration, the mechanisms utilized by the non-LTR retrotransposons must be fundamentally different. Internal promoter sequences have been found in several non-LTR elements that initiate transcription upstream at the first nucleotide. Current models for retrotransposition of non-LTR elements propose that the 3' ends of staggered nicks at the chromosomal insertion site serve as primers for first- and second-staggered nicks at the chromosomal insertion site serve as primers for first- and second-strand synthesis from the RNA template. These models suggest that the enzymatic machinery of non-LTR elements is likely to be responsible for the integration of SINEs and processed pseudogenes.

Animals↗

PubMed1992

Two distinct subforms of the retrotransposable DRE element in NC4 strains of Dictyostelium discoideum.

Approximately 2% of the Dictyostelium discoideum genome consists of multiple copies of a retrotransposable element termed DRE (Dictyostelium Repetitive Element). These elements have always been found integrated in a position and orientation-specific manner 50 +/- 4 nucleotides upstream of the coding region of tRNA genes (tDNAs). An intact DRE is 5.7 kb long. It carries an extensive coding region flanked by non-identical long terminal repeats (LTRs), composed of three distinct modules A, B and C. The left LTR proximal to the tRNA gene contains one or several A-modules followed by a single B-module (AnB). By contrast, the right LTR is composed of a B-module followed by a C-module (BC). Approximately 50% of the DRE elements in NC4 derivatives of D. discoideum are structurally different from the 5.7 kb DRE described above. They carry the following alterations: a) a 3.1 kb deletion in the coding region; b) two small deletions of 8 and 29 nucleotides in the B-module of the right LTR; c) a 72 bp deletion in the B-C junction; and d) three distinct point mutations within the A-module of the left LTR. The deletion in the open reading frame encompasses the putative coding regions for reverse transcriptase adn integrase. At least 60 copies of this smaller 2.4 kb DRE subtype are found in the genome of D. discoideum NC4 strains associated with tRNA genes. Thus, inspite of their lack in reverse transcriptase and integrase those 2.4 kb elements are presumably transposable and at least all isolated copies are found exclusively in the proximity of tRNA gene loci. The enzymes needed for their replication and transposition are likely to be provided by the intact 5.7 kb DREs.

Animals↗

PubMed1990

A rapidly rearranging retrotransposon within the miniexon gene locus of Crithidia fasciculata.

The tandemly arrayed miniexon genes of the trypanosomatid Crithidia fasciculata are interrupted at specific sites by multiple copies of an inserted element. The element, termed Crithidia retrotransposable element 1 (CRE1), is flanked by 29-base-pair target site duplications and contains a long 3'-terminal poly(dA) stretch. A single 1,140-codon reading frame is similar in sequence to the integrase and reverse transcriptase regions of retroviral pol polyproteins. Cloned lines derived from a stock of C. fasciculata have unique arrangements of CRE1s. In different cloned lines, CRE1s, in association with miniexon genes, are located on multiple chromosomes. By examining the arrangement of CRE1s in subclones, we estimate that the element rearranges at a rate of ca. 1% per generation. These results indicate that the C. fasciculata miniexon locus is the target for a novel retrotransposon.

Amino Acid Sequence↗

PubMed1990

Origin and evolution of retroelements based upon their reverse transcriptase sequences.

To study the evolutionary relationship of reverse transcriptase (RT) containing genetic elements, a phylogenetic tree of 82 retroelements from animals, plants, protozoans and bacteria was constructed. The tree was based on seven amino acid domains totalling 178 residues identified in all RTs. We have also identified these seven domains in the RNA-directed RNA polymerases from various plus-strand RNA viruses. The sequence similarity of these RNA polymerases to RT suggests that these two enzymes evolved from a common ancestor, and thus RNA polymerase can be used as an outgroup to root the RT tree. A comparison of the genetic organization of the various RT containing elements and their position on the tree allows several inferences concerning the origin and evolution of these elements. The most probable ancestor of current retroelements was a retrotransposable element with both gag-like and pol-like genes. On one major branch of the tree, organelle and bacterial sequences (e.g. group II introns and bacterial msDNA) appear to have captured the RT sequences from retrotransposons which lack long terminal repeats (LTRs). On the other major branch, acquisition of LTRs gave rise to two distinct groups of LTR retrotransposons and three groups of viruses: retroviruses, hepadnaviruses and caulimoviruses.

