Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Alu elements”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources
PubMed1989

Independent insertion of Alu elements in the human ribosomal spacer and their concerted evolution.

A 2,700-bp segment of human ribosomal DNA (rDNA) spacer upstream of the rRNA promoter contains a set of four Alu elements, two in the direction of rRNA transcription and two in the opposite orientation. We report and compare the sequences of these Alu elements found in three rDNA clones and seek to determine the origin of the cluster, either from a single insertion followed by duplications or from multiple simultaneous or independent insertions. The high (20%-27%) divergence among members of a set and the lack of similarity/complementarity of sequences flanking different members of the set demonstrate the independent insertion of each of the four Alu elements into A-rich sequences on the appropriate strand of the rDNA. We also demonstrate that the Alu sets found in different rDNA repeats are subject to concerted evolution, yielding divergences of only 0.4%-3% between Alu elements in equivalent positions. However, the pairs of adjacent similarly oriented Alu elements do not show reduced divergence, indicating that there is no recombination or gene conversion between similarly oriented but not equivalently positioned Alu elements. Finally, crossing-over must occur in the rDNA junction region between Alu element 3 and the nonribosomal sequences at the telomere end of the acrocentric chromosome, so that the Alu elements of the terminal rDNA repeats and the terminal repeats themselves evolve in concert with the rDNA repeats located internally in the tandem array.

Base Sequence↗
PubMed2006

Estimating the retrotransposition rate of human Alu elements.

Mobile elements such as Alu repeats have substantially altered the architecture of the human genome, and de novo mobile element insertions sometimes cause genetic disorders. Previous estimates for the retrotransposition rate (RR) of Alu elements in humans of one new insertion every approximately 100-125 births were developed prior to the sequencing of the human and chimpanzee genomes. Here, we used two independent methods (based on the new genomic data and on disease-causing de novo Alu insertions) to generate refined Alu RR estimates in humans. Both methods consistently yielded RR on the order of one new Alu insertion every approximately 20 births, despite the fact that the evolutionary-based method represents an average RR over the past approximately 6 million years while the mutation-based method better reflects the current-day RR. These results suggest that Alu elements retrotranspose at a faster rate in humans than previously thought, and support the potential of Alu elements as mutagenic factors in the human genome.

Alu Elements↗
PubMed1993

An Alu element retroposition in two families with Huntington disease defines a new active Alu subfamily.

Alu repetitive elements represent the most common short interspersed elements (SINEs) found in primates, with an estimated 500,000 members in the haploid human genome. Considerable evidence has accumulated that these elements have dispersed in the genome by active transcription followed by retroposition, and that this process is ongoing. Sequence variation between the individual elements has lead to the hierarchical classification of Alu repeats into families and subfamilies. Young subfamilies that are still being actively transposed are of considerable interest, and the identification of one such subfamily (designated 'PV') has lead to the hypothesis that the most recent retroposition events are due to a single master Alu source gene. In the course of our search for the gene causing Huntington disease, we have detected an Alu retroposition event in two families. Sequence analysis demonstrates that this Alu element is not a member of the PV subfamily, but is similar to 5 other Alu elements in the GenBank database. Together, these Alu elements, all of which contain a 7 base-pair internal duplication, define a distinct subfamily, designated as the Sb2 subfamily, providing evidence for a second actively retroposing Alu source gene. These data provide support for multiple source genes for Alu retroposition in the human genome.

Base Sequence↗
PubMed1996

A naturally occurring T14A11 tract blocks nucleosome formation over the human neurofibromatosis type 1 (NF1)-Alu element.

