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A novel tRNA species as an origin of short interspersed repetitive elements (SINEs). Equine SINEs may have originated from tRNA(Ser).

Short interspersed repetitive elements (SINEs) were isolated from the equine genome and characterized. The equine SINE (ERE-1) family has several features characteristic of tRNA-derived retroposons. The five members of the equine family of SINEs are approximately 230 nucleotides in length and terminate with a sequence rich in oligo(A). They are all flanked by direct repeats at the 5' and 3' ends, and such repeats are the hallmarks of retroposons. In addition, the ERE-1 family has a tRNA-related region, which is similar to tRNA(Ser) of Drosophila (65% identity). tRNA(Ser) is a novel tRNA with respect to the origin of SINEs and has not previously been recognized among the twenty tRNA-derived SINEs characterized to date. The members of the ERE-1 family were found to be distributed among five species in the genus Equus, and their amplification may have contributed to the genetic variability of their hosts during evolution.

Animals↗

Non-homologous recombination between Alu and LINE-1 repeats caused a 430-kb deletion in the dystrophin gene: a novel source of genomic instability.

Although large deletions in the dystrophin gene have been identified in more than two-thirds of Duchenne and Becker muscular dystrophy patients, the molecular mechanisms that lead to the generation of these deletions are largely unknown. Here, Alu and LINE-1 (L1) repetitive elements were shown to be present at one or other of the two ends, respectively, of a 430-kb deletion in the dystrophin gene. The breakpoint of the deletion, which stretches from exons 2 to 7, was defined more precisely by polymerase chain reaction (PCR) walking on introns 1 and 7. Finally, the region containing the breakpoint was amplified as a fragment of more than 10kb. Sequencing of the deletion endpoint revealed the presence of an Alu sequence in intron 1, 25 kb downstream from the 3' end of exon 1 that was joined directly to an L1 sequence in intron 7, 4.5kb downstream from the 3' end of exon 7. The deletion was calculated to be 430kb. To our knowledge, this is a novel recombination event joining non-homologous Alu and L1 repeats, and is the largest known intrachromosomal deletion that is thought to involve repetitive genetic elements. Sequence characteristics around the breakpoint are discussed.

Alu Elements↗

Correlation between alterations in nucleosomal organization of LINEs in the promoter of cytochrome P450 2B1/2 gene and induction of CYP 2B1/2B2 mRNA expression by phenobarbitone in rat liver.

Mammalian genome contains a high proportion of repetitive DNA with a sizeable fraction of Long Interspersed Nuclear Elements (LINEs). LINEs have been functionally implicated in the organization and evolution of mammalian genome. However, functions of LINEs in the promoter region and gene expression are poorly understood. Here, we report two small, conserved LINE sequences (3P and 5P) that occur as multiple copies of inverted repeats in the rat Cytochrome P450 2B1/2B2 (CYP 2B1/2) gene promoter. Using 3P or 5P as a single primer, the CYP 2B1/2 promoter DNA was amplified by PCR from the rat genome. Phenobarbitone (PB), a prototype xenobiotic drug, strongly induced CYP 2B1/2 mRNA expression in the rat liver. 3P and 5P LINE sequences showed an alteration in the nucleosomal organization in the CYP 2B1/2 promoter after 2, 4, and 6 h of PB induction, and the promoter was mostly devoid of nucleosomes during the induction. Reorganization of nucleosomes associated with these LINE sequences were strongly correlated with induction of CYP 2B1/2 mRNA expression by PB in vivo. Our results strongly suggest that these LINE sequences in CYP 2B1/2 gene promoter(s) may facilitate transcriptional activation of the gene(s) by PB through retention and reorganization of nucleosomes. This might be a novel function of LINEs in the mammalian genome that correlates the chromatin structure with gene expression during drug metabolism.

Animals↗

[Organization of nucleotide sequences in the genome of the sterlet Acipenser acipenser].

Three fractions of repeated sequences with different thermal stability after reassociation and zero time and single copy fractions as well were isolated from a sterlet (acipenser acipenser) genome. Repeated sequences with different thermal stabilities are organized as homogeneous families not reassociating with one another when being repeatedly annealed. These fractions consist of the similar kinetic components; the exception is the slowly reassociating component which is found only in the low temperature fraction. The sterlet repeated sequences were also fractionated according to their length on agarose A-50 columns. The long (no less than 1350 nucleotides) sequences are heterogeneous by extent of their divergency, some part of them being highly divergent and contain sequences that are homologous to repeated sequences with low thermal stability. A suggestion is made that long and short repeated sequences in the sterlet genome are partly shared. The short (about 400-600 nucleotides) repeated sequences in the sterlet genome are interspersed within single copy ones.

