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PubMed2006

Identification of Alu elements mediating a partial PMP22 deletion.

Hereditary neuropathy with liability to pressure palsies (HNPP) is most frequently caused by deletion of a 1.4-Mb region in chromosome 17p11.2-12 including the peripheral myelin protein 22 (PMP22) gene. Smaller deletions partially affecting the PMP22 gene are less frequently observed. We identified in a HNPP patient a deletion of the 5' region of PMP22 including non-coding exon 1, coding exons 2 and 3, whereas, exons 4 and 5 were present. PMP22 exon 3- and 4-specific qPCR resulted in a deletion of one exon 3 allele but in the presence of 2 exon 4 alleles. SNP analysis revealed the presence of heterozygosity for PMP22 coding exons 4 and 5. Finally, MLPA specific for the CMT1A region defined this deletion for the entire 5' region of PMP22 (exons 1, 2 and 3). These partial HNPP deletions may be missed by other techniques, e.g., STR marker analysis. Alu elements have been reported to mediate non-allelic recombination events. Bioinformatic analysis revealed 12 Alu elements flanking in close neighbourhood the estimated 40-kb deletion region as candidates for recombination events. PCR primers were designed to identify a breakpoint-spanning product including the respective Alu elements. PCR-driven identification of a junction fragment was successful with AluJo-AluSq and AluYb9-AluSq specific primer pairs comprising the same intronic region of PMP22. Sequence analysis of these breakpoint-overlapping PCR fragments revealed a 29-bp motif including a chi-like sequence (GCTGG) present both in the AluYb9 and the AluSq element. These data confirm that low-copy repeats (LCRs) mediate non-allelic homologous recombinations (NAHR).

Alu Elements↗
PubMed2000

An Alu element from the K18 gene confers position-independent expression in transgenic mice.

We have identified a 323-base pair fragment of the 5'-flanking sequence of the K18 gene, which confers position-independent and copy number-dependent expression on two heterologous transgenes. This fragment is composed primarily of an Alu repetitive element. Its activity in mice is correlated with its RNA polymerase III promoter activity and its orientation-dependent ability to inhibit potential transcriptional interference in a transfection assay. However, the activity of the Alu element is not correlated with its enhancer blocking activity, a characteristic of insulator elements. In addition, this Alu element did not block the suppressive effect of co-injecting mouse alpha satellite DNA with the transgene. This Alu element is likely responsible for at least part of the protective effects of the sequences flanking the K18. These results suggest that transcriptionally active Alu elements may eliminate transcriptional interference of neighboring genes. This Alu element is one component of the locus control region associated with the K18 gene. Other Alu repetitive elements may also function to define regulatory domains.

Alkaline Phosphatase↗
PubMed1996

Specific binding sites for a pol III transcriptional repressor and pol II transcription factor YY1 within the internucleosomal spacer region in primate Alu repetitive elements.

Alu interspersed repetitive elements possess internal RNA polymerase III promoters that are transcribed in vitro and in transfected mouse cells but are nearly silent in human HeLa cells. Transcriptional repression of these elements is to some extent reversible, as pol III-dependent Alu expression can be induced with herpes simplex or adenovirus. To assess whether sequence-specific DNA binding proteins might contribute to Alu transcriptional silencing, we examined the internucleosomal spacer region surrounding the B box of the Alu pol III promoter in HeLa cell nuclei for evidence of proteins bound at specific sites in vivo. We identified a DNase I-hypersensitive site 5' to the B box and a DNase I-resistant region 3' to the B box in nuclei. An Alu-specific repressor binds to a 5-bp inverted repeat motif overlapping the 5' end of the TFIIIC binding site and may inhibit pol III transcription through competitive displacement. The level of Alu-specific pol III repressor activity is significantly reduced in adenovirus-infected HeLa cells, suggesting that the repressor may contribute to Alu transcriptional silencing in vivo. The 3' DNase I-resistant region coincided with a binding site for the pol II transcription factor YY1 in vitro. YY1 is one of the major proteins in HeLa cells having binding specificity for Alu elements. YY1 bound to tandem arrays of genomic Alu elements may play a role in chromatin organization and silencing.

Adenoviridae↗
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↗
PubMed2001

Alu elements in human growth hormone receptor gene 5' untranslated region exons.