The nature of chromatin organization over Alu repetitive elements is of interest with respect to the maintenance of their transcriptional silencing as well as their potential to influence local chromatin structure. We previously demonstrated that the pattern of nucleosomal organization over Alu elements in native chromatin is specific and similar to the pattern observed with an in vitro reconstituted Alu template. This pattern, distinguished by a nucleosome centered over the 5 -end of the Alu element, is associated with repression of polymerase III-dependent transcription in vitro (Englander, E. W., Wolffe, A. P., and Howard, B. H. (1993) J. Biol. Chem. 268, 19565-19573; Englander, E. W., and Howard, B. H. (1995) J. Biol. Chem. 270, 10091-10096). In the current study, additional templates representing both evolutionarily old and young Alu subfamilies were found to direct a similar pattern of nucleosome assembly, consistent with the view that nucleosome positioning in vitro is shared by a majority of Alus. We discovered however, that the specific nucleosome positioning pattern was disrupted over one member of a young Alu subfamily, which recently transposed immediately downstream to a T14A11 sequence in the neurofibromatosis type 1 locus (Wallace, M. R., Andersen, L. B., Saulino, A. M., Gregory, P. E., Glover, T. W., and Collins, F. S. (1991) Nature 353, 864-866). Upon removal of this sequence motif, the expected pattern of assembly was restored to the neurofibromatosis type 1-Alu template. This finding indicates that, at least in vitro, certain sequences can override the propensity for positioning nucleosomes that is inherent to Alu elements. The finding also raises the possibility that a similar situation may occur in vivo, with potential implications for understanding mechanisms by which certain Alu elements may evade chromatin-mediated transcriptional silencing.

Animals↗
PubMed2004

Evolution and distribution of RNA polymerase II regulatory sites from RNA polymerase III dependant mobile Alu elements.

BACKGROUND: The primate-specific Alu elements, which originated 65 million years ago, exist in over a million copies in the human genome. These elements have been involved in genome shuffling and various diseases not only through retrotransposition but also through large scale Alu-Alu mediated recombination. Only a few subfamilies of Alus are currently retropositionally active and show insertion/deletion polymorphisms with associated phenotypes. Retroposition occurs by means of RNA intermediates synthesised by a RNA polymerase III promoter residing in the A-Box and B-Box in these elements. Alus have also been shown to harbour a number of transcription factor binding sites, as well as hormone responsive elements. The distribution of Alus has been shown to be non-random in the human genome and these elements are increasingly being implicated in diverse functions such as transcription, translation, response to stress, nucleosome positioning and imprinting. RESULTS: We conducted a retrospective analysis of putative functional sites, such as the RNA pol III promoter elements, pol II regulatory elements like hormone responsive elements and ligand-activated receptor binding sites, in Alus of various evolutionary ages. We observe a progressive loss of the RNA pol III transcriptional potential with concomitant accumulation of RNA pol II regulatory sites. We also observe a significant over-representation of Alus harboring these sites in promoter regions of signaling and metabolism genes of chromosome 22, when compared to genes of information pathway components, structural and transport proteins. This difference is not so significant between functional categories in the intronic regions of the same genes. CONCLUSIONS: Our study clearly suggests that Alu elements, through retrotransposition, could distribute functional and regulatable promoter elements, which in the course of subsequent selection might be stabilized in the genome. Exaptation of regulatory elements in the preexisting genes through Alus could thus have contributed to evolution of novel regulatory networks in the primate genomes. With such a wide spectrum of regulatory sites present in Alus, it also becomes imperative to screen for variations in these sites in candidate genes, which are otherwise repeat-masked in studies pertaining to identification of predisposition markers.

Alu Elements↗
PubMed2005

Interindividual variability and parent of origin DNA methylation differences at specific human Alu elements.