Amino Acid Sequence↗

PubMed2025

STING inhibits LINE-1 retrotransposition through sorting ORF1p to lysosomes for degradation.

The cyclic dinucleotide sensor stimulator of interferon (IFN) genes (STING) is known for its critical role in interferon and inflammatory responses. In addition, STING also has functions independent of interferon induction. In this study, we report that STING restricts the mobilization of the cellular retrotransposon long interspersed nuclear element 1 (LINE-1) independent of cGAS and interferon induction. LINE-1 is the only active autonomous retrotransposable element in the human genome and its transposition can cause genetic and autoimmune diseases. STING inhibition of LINE-1 requires its dimerization. Mechanistically, STING interacts with LINE-1 ORF1p, then the complex translocates to the ER-Golgi intermediate compartment (ERGIC) and the Golgi followed by sorting to Rab7-positive lysosomes for degradation. Our data unveil a function of STING in maintaining host genome integrity by restricting LINE-1 retrotransposition via an IFN-independent mechanism.

Humans↗

PubMed1990

Independent regulation of mouse VL30 retrotransposon expression in response to serum and oncogenic cell transformation.

The nucleotide sequence of the long terminal repeats (LTRs) of retrovirus-transmissible mouse VL30 cDNA clones, NVL-1 and NVL-2 were determined and compared with that of the prototype NVL-3. Both shared the typical U3 R U5 structure together with unusual features of redundancy in the tRNAgly primer binding site and adjacent inverted repeat. NVL-1 and NVL-2 LTRs were almost identical and differed from the NVL-3 LTR in the U3 domain harbouring transcriptional regulatory determinants. S1 nuclease analysis of cellular and virus-encapsidated RNA suggested that NVL-1/2 and NVL-3 elements retrotranspose with comparable efficiency but that in contrast to transformation-regulated VL30 expression which affects all types of NVL element, only NVL-1/2 elements were found to be serum responsive. Both modes of VL30 regulation were found to be coupled through protein kinase C-independent pathways. Expression of N-ras transactivated U3 enhancer determinants in all classes of LTR. However the same region of NVL-1/2 LTR did not confer serum responsiveness implying that cis regulatory determinants of VL30 elements mediating growth factor responsiveness are at least in part dissociable from those responsible for cell transformation-regulated expression.

Base Sequence↗

PubMed1991

Reverse transcriptase encoded by a retrotransposon from the trypanosomatid Crithidia fasciculata.

The long interspersed nuclear element (LINE)-like elements are a distinct family of eukaryotic transposons that contain a long open reading frame with limited sequence homology to retroviral reverse transcriptases. Unlike many retrotransposons, they lack long terminal repeats. The mechanism by which LINE-like elements move within the genomes of their hosts remains speculative. We have used an unusual approach to express and detect enzymatic activities associated with Crithidia retrotransposable element 1 (CRE1), a site-specific LINE-like element found in the insect trypanosomatid Crithidia fasciculata. A chimeric gene fusing the yeast retrotransposon Ty1 and the CRE1 open reading frame is constructed and then overexpressed in yeast. Fusion proteins are packaged into virus-like particles, which can be partially purified and directly analyzed for enzymatic activity. Here we demonstrate that CRE1 encodes an RNA-directed DNA polymerase. These data provide direct biochemical evidence that this widely distributed class of retrotransposons encodes reverse transcriptase and sets the stage for a detailed understanding of the mechanisms involved in LINE-like element transposition.

Animals↗

PubMed1988

Ribosomal DNA insertion elements R1Bm and R2Bm can transpose in a sequence specific manner to locations outside the 28S genes.