The human growth hormone receptor (hGHR) is encoded by exons 2-10 of the hGHR gene on chromosome 5p13.1-p12. There are several different 5' untranslated region (5'UTR) variants of hGHR mRNA (V1-V9) that all encode the same protein. We have recently mapped the V1-V9 5'UTR sequences within 40 kb of the 5' flanking region of the hGHR gene. Seven of the exons are clustered within two small modules, module A (V2-V9-V3) and module B (V7-V1-V4-V8), approximately 38 kb and approximately 18 kb respectively upstream of exon 2 of the coding region; V6 lies midway between the two modules and V5 is adjacent to exon 2. We now report the existence of two subvariant V3 exons, one upstream of module A (exon V3b) and one midway between module B and exon 2 (exon V3a/b). Both have sequences homologous to Alu elements. In addition, we determined the alternative splicing mechanisms that produce three different mRNAs from these exons: V3c (from the V3 exon in module A) or V3a and V3b (from a combination of exon V3 and the Alu-containing V3 subvariant exons). hGHR expression is under developmental- and tissue-specific regulation: module A-derived mRNAs are widely expressed in human tissues, while module B-derived mRNAs are only detectable in postnatal liver. Expression of the variant V3 mRNAs is similar to those from module A, being produced ubiquitously in human fetal and postnatal tissues, with V3c always the major variant detected. The Alu-containing mRNAs (V3a and V3b) are also detectable in baboon and rhesus tissues, in accordance with the finding of Alu elements throughout the primate genome. In summary, we have mapped the relative locations of two new 5'UTR exons within the 5' flanking region of the hGHR gene and described the derivation and expression patterns for two variant hGHR mRNAs from these primate-specific exons. The introduction of Alu elements has contributed to the evolution of the primate GHR gene as a highly complex transcriptional unit.

5' Untranslated Regions↗
PubMed2006

Alu elements within human mRNAs are probable microRNA targets.

Recently, we reported that four microRNAs show perfect complementarity with MIR/LINE-2 elements within human mRNAs. This finding raises the question of whether microRNAs might also target other genomic repeats and transposable elements. Here, we demonstrate that almost 30 human microRNAs exhibit typical short-seed complementarity with a specific site within Alu elements that is highly conserved within 3' untranslated regions of human mRNAs. The results suggest that at least some Alu elements within human mRNAs serve as microRNA targets.

3' Untranslated Regions↗
PubMed1998

Monophyletic origin of Alu elements in primates.

To get insight into the early evolution of the primate Alu elements, we characterized sequences of these repeats from the Malagasy prosimians, lemurs (Lemuridae) and sifakas (Indriidae), as well as from galagos (Lorisidae). These sequences were compared with the oldest Alu species known from the human genome: dimeric Alu J and S and free Alu monomers. Our analysis indicates that about 60 Myr ago, before the prosimian divergence, free left and right monomers formed an Alu heterodimer connected by a 19-nucleotide-long A-rich linker. The resulting elements successfully propagated in diverging primate lineages until about approximately 20 Myr ago, conserving similar sequence features and essentially the same Alu RNA secondary structure. We suggest that until that time the same "retropositional niche", molecular machinery making possible the proliferation by retroposition, constrained the evolution of Alu elements in extant primate species. These constraints became subsequently relaxed. In the Malagasy prosimians the dimeric Alu continued to amplify after acquiring a 34- to 36-nucleotide extension of their linker segment, whereas in the galago genome the "retropositional niche" was occupied by novel short elements.

Animals↗
PubMed1995

Repetitive Alu elements form a cruciform structure that regulates the function of the human CD8 alpha T cell-specific enhancer.

We previously identified a T cell-specific enhancer in the last intron of the human CD8 alpha gene that is adjacent to a sequence element that significantly represses enhancer function. This negative regulatory region consists of a half-Alu sequence that has potential to base-pair with a downstream Alu element, which is part of the fully active enhancer, to form a cruciform structure. The activity of this half-Alu silencer sequence is position and orientation-dependent, suggesting that DNA structure plays an important role in its function. Using site-directed mutational analysis and P1 nuclease mapping, we directly demonstrate that formation of a cruciform structure is required for repression of enhancer function in transient transfection assays. Finally, a P1 nuclease-sensitive site is present in the endogenous CD8 alpha gene in T cell lines providing indirect evidence that the stem-loop may form in vivo. Taken together, these results suggest that Alu elements may contribute to the regulation of the CD8 alpha gene enhancer through the formation of secondary structure that disrupts enhancer function.

Base Sequence↗
PubMed1998

Alu elements in a Plasmodium vivax antigen gene.

Plasmodium vivax is a very common human malaria parasite but it is poorly characterized at the molecular level. Here, we describe the isolation and characterization of an antigen coding gene of P. vivax which contains Alu elements. This gene, called Pv-Alu, is expressed during the erythrocytic phase of the parasite. The encoded 200 amino acid long polypeptide is highly hydrophobic, contains transmembrane domains, and is rich in leucine (19.4%), serine (15.9%), proline (15.4%) and phenylalanine (15.4%). The 5'-untranslated region and part of the 3'-end coding region of Pv-Alu show significant homology to different Alu families. The presence of Alu elements in the coding region of a parasite antigen gene is significant from a functional and evolutionary viewpoint.