Animals↗

Isolation, characterization and chromosomal localization of a human pseudogene for hexokinase II.

A processed pseudogene for hexokinase II (HKII), the first such reported for a member of the hexokinase gene family, was isolated from a human genomic library by using a rat HKII cDNA as a probe. The pseudogene contains a region that is identical to the open reading frame of the human HKII cDNA at 97% of the nucleotide positions, but it contains several frameshift mutations, small deletions and insertions, and several stop codons. The human HKII pseudogene is located on the X chromosome and is integrated into a long interspersed nuclear repetitive DNA element (LINE). We estimate that this integration event occurred approximately 14-16 Myr (million years) ago.

Animals↗

Identification of a novel family of sequence repeats among prokaryotes.

The rapid increase in genomic sequences provides new opportunities for comparative genomics. In this report, we describe a novel family of repeat sequences that is present in Bacteria and Archaea but not in Eukarya. The repeat loci typically consisted of repetitive stretches of nucleotides with a length of 25 to 37 bp alternated by nonrepetitive DNA spacers of approximately equal size as the repeats. The nucleotide sequences and the size of the repeats were highly conserved within a species, but between species the sequences showed no similarity. Due to their characteristic structure, we have designated this family of repeat loci as SPacers Interspersed Direct Repeats (SPIDR). The SPIDR loci were identified in more than forty different prokaryotic species. Individual species such as Mycobacterium tuberculosis contain one SPIDR locus, while other species such as Methanococcus jannaschii contained up to 20 different loci. The number of repeats in a locus varies greatly from two repeats to several dozens of repeats. The SPIDR loci were flanked by a common 300-500-bp leader sequence, which appeared to be conserved within a species but not between species. The SPIDR locus of M. tuberculosis is extensively used for strain typing. The finding of SPIDR loci in other prokaryotes, including the pathogens Salmonella, Campylobacter, and Pasteurella may extend this surveillance to other species.

Archaea↗

Reverse transcriptase: mediator of genomic plasticity.

Reverse transcription has been an important mediator of genomic change. This influence dates back more than three billion years, when the RNA genome was converted into the DNA genome. While the current cellular role(s) of reverse transcriptase are not yet completely understood, it has become clear over the last few years that this enzyme is still responsible for generating significant genomic change and that its activities are one of the driving forces of evolution. Reverse transcriptase generates, for example, extra gene copies (retrogenes), using as a template mature messenger RNAs. Such retrogenes do not always end up as nonfunctional pseudogenes but form, after reinsertion into the genome, new unions with resident promoter elements that may alter the gene's temporal and/or spatial expression levels. More frequently, reverse transcriptase produces copies of nonmessenger RNAs, such as small nuclear or cytoplasmic RNAs. Extremely high copy numbers can be generated by this process. The resulting reinserted DNA copies are therefore referred to as short interspersed repetitive elements (SINEs). SINEs have long been considered selfish DNA, littering the genome via exponential propagation but not contributing to the host's fitness. Many SINEs, however, can give rise to novel genes encoding small RNAs, and are the migrant carriers of numerous control elements and sequence motifs that can equip resident genes with novel regulatory elements [Brosius J. and Gould S.J., Proc Natl Acad Sci USA 89, 10706-10710, 1992]. Retrosequences, such as SINEs and portions of retroelements (e.g., long terminal repeats, LTRs), are capable of donating sequence motifs for nucleosome positioning, DNA methylation, transcriptional enhancers and silencers, poly(A) addition sequences, determinants of RNA stability or transport, splice sites, and even amino acid codons for incorporation into open reading frames as novel protein domains. Retroposition can therefore be considered as a major pacemaker for evolution (including speciation). Retroposons, with their unique properties and actions, form the molecular basis of important evolutionary concepts, such as exaptation [Gould S.J. and Vrba E., Paleobiology 8, 4-15, 1982] and punctuated equilibrium [Elredge N. and Gould S.J. in Schopf T.J.M. (ed). Models in Paleobiology. Freeman, Cooper, San Francisco, 1972, pp. 82-115].