We investigated the CpG methylation of 19 specific members of Alu sub-families in human DNA isolated from whole blood, using an assay based on methylation-sensitive restriction endonuclease digestion of genomic DNA and 'hot-stop' polymerase chain reaction. We found significant interindividual variability in the level of methylation for specific Alu elements among the members of 48 three-generation families. Surprisingly, some of the elements also displayed quantitative parent of origin methylation differences; i.e. the mean level of methylation differed significantly when the insertions were transmitted through paternal versus maternal meiosis. Bisulfite sequence analysis of individual elements at such loci suggests, further, that maternal and paternal elements differ in the propensity of particular CpG sites to become unmethylated. Some individuals who exhibited high levels of methylation at specific Alu elements came from families in which more than one member also exhibited abnormal patterns of methylation at the differentially methylated regions of the IGF2/H19 or IGF2R loci, suggesting that there may be heritable differences between individuals in the fidelity with which allelic DNA methylation differences are established or maintained. Quantitative parental origin differences in methylation were identified only for Alu elements that lie in sub-telomeric or sub-centromeric bands of human chromosomes, whereas those assayed at intermediate positions did not exhibit any significant differences. The centromere/telomere restricted location of the methylation differences and the fact that none of these differences occur in regions of chromosomes known to contain transcriptionally imprinted genes suggest that maternal/paternal epigenetic modifications may play additional roles in processes other than transcriptional control.

Alu Elements↗
PubMed2002

Active Alu element "A-tails": size does matter.

Long and short interspersed elements (LINEs and SINEs) are retroelements that make up almost half of the human genome. L1 and Alu represent the most prolific human LINE and SINE families, respectively. Only a few Alu elements are able to retropose, and the factors determining their retroposition capacity are poorly understood. The data presented in this paper indicate that the length of Alu "A-tails" is one of the principal factors in determining the retropositional capability of an Alu element. The A stretches of the Alu subfamilies analyzed, both old (Alu S and J) and young (Ya5), had a Poisson distribution of A-tail lengths with a mean size of 21 and 26, respectively. In contrast, the A-tails of very recent Alu insertions (disease causing) were all between 40 and 97 bp in length. The L1 elements analyzed displayed a similar tendency, in which the "disease"-associated elements have much longer A-tails (mean of 77) than do the elements even from the young Ta subfamily (mean of 41). Analysis of the draft sequence of the human genome showed that only about 1000 of the over one million Alu elements have tails of 40 or more adenosine residues in length. The presence of these long A stretches shows a strong bias toward the actively amplifying subfamilies, consistent with their playing a major role in the amplification process. Evaluation of the 19 Alu elements retrieved from the draft sequence of the human genome that are identical to the Alu Ya5a2 insert in the NF1 gene showed that only five have tails with 40 or more adenosine residues. Sequence analysis of the loci with the Alu elements containing the longest A-tails (7 of the 19) from the genomes of the NF1 patient and the father revealed that there are at least two loci with A-tails long enough to serve as source elements within our model. Analysis of the A-tail lengths of 12 Ya5a2 elements in diverse human population groups showed substantial variability in both the Alu A-tail length and sequence homogeneity. On the basis of these observations, a model is presented for the role of A-tail length in determining which Alu elements are active.

3' Flanking Region↗
PubMed1998

Comprehensive Sequence Analyses of 5' Flanking Regions of Primate Alu Elements.

Retrotransposons have been generally known to integrate randomly into host genomes. Jurka (Proc. Natl. Acad. Sci. USA 94: 1872-1877, 1977), however, showed consensus sequence patterns at integration sites of certain mammalian retrotransposons, and suggested involvement of sequence specific enzymes that mediate integration. We have conducted comprehensive sequence analyses of 5' flanking regions of primate Alu elements. In contrast to the small but clean data set Jurka (1977) used, (1) larger number of samples were used, (2) wider region of 5' end of Alu elements was analyzed, and (3) comparisons were made among different subfamilies for comprehensive analyses in order to identify characteristic sequence pattern(s) preceding 5' end of Alu elements. The nucleotide occurrences at each position within 500 bases of 5' end of Alus were counted to obtain profiles. Information content at each nucleotide position in the same region was, then, computed. Distinctive difference in the nucleotide composition and information content values that divides the region into two was observed. The region between -20 and 5' end of Alu elements is found to be highly adenine-rich and shows significantly higher information content values compared to the rest of the region, implying the existence of certain characteristic sequence pattern in this region. Also, younger subfamilies of Alu elements show higher information content values than older subfamilies. This implies that certain characteristic sequence pattern already existed in the region between -20 and 5' end of Alu elements at the time of Alu integration, and accumulation of mutation in the course of time resulted in the less distinctive sequence pattern in older sequences. Frequencies of all possible triplets (total of 64) were measured in the same region in order to identify characteristic sequence pattern(s). Observation that frequencies of triplets aaa, taa and tta in the 5' flanking sequences were high is consistent with Jurka (1977). Frequencies of some other triplets such as gaa, caa, aac, ctt, gtt, atg, etc. which do not comprise the primary candidates for the nick site in Jurka (1977) also show significantly high frequencies.