Amino Acid Sequence↗
PubMed2004

Retrotransposition of Alu elements: how many sources?

It is generally thought that only a few Alu elements are capable of retrotransposition and that these 'master' sources produce inactive copies. Here, we use a network phylogenetic approach to demonstrate that recently integrated human-specific Alu subfamilies typically contain 10-20% of secondary source elements that contributed 20-40% of all subfamily members. This multiplicity of source elements provides new insight into the remarkably successful amplification strategy of the Alu family.

Alu Elements↗
PubMed1995

Activation of expression of multiple subfamilies of human Alu elements by adenovirus type 5 and herpes simplex virus type 1.

The nearly one million Alu repetitive elements in the human genome can be grouped into a number of subfamilies. Comparisons between subfamily consensus sequences suggest that Alu evolution is characterized by the sequential amplification and dispersal of a limited number of Alu founder sequences. The S, Sb and Sb1 subfamilies provide an example of such a related series of Alu subfamilies. We have previously demonstrated that adenovirus type 5 and herpes simplex virus type 1 activate RNA polymerase III transcription of endogenous Alu elements in HeLa cells. Here, we report that expression of Alu sequences belonging to the S, Sb and Sb1 subfamilies was activated following infection with these viruses. The data indicate that transpositionally inactive Alu elements can give rise to high levels of pol III transcripts in the presence of appropriate trans-acting factors and demonstrate that the class III promoters of a significant number and variety of Alu sequences are functional in vivo. Multiple subfamilies of Alu sequences were induced in transformed and non-transformed cell types, suggesting that induction of Alu expression may be part of the normal cellular response to viral infection.

Adenoviruses, Human↗
PubMed2002

[Research on Alu element inserted mutation in porcine FSH beta subunit gene].

The inserted fragment of FSH beta subunit gene in Laiwu pigs, an excellent local pig breed in North China, Duli pigs and Landrace pigs was amplified, cloned and sequenced. Sequence analysis showed that the length of the fragments inserted between +809 bp and +810 bp of the published sequences (D00621) were 275 bp, 277 bp and 274 bp in Laiwu, Duli and Landrace pigs, respectively. And the poly (A)s in these inserted fragments were 17, 19 and 16 adenines, respectively. They were all shorter than those in Taihu pigs(292 bp and 32 adenines, respectively) reported formerly. According to the RNA polymerase III promoter structure and Alu I restriction enzyme site in the inserted fragment, it should be regarded as an Alu element. FSH beta subunit gene was considered as one candidate gene of pig litter size trait, while RNA polymerase III promoter could promote the transcription of the neighboring chromosome sequence so as to control the expression of FSH beta subunit gene or other genes. As a result, the major difference of the inserted fragment among different pig breeds was originated from the length of poly (A) end. So it was assumed that the poly (A) structure in the inserted fragment could influence the pig litter size. Because Laiwu pigs with genotype AA had 1.2 litter size more than those with genotype BB, it could be concluded that FSH beta subunit gene was related with pig litter size traits or linked with the genes of which, and the poly(A) structure in this Alu element played a critical role.

Alu Elements↗
PubMed1999

Insertion of Alu element responsible for acute intermittent porphyria.

In this study, we report a large Finnish family in which an Alu element interferes with the coding region of the porphobilinogen deaminase (PBGD) gene resulting in acute intermittent porphyria (AIP). Polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) analysis of exon 5 among patients showed an abnormal band around 350 bp apart from the normal bands. Subcloning and sequencing of the fragment revealed a 333-bp Alu sequence that was directly inserted into exon 5 in antisense orientation. The junction sequences included a 13-bp target site duplication. This Alu cassette belongs to a Ya5 subfamily, one of the youngest and currently most active Alu subfamilies in evolution. The Alu insertion resulted in a dramatically decreased steady-state level of the allelic transcript, as this Alu sequence could not be demonstrated by direct sequencing of the amplified cDNA synthesized from total RNA extracted from the patients' lymphoblast cell lines. A stop codon present in the reading frame causes premature termination of PBGD synthesis. The predicted polypeptide contains 64 of the 361 amino acids of PBGD, followed by 13 amino acids that are not identical to the PBGD polypeptide. To further characterize the consequences of the insertion, the Alu sequence was inserted into exon 5 of the PBGD cDNA and expressed in the eukaryotic COS-1 cell line. The mutated construct expressed no enzyme activity comparable to that of the wild-type PBGD; furthermore, no mutant protein could be detected by Western blot analysis.

Adult↗
PubMed1999

Sequence patterns observed in 5' flanking regions of primate Alu elements.