Animals↗

Physical mapping and identification of interspersed homologous sequences in the Trichoplusia ni granulosis virus genome.

A restriction fragment library representing 89.3% of the genome of Trichoplusia ni granulosis virus (TnGV) was constructed. The library consisted of 13 of the 16 BamHI fragments, 18 of the 22 EcoRI fragments, and 6 of the 27 PstI fragments. By restriction endonuclease and Southern blot analysis of cloned or genomic viral DNA fragments, a complete physical map of TnGV was constructed for BamHI, EcoRI, PstI and XhoI. Three interspersed homologous regions (ihs1-ihs3) were identified from hybridization experiments and sequenced. Each TnGV ihs has an approximate size of 400 bp and shows homology to the other two. The orientation of ihs2 is inverted relative to ihs1 and ihs3. TnGV ihs regions do not have repetitive motifs or palindromic sequences, in contrast to homologous regions (hrs) of nuclear polyhedrosis viruses (NPVs). The genomic locations of TnGV ihs1-ihs3, represented in percentage map units, were very similar to those of ihs sequences previously reported in Bombyx mori NPV, suggesting that the ihs may be a novel type of cis-acting element common among baculoviruses. Additionally, an inverted repeat sequence, having overlapping, multiple inverted repeats of 400 bp, was identified to the left of ihs3 on the linearized genome map of TnGV.

Animals↗

Structural organization and DNA methylation patterning within the mouse L1 family.

We have studied stable differences in patterns of DNA methylation seen in the repeated sequences of mouse cells. A cloned 1330-base pair fragment of mouse repetitive DNA (pFS-13) was used as a probe in Southern blotting experiments. Mouse spleen and L1210 lymphoma DNA appeared to be normally methylated at HpaII sites probed by this sequence. Friend erythroleukemia cell, and Sp2 cell DNA both showed an abnormal banding pattern in HpaII digests. Hybridization in situ to metaphase chromosomes showed that probed sequences were broadly interspersed along the arms of each mouse chromosome. The DNA sequence of the 1330-base pair insert in the clone was determined; a copy of the R sequence of L1 was found at its 5' end. Walking experiments using M13 subclones from pFS-13 permitted the construction of a map for d(pCCGG) sites at the 3' end of the mouse L1 family. The unmethylated d(pCCGG) sites in Sp2 and Friend cells could then be assigned to polymorphic-repeated sequence groups within L1, homologous to the region spanned by BAM5 and R. Since there are several thousand copies of each of the fragments seen in autoradiographs, these sequences must possess a common methylation state at many genomic locations. Concerted (nonrandom) hypomethylation of certain subfamilies of L1 appears to be a stable characteristic of several cell lineages. These findings suggest that certain L1 families possess commonalities that permit and perhaps require differential DNA methylation in established cell lineages.

Animals↗

Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC).

A systematic search by Southern blot analysis in a cohort of 439 hereditary nonpolyposis colorectal cancer (HNPCC) families for genomic rearrangements in the main mismatch repair (MMR) genes, namely, MSH2, MLH1, MSH6, and PMS2, identified 48 genomic rearrangements causative of this inherited predisposition to colorectal cancer in 68 unrelated kindreds. Twenty-nine of the 48 rearrangements were found in MSH2, 13 in MLH1, 2 in MSH6, and 4 in PMS2. The vast majority were deletions, although one previously described large inversion, an intronic insertion, and a more complex rearrangement also were found. Twenty-four deletion breakpoints have been identified and sequenced in order to determine the underlying recombination mechanisms. Most fall within repetitive sequences, mainly Alu repeats, in agreement with the differential distribution of deletions between the MSH2 and MLH1 genes: the higher number and density of Alu repeats in MSH2 corresponded with a higher incidence of genomic rearrangement at this disease locus when compared with other MMR genes. Long interspersed nuclear element (LINE) repeats, relatively abundant in, for example, MLH1, did not seem to contribute to the genesis of the deletions, presumably because of their older evolutionary age and divergence among individual repeat units when compared with short interspersed nuclear element (SINE) repeats, including Alu repeats. Moreover, Southern blot analysis of the introns and the genomic regions flanking the MMR genes allowed us to detect 6 novel genomic rearrangements that left the coding region of the disease-causing gene intact. These rearrangements comprised 4 deletions upstream of the coding region of MSH2 (3 cases) and MSH6 (1 case), a 2-kb insertion in intron 7 of PMS2, and a small (459-bp) deletion in intron 13 of MLH1. The characterization of these genomic rearrangements underlines the importance of genomic deletions in the etiology of HNPCC and will facilitate the development of PCR-based tests for their detection in diagnostic laboratories.