Journal Article↗
PubMed1995

Adenovirus type 2 preferentially stimulates polymerase III transcription of Alu elements by relieving repression: a potential role for chromatin.

The number of Alu transcripts that accumulate in HeLa and other human cells is normally very low; however, infection with adenovirus type 5 increases the expression of Alu elements dramatically, indicating that the potential for polymerase III (pol III)-dependent Alu transcription in vivo is far greater than generally observed (B. Panning and J.R. Smiley, Mol. Cell. Biol. 13:3231-3244, 1993). In this study, we employed nuclear run-on in combination with a novel RNase H-based assay to investigate transcription from uninfected and adenovirus type 2-infected nuclei, as well as genomic DNAs from uninfected and infected cells. When performed in the presence of excess uninfected nuclear extract, such assays revealed that (i) the vast majority of transcriptionally competent Alu elements in nuclei are masked from the pol III transcriptional machinery and (ii) the induction of Alu expression upon adenovirus infection can be largely accounted for by an increased availability of these elements to the pol III transcription machinery. We also investigated the role of H1 histone for silencing of Alu genes and, in comparison, mouse B2 repetitive elements. Depletion of H1 led to an approximately 17-fold activation of B2 repetitive elements but did not change Alu transcription relative to that of constitutively expressed 5S rRNA genes. These results are consistent with the view that Alu repeats are efficiently sequestered by chromatin proteins, that such masking cannot be accounted for by nonspecific H1-dependent repression, and that adenovirus infection at least partially overrides the repressive mechanism(s).

3T3 Cells↗
PubMed1995

Nucleosome positioning by human Alu elements in chromatin.

Alu sequences are interspersed throughout the genomes of primate cells, occurring singly and in clusters around RNA polymerase II-transcribed genes. Because these repeat elements are capable of positioning nucleosomes in in vitro reconstitutes (Englander, E. W., Wolffe, A. P., and Howard, B. H. (1993) J. Biol. Chem. 268, 19565-19573), we investigated whether they also influence in vivo chromatin structure. When assayed collectively using consensus sequence probes and native chromatin as template, Alu family members were found to confer rotational positioning on nucleosomes or nucleosome-like particles. In particular, a 10-base pair pattern of DNase I nicking that spanned the RNA polymerase III box A promoter motif extended upstream to cover diverse 5'-flanking sequences, suggesting that Alu repeats may influence patterns of nucleosome formation over neighboring regions. Computational analysis of a set of naturally occurring Alu sequences indicated that nucleosome positioning information is intrinsic to these elements. Inasmuch as local chromatin organization influences gene expression, the capacity of Alu sequences to affect chromatin structure as demonstrated here may help to clarify some features of these elements.

Base Sequence↗
PubMed2002

Active Alu elements are passed primarily through paternal germlines.