Retrotransposons have generally been known to integrate randomly into host genomes. Jurka, however, showed some consensus sequence patterns at insertion sites of some mammalian retrotransposons and proposed enzymatic involvement that mediates integration. Jurka used about 400 complete human Alu and rodent ID sequences which retain full length with identical flanking sequences at both ends. In our study, more than 25,000 Alu sequences longer than 250 bp were used for comprehensive analysis to identify any consensus sequence(s) preceding the 5' end of Alu elements. "Entropy" at each nucleotide position within 500 bases of the 5' Alu end was computed. Significant drop of entropy was observed between position -20 and -10 of the 5' end of Alu, suggesting the existence of certain consensus sequence(s) in the region. Frequencies of all possible triplets (total of 64) were measured in the same region. Observation that frequencies of triplets "aaa," "taa," and "tta" in the 5' flanking sequences were high is consistent with Jurka. However, frequencies of triplets "att" and "aca" were also significantly high, which are not the primary candidates for nick site in Jurka.

Alu Elements↗
PubMed1997

Alu elements as an aid in deciphering genome rearrangements.

Genomic rearrangements result in genomic duplications that lead to the generation of more complex genomes. Some attempts have been made to trace duplication histories of different loci using Alu elements because of their large population in primate genomes (Chen et al., 1989; Mnuková-Fajdelová et al., 1994). In this short report, using the human growth hormone locus as an example, we demonstrate the usefulness of Alu repetitive elements in computer sequence analyses when tracing duplication histories. Information on subfamily classification, direction, arrangements, Poly(A) tails and direct repeats can aid our understanding of genome rearrangements.

Chromosome Mapping↗
PubMed2002

Origin and instability of GAA repeats: insights from Alu elements.

Expansion of GAA repeats in the intron of the frataxin gene is involved in the autosomal recessive Friedreich's ataxia (FRDA). The GAA repeats arise from a stretch of adenine residues of an Alu element. These repeats have a size ranging from 7- 38 in the normal population, and expand to thousands in the affected individuals. The mechanism of origin of GAA repeats, their polymorphism and stability are not well understood. In this study, we have carried out an extensive analysis of GAA repeats at several loci in the humans. This analysis indicates the association of a majority of GAA repeats with the 3' end of an "A" stretch present in the Alu repeats. Further, the prevalence of GAA repeats correlates with the evolutionary age of Alu subfamilies as well as with their relative frequency in the genome. Our study on GAA repeat polymorphism at some loci in the normal population reveals that the length of the GAA repeats is determined by the relative length of the flanking A stretch. Based on these observations, a possible mechanism for origin of GAA repeats and modulatory effects of flanking sequences on repeat instability mediated by DNA triplex is proposed.

3' Flanking Region↗
PubMed2004

Alu element mutation spectra: molecular clocks and the effect of DNA methylation.

In primate genomes more than 40% of CpG islands are found within repetitive elements. With more than one million copies in the human genome, the Alu family of retrotransposons represents the most successful short interspersed element (SINE) in primates and CpG dinucleotides make up about 20% of Alu sequences. It is generally thought that CpG dinucleotides mutate approximately ten times faster than other dinucleotides due to cytosine methylation and the subsequent deamination and conversion of C-->T. However, the disparity of Alu subfamily age estimations based upon CpG or non-CpG substitution density indicates a more complex relationship between CpG and non-CpG substitutions within the Alu elements. Here we report an analysis of the mutation patterns for 5296 Alu elements comprising 20 subfamilies. Our results indicate a relatively constant CpG versus non-CpG substitution ratio of approximately 6 for the young (AluY) and intermediate (AluS) Alu subfamilies. However, a more complex non-linear relationship between CpG and non-CpG substitutions was observed when old (AluJ) subfamilies were included in the analysis. These patterns may be the result of the slowdown of the neutral mutation rate during primate evolution and/or an increase in the CpG mutation rate as the consequence of increased DNA methylation in response to a burst of retrotransposition activity approximately 35 million years ago.

Alu Elements↗
PubMed1994

Activation of RNA polymerase III transcription of human Alu elements by herpes simplex virus.

We found that HSV infection of HeLa cells strongly induces RNA polymerase III transcription of endogenous human Alu elements, resulting in the accumulation of high levels of cytoplasmic RNAs initiated from Alu pol III promoters. Induction required viral protein synthesis and occurred during infection with a viral mutant bearing a null mutation in the immediate-early (IE) gene encoding ICP4, suggesting that one or more IE proteins are sufficient for activation. However, mutations in each of the other four IE genes had no effect on activation of Alu expression. We therefore conclude that HSV most likely encodes at least two proteins that are each sufficient to activate Alu transcription and that at least one of these is an IE protein other than ICP4.

Animals↗