Adaptor Proteins, Signal Transducing↗

Analysis of rat repetitive DNA sequences.

Parameters of repetitive sequence organization have been measured in the rat genome. Experiments using melting, hydroxylapatite binding, and single strand specific nuclease digestion have been used to measure the number, length, and arrangement of repeated DNA sequences. Renaturation and melting or S1 nuclease digestion of 1.0 kbp DNA fragment show about 20% of rat DNA sequences are 3000-fold repeated. Renatured duplexes from 4.0 kbp DNA fragments display two repetitive size fractions after nuclease digestion. About 60% of the repeated sequences are 0.2-0.4 kbp long while the remainder are longer than 1.5 kbp. The arrangement of the repeated sequences has been measured by hydroxylapatite fractionation of DNA fragments of varying lengths bearing a repeated sequence. Repeated DNA sequences are interspersed among 2.5 kbp long nonrepeated sequences throughout more than 70% of the rat genome. There are approximately 350 different 3000-fold short repeated sequences in the rat interspersed among 600,000 nonrepeated DNA sequences.

Animals↗

Complete nucleotide sequence of the rabbit beta-like globin gene cluster: insights into evolution and regulation.

The general pattern of sequence matches between the beta-like globin gene clusters of rabbits and humans are summarized in Fig. 7. The regions of matching sequences are shaded, and it can be seen that the matches extend from one end of the gene cluster to the other. This provides very strong evidence that the ancestral species had a gene cluster containing the parents to all the contemporary beta-like globin genes in the same arrangement that we observe today. Much of the intergenic DNA has been diverging at a rate consistent with neutral drift, but smaller regions can be detected that are diverging more slowly and which are good candidates for functional sequences. The comparisons between this same gene cluster in mouse and humans show many fewer matches in the intergenic regions (Shehee et al., 1989), indicating either an earlier split between rodents and primates or a faster rate of divergence in rodents. However, this more divergent sequence may prove particularly valuable in a search for functional sequences, especially in a three-way alignment between the sequenced gene clusters. Every repetitive element in homologous segments of the rabbit and human beta-like globin gene clusters interrupts the homology; no repeat is in the same position in both species. Hence all the repeats have been inserted into the gene clusters after the divergence between lagomorphs and primates. This is true even for the L1 repeats, which are very similar between species in their ORF regions. This pattern of interspersion of repeats in long orthologous regions shows that many members of the LINE and SINE families are recent additions to the genome, and that these repeats are in fact transposable elements. It is easy to imagine negative and neutral effects of the expansion and transpositions of these repeat families, but some positive effect has not been ruled out. One of the intriguing inferences from the observations about repeats is that the ancestral gene cluster may not have contained repetitive elements. If it did, then those repeats have been completely replaced by different repeats independently in lagomorphs and primates.

Animals↗

A novel group of families of short interspersed repetitive elements (SINEs) in Xenopus: evidence of a specific target site for DNA-mediated transposition of inverted-repeat SINEs.

We have isolated from Xenopus borealis members of a family of short interspersed repetitive elements (SINEs) that we have termed Xbr. Xbr elements are also present in other Xenopus genomes and are typically framed by 46 bp terminal inverted repeats (TIRs). These TIRs and those of two previously described families of inverted-repeat SINEs from X. laevis begin with the sequence TTAAAGGRR. Knowledge of this consensus, termed the T2 motif, allowed us to define four previously uncharacterized families of inverted-repeat SINEs from Xenopus database sequences. We estimate that the group of seven SINE families that possess the T2 motif accounts for about 10% of all X. laevis SINEs. Novel evidence for the transposition of inverted-repeat SINEs is provided: (1) by examples of the presence/absence of T2 elements at corresponding locations in either duplicated genes or pseudotetraploid gene homeologues; and (2) by the existence of contiguous elements from different T2 families that are joined precisely by their TIRs. These examples provide novel evidence for a DNA-mediated mechanism of T2 element transposition. They also show that the tetranucleotide, TTAA, which flanks integrated elements on both sides and is present once at unoccupied sites, is the obligate target site for T2 insertion. The use of a specific sequence as a target site for SINE insertion is unexpected, although such specificity is exhibited by a limited number of larger transposable elements that encode their own transposase. The clear evidence for DNA-mediated transposition provided by T2 elements demonstrates that the evolution and maintenance of SINE families in vertebrate genomes results from two distinctive mechanisms.