Repetitive elements are distributed non-randomly in the human genome but, as reviewed in this paper, biological processes underlying the observed patterns appear to be complex and remain relatively obscure. Recent findings indicate that chromosomal distribution of Alu retroelements deposited in the past is different from the distribution of Alu elements that continue to be inserted in human population. These active elements from AluY sub(sub)families are the major focus of this paper. In particular, we analyzed chromosomal proportions of 19 AluY subfamilies, of which nine are reported for the first time in this paper. These 19 subfamilies contain over 80% of Alu elements that are polymorphic in the human genome. The chromosomal density of these most recent Alu insertions is around three times higher on chromosome Y than on chromosome X and over two times higher than the average density for all human autosomes. Based on this observation and other data we propose that active Alu elements are passed through paternal germlines. There is also some evidence that a small fraction of active Alu elements from less abundant subfamilies can be retroposed in female germlines or in the early embryos. Finally, we propose that the origin of Alu subfamilies in human populations may be related to evolution of chromosome Y.

Base Sequence↗
PubMed2004

Widespread RNA editing of embedded alu elements in the human transcriptome.

More than one million copies of the approximately 300-bp Alu element are interspersed throughout the human genome, with up to 75% of all known genes having Alu insertions within their introns and/or UTRs. Transcribed Alu sequences can alter splicing patterns by generating new exons, but other impacts of intragenic Alu elements on their host RNA are largely unexplored. Recently, repeat elements present in the introns or 3'-UTRs of 15 human brain RNAs have been shown to be targets for multiple adenosine to inosine (A-to-I) editing. Using a statistical approach, we find that editing of transcripts with embedded Alu sequences is a global phenomenon in the human transcriptome, observed in 2674 ( approximately 2%) of all publicly available full-length human cDNAs (n = 128,406), from >250 libraries and >30 tissue sources. In the vast majority of edited RNAs, A-to-I substitutions are clustered within transcribed sense or antisense Alu sequences. Edited bases are primarily associated with retained introns, extended UTRs, or with transcripts that have no corresponding known gene. Therefore, Alu-associated RNA editing may be a mechanism for marking nonstandard transcripts, not destined for translation.

Alternative Splicing↗
PubMed2006

Alu elements contain many binding sites for transcription factors and may play a role in regulation of developmental processes.

BACKGROUND: The human genome contains over one million Alu repeat elements whose distribution is not uniform. While metabolism-related genes were shown to be enriched with Alu, in structural genes Alu elements are under-represented. Such observations led researchers to suggest that Alu elements were involved in gene regulation and were selected to be present in some genes and absent from others. This hypothesis is gaining strength due to findings that indicate involvement of Alu elements in a variety of functions; for example, Alu sequences were found to contain several functional transcription factor (TF) binding sites (BSs). We performed a search for new putative BSs on Alu elements, using a database of Position Specific Score Matrices (PSSMs). We searched consensus Alu sequences as well as specific Alu elements that appear on the 5 Kbp regions upstream to the transcription start site (TSS) of about 14000 genes. RESULTS: We found that the upstream regions of the TSS are enriched with Alu elements, and the Alu consensus sequences contain dozens of putative BSs for TFs. Hence several TFs have Alu-associated BSs upstream of the TSS of many genes. For several TFs most of the putative BSs reside on Alu; a few of these were previously found and their association with Alu was also reported. In four cases the fact that the identified BSs resided on Alu went unnoticed, and we report this association for the first time. We found dozens of new putative BSs. Interestingly, many of the corresponding TFs are associated with early markers of development, even though the upstream regions of development-related genes are Alu-poor, compared with translational and protein biosynthesis related genes, which are Alu-rich. Finally, we found a correlation between the mouse B1 and human Alu densities within the corresponding upstream regions of orthologous genes. CONCLUSION: We propose that evolution used transposable elements to insert TF binding motifs into promoter regions. We observed enrichment of biosynthesis genes with Alu-associated BSs of developmental TFs. Since development and cell proliferation (of which biosynthesis is an essential component) were proposed to be opposing processes, these TFs possibly play inhibitory roles, suppressing proliferation during differentiation.

Alu Elements↗
PubMed1993

Nucleosome interactions with a human Alu element. Transcriptional repression and effects of template methylation.