A fraction of the ribosomal 28S genes in some insects are interrupted at specific sites by insertion elements R1 and R2 (also called Type I and II). These elements contain long open-reading frames with homology to reverse transcriptase. We have identified in the silkmoth, Bombyx mori, copies of these elements which have inserted into sites outside the ribosomal DNA (rDNA) units. The 3' ends of all "non-rDNA" elements are identical to the elements within the 28S genes; however their 5' ends are often truncated. Each non-rDNA copy has inserted into sequences that exhibit similarity to their target sites in the 28S gene. We also demonstrate by genomic blot analysis of different strains of B. mori that insertions of R1 and R2 outside the rDNA units have been infrequent, while considerable turnover of elements has occurred within the rDNA locus. One race of B. mori has lost all copies of R1 from its rDNA units, while retaining normal levels of R2. The level of both R1 and R2 have significantly increased in a tissue culture line. These findings add considerable support to the model that R1 and R2 are retrotransposable elements that utilize sequence specific endonucleases in their integration into the genome.

Animals↗

PubMed1992

Retrotransposons and the evolution of mammalian gene expression.

Transposable elements, and retroviral-like elements in particular, are a rich potential source of genetic variation within a host's genome. Many mutations of endogenous genes in phylogenetically diverse organisms are due to insertion of elements that affect gene expression by altering the normal pattern of regulation. While few such associations are known to have been maintained over time, two recently elucidated examples suggest transposable elements may have a significant impact in evolution of gene expression. The first example, concerning the mouse sex-limited protein (Slp), clearly establishes that ancient retroviral enhancer sequences now confer hormonal dependence on the adjacent gene. The second example shows that within the human amylase gene family, salivary specific expression has arisen due to inserted sequences, deriving perhaps from a conjunction of two retrotransposable elements.

Amylases↗

PubMed1991

Properties of promoter regions of mdg1 Drosophila retrotransposon indicate that it belongs to a specific class of promoters.

A sequence 30 bp downstream from the start site of the Drosophila melanogaster retrotransposon mdg1 is shown to be responsible for correct and precise initiation of mdg1 RNA synthesis in combination with the RNA start-site sequence TCAGTT. A sequence-specific DNA binding protein is demonstrated to interact with the +30 sequence, and the efficient binding of this factor is necessary for in vivo transcriptional activity of the plasmid constructs containing mdg1 promoter fragments. The nucleotides -8/+34 of mdg1 represent a minimal promoter which is able to provide correct initiation of transcription by RNA polymerase II at basal levels. A comparison with properties of some other retrotransposable elements and several developmentally regulated cellular genes allows us to conclude that together they form a specific class of RNA polymerase II promoter. This promoter class characteristically lacks upstream sequences necessary for transcription initiation, such as TATA boxes, but requires a specific downstream promoter element within 40 bp downstream of the RNA start site. The level of transcription can, however, be modulated by upstream regulatory elements. The identified sequence-specific downstream initiation factor may be responsible for transcription initiation on promoters of some genes which belong to this class.

Animals↗

PubMed1991

A superfamily of Arabidopsis thaliana retrotransposons.

We describe a superfamily of Arabidopsis thaliana retrotransposable elements that consists of at least ten related families designated Ta1-Ta10. The Ta1 family has been described previously. Two genomic clones representing the Ta2 and Ta3 elements were isolated from an A. thaliana (race Landsberg erecta) lambda library using sequences derived from the reverse transcriptase region of Ta1 as hybridization probes. Nucleotide sequence analysis showed that the Ta1, Ta2 and Ta3 families share greater than 75% amino acid identity in pairwise comparisons of their reverse transcriptase and RNase H genes. In addition to Ta1, Ta2 and Ta3, we identified seven other related retrotransposon families in Landsberg erecta, Ta4-Ta10, using degenerate primers and the polymerase chain reaction to amplify a highly conserved region of retrotransposon-encoded reverse transcriptase. One to two copies of elements Ta2-Ta10 are present in the genomes of the A. thaliana races Landsberg erecta and Columbia indicating that the superfamily comprises at least 0.1% of the A. thaliana genome. The nucleotide sequences of the reverse transcriptase regions of the ten element families place them in the category of copia-like retrotransposons and phylogenetic analysis of the amino acid sequences suggests that horizontal transfer may have played a role in their evolution.

Amino Acid Sequence↗