Animals↗

Repetitive nucleotide sequence insertions into a novel calmodulin-related gene and its processed pseudogene.

A gene containing a transposon-like human repeat element, called THE 1, has been isolated and characterized. The gene, termed T+, encodes a polypeptide resembling known calcium-binding proteins. The THE 1 element is present in the 3'-untranslated region of its message. The cDNA clone corresponding to the gene's mRNA product led to the identification of this gene. A processed RNA pseudogene related to the authentic gene has also been isolated. In addition to intron processing, this pseudogene differs from the gene in that it contains an interspersed Alu repeat instead of a THE 1 element in the 3'-untranslated region. Thus, we compare a site containing a THE 1 element to an ancestrally related transposon-less target site. The comparison suggests a retroviral-related mechanism of THE 1 insertion. This system is unusual in that the parent gene is associated with three distinct retrotransposition events: the parent gene was converted to a processed RNA pseudogene, an Alu repeat inserted into the pseudogene, and a THE 1 element inserted into the parent gene.

Amino Acid Sequence↗

Insertions and deletions are male biased too: a whole-genome analysis in rodents.

It is presently accepted that, in mammals, due to the greater number of cell divisions in the male germline than in the female germline, nucleotide substitutions occur more frequently in males. The data on mutation bias in insertions and deletions (indels) are contradictory, with some studies indicating no sex bias and others indicating either female or male bias. The sequenced rat and mouse genomes provide a unique opportunity to investigate a potential sex bias for different types of mutations. Indeed, mutation rates can be accurately estimated from a large number of orthologous loci in organisms similar in generation time and in the number of germline cell divisions. Here we compare the mutation rates between chromosome X and autosomes for likely neutral sites in eutherian ancestral interspersed repetitive elements present at orthologous locations in the rat and mouse genomes. We find that small indels are male biased: The male-to-female mutation rate ratio (alpha) for indels in rodents is approximately 2. Similarly, our whole-genome analysis in rodents indicates an approximately twofold excess of nucleotide substitutions originating in males over that in females. This is the same as the male-to-female ratio of the number of germline cell divisions in rat and mouse. Thus, this is consistent with nucleotide substitutions and small indels occurring primarily during DNA replication.

Animals↗

Chromosome rearrangement by ectopic recombination in Drosophila melanogaster: genome structure and evolution.

Ectopic recombination between interspersed repeat sequences generates chromosomal rearrangements that have a major impact on genome structure. A survey of ectopic recombination in the region flanking the white locus of Drosophila melanogaster identified 25 transposon-mediated rearrangements from four parallel experiments. Eighteen of the 25 were generated from females carrying X chromosomes heterozygous for interspersed repeat sequences. The cytogenetic and molecular analyses of the rearrangements and the parental chromosomes show: (1) interchromosomal and intrachromosomal recombinants are generated in about equal numbers; (2) ectopic recombination appears to be a meiotic process that is stimulated by the interchromosomal effect to about the same degree as regular crossing over; (3) copies of the retrotransposon roo were involved in all of the interchromosomal exchanges; some copies were involved much more frequently than others in the target region; (4) homozygosis for interspersed repeat sequences and other sequence variations significantly reduced ectopic recombination.

Animals↗

A general model for the surface glycoproteins of HIV and other retroviruses.

A hypothetical model of the surface (SU) glycoproteins of human immunodeficiency virus (HIV) and other retroviruses is proposed. The model is based on repetition of a limited number of sequence motifs conserved within the virus family; similarities in biological, immunological, or genetic properties; as well as the tendency for regions of dissimilar sequence to share protein structures predicted by computer algorithms. It is proposed that the protein consists of three structural and functional domains interspersed by relatively conserved interdomain regions. For each retrovirus, these amino-terminal, central, and carboxy-terminal domains may play different roles in binding, postbinding events, and the immune response to viral infection.

Amino Acid Sequence↗