Alu interspersed repetitive elements possess internal RNA polymerase III promoters which are strongly transcribed in vitro, yet these elements are nearly silent in somatic cells. To examine whether repression by chromatin proteins could contribute to the low level of Alu expression, a conserved Alu element from the fourth intron of the human alpha-fetoprotein gene was reconstituted with purified octamer or tetramer particles. Analysis of reconstitutes revealed that this Alu element directed translational and rotational positioning of octamers as well as tetramers. In vitro transcription experiments with reconstituted templates demonstrated that RNA polymerase III-dependent transcription of the Alu element was profoundly repressed by positioned octamer particles. Furthermore, complete CpG methylation of this template enhanced the capacity of tetramers to repress transcription.

Animals↗
PubMed2005

Chromosomal translocation mechanisms at intronic alu elements in mammalian cells.

Repetitive elements comprise nearly half of the human genome. Chromosomal rearrangements involving these elements occur in somatic and germline cells and are causative for many diseases. To begin to understand the molecular mechanisms leading to these rearrangements in mammalian cells, we developed an intron-based system to specifically induce chromosomal translocations at Alu elements, the most numerous family of repetitive elements in humans. With this system, we found that when double-strand breaks (DSBs) were introduced adjacent to identical Alu elements, translocations occurred at high frequency and predominantly arose from repair by the single-strand annealing (SSA) pathway (85%). With diverged Alu elements, translocation frequency was unaltered, yet pathway usage shifted such that nonhomologous end joining (NHEJ) predominated as the translocation pathway (93%). These results emphasize the fluidity of mammalian DSB repair pathway usage. The intron-based system is highly adaptable to addressing a number of issues regarding molecular mechanisms of genomic rearrangements in mammalian cells.

Alu Elements↗
PubMed1996

Chromosomal stabilisation by a subtelomeric rearrangement involving two closely related Alu elements.

We have characterised a subtelomeric rearrangement involving the short arm of chromosome 16 that gives rise to alpha-thalassaemia by deleting the major, remote regulatory element controlling alpha-globin expression. The chromosomal breakpoint lies in an Alu family repeat located only approximately 105 kb from the 16p subtelomeric region. The broken chromosome has been stabilised with a newly positioned telomere acquired by recombination between this 16p Alu element and a closely related subtelomeric Alu element of the Sx subfamily. It seems most likely that this abnormal chromosome has been rescued by the mechanism of telomere capture which may reflect a more general process by which subtelomeric sequences are normally dispersed between chromosomal ends.

Adolescent↗
PubMed2000

Alu elements support independent origin of prosimian, platyrrhine, and catarrhine Mhc-DRB genes.

The primate major histocompatibility complex (Mhc) genes fall into two classes and each of the classes into several families. Of the class II families, the DRB family has a long and complex evolutionary history marked by gene turnover, rearrangement, and molecular convergence. Because the history is not easily decipherable from sequences alone, Alu element insertions were used as cladistic markers to support the surmised phylogenetic relationships among the DRB genes. Intron 1 segments of 24 DRB genes from five platyrrhine species and five DRB genes from three prosimian species were amplified by PCR and cloned, and the amplification products were sequenced or PCR-typed for Alu repeats. Three Alu elements were identified in the platyrrhine and four in the prosimian DRB genes. One of the platyrrhine elements (Alu50J) is also found in the Catarrhini, whereas the other two (Alu62Sc, Alu63Sc) are restricted to the New World monkeys. Similarly, the four prosimian elements are found only in this taxon. This distribution of Alu elements is consistent with the phylogeny of the DRB genes as determined from their intron 1 sequences in an earlier and the present study. It contradicts the exon 2-based phylogeny and thus corroborates the conclusion that the evolution of DRB exon 2 sequences is, to some extent, shaped by molecular convergence. Taken together, the data indicate that each of the assemblages of DRB genes in prosimians, platyrrhines, and catarrhines is derived from a separate ancestral gene.

Alu Elements↗