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At least 199 records · Page 11Linked to original sources
PubMed2001

Birth of a gene: locus of neuronal BC200 snmRNA in three prosimians and human BC200 pseudogenes as archives of change in the Anthropoidea lineage.

The gene encoding brain-specific dendritic BC200 small non-messenger RNA is limited to the primate order and arose from a monomeric Alu element. It is present and neuronally expressed in all Anthropoidea examined. By comparing the human sequence of about 13.2 kb with each of the prosimian (lemur 14.6 kb, galago 12 kb, and tarsier 13.8 kb) orthologous loci, we could establish that the BC200 RNA gene is absent from the prosimian lineages. In Strepsirhini (lemurs and lorises), a dimeric AluJ-like element integrated very close to the BC200 insertion point, while the corresponding tarsier region is devoid of any repetitive element. Consequently, insertion of the Alu monomer that gave rise to the BC200 RNA gene must have occurred after the anthropoid lineage diverged from the prosimian lineage(s). Shared insertions of other repetitive elements favor proximity of simians and tarsiers in support of their grouping into Haplorhini and the omomyid hypothesis. On the other hand, the nucleotide sequences in the segment that is available for comparison in all four species reveal less exchanges between Strepsirhini (lemur and galago) and human than between tarsier and human. Our data imply that the early activity of dimeric Alu sequences must have been concurrent with the activity of monomeric Alu elements that persisted longer than is usually thought. As BC200 RNA gave rise to more than 200 pseudogenes, we used their consensus sequence variations as a molecular archive recording the BC200 RNA sequence changes in the anthropoid lineage leading to Homo sapiens and timed these alterations over the past 35-55 million years.

Alu Elements↗
PubMed2003

[Polymorphism of six Alu-insertions in residents of Morocco: comparative study in Arab and Berber populations and residents of Casablanca].

Alu elements are the largest family of short tandem interspersed elements (SINEs) in human who have arisen to a copy number with an excess of 500,000 copies per haploid human genome and mobilize through an RNAse polymerase III derived transcript in a process termed "retroposition." Several features make Alu insertions a powerful tool used in population genetic studies: the polymorphic nature of many Alu insertions, the stability of an Alu insertion event and, furthermore, the ancestral state of an Alu insertion is known to be the absence (complete and exact) of the Alu element at a particular locus and the presence of an Alu insertion at the site that forward mutational change. Here we report on the distribution of six polymorphic Alu insertions in a general Moroccan population and in the Arab and Berber populations from Morocco and their relationships with other populations previously studied. Our results show that there is a small difference between Arabs and Berbers and that the Arab population was closer to African populations than Berber population which is closest to Europeans.

Alu Elements↗
PubMed1995

The human myelin oligodendrocyte glycoprotein (MOG) gene: complete nucleotide sequence and structural characterization.

Human myelin oligodendrocyte glycoprotein (MOG), a myelin component of the central nervous system, is a candidate target antigen for autoimmune-mediated demyelination. We have isolated and sequenced part of a cosmid clone that contains the entire human MOG gene. The primary nuclear transcript, extending from the putative start of transcription to the site of poly(A) addition, is 15,561 nucleotides in length. The human MOG gene contains 8 exons, separated by 7 introns; canonical intron/exon boundary sites are observed at each junction. The introns vary in size from 242 to 6484 bp and contain numerous repetitive DNA elements, including 14 Alu sequences within 3 introns. Another Alu element is located in the 3'-untranslated region of the gene. Alu sequences were classified with respect to subfamily assignment. Seven hundred sixty-three nucleotides 5' of the transcription start and 1214 nucleotides 3' of the poly(A) addition sites were also sequenced. The 5'-flanking region revealed the presence of several consensus sequences that could be relevant in the transcription of the MOG gene, in particular binding sites in common with other myelin gene promoters. Two polymorphic intragenic dinucleotide (CA)n and tetranucleotide (TAAA)n repeats were identified and may provide genetic marker tools for association and linkage studies.

Base Sequence↗
PubMed1991

An unusual Alu repeat sequence within the CAD gene.

There are several hundred thousand members of the Alu repeat family in the human genome. Those Alu elements sequenced to date appear to fit into subfamilies. A novel Alu has been found in an intron of the human CAD gene: it appears to be due to rearrangement between Alu repeats belonging to two different subfamilies. Further sequence data from this intron suggest that the Alu element may have rearranged prior to its entry into the CAD gene. Such findings indicate that, in addition to single nucleotide substitutions and deletions, DNA rearrangements may be a factor in generating the diversity of Alu repeats found in primate genomes.

Animals↗
PubMed2002

Evolution of a polymorphic regulatory element in interferon-gamma through transposition and mutation.

Mammalian transposable elements have intrinsic regulatory elements that can activate neighboring genes, and it is speculated that they can also carry extrinsic transactivating DNA sequences to new genomic locations. We have identified a polymorphic segment of the human interferon-gamma promoter region where two adjacent binding sites for NF-kappaB and NFAT originated from the insertion of an Alu element approximately 22-34 MYA. Both binding sites lie outside the Alu consensus sequence but within the boundaries of the insertion, suggesting that this segment of DNA was comobilized when the Alu element moved from another part of the genome. Sequence comparisons and examination of DNA-protein interactions across nine different primate species indicate that the inserted sequence contained the intact NFAT binding site, whereas the ability to bind NF-kappaB evolved through a series of mutations after the insertion. These observations are consistent with the notion that retropseudogenes can comobilize intact regulatory sequences to new locations and thereby influence the evolution of gene regulatory networks; however, the extent to which such events have shaped the evolution of gene regulation remains unknown.

Alu Elements↗
PubMed2001

An Alu insert as the cause of a severe form of hemophilia A.

Alu sequences represent a specific human family of interspersed repetitive DNA, with a copy number in excess of 500,000 within the human genome. Alu repeats are rarely present in protein-coding regions of mature RNA, and only a few Alu insert mutations have been described so far. In this paper we present an Alu retroposition event in a family with a severe form of hemophilia A. The inserted Alu element belonging to the youngest Yb8 subfamily disrupts the reading frame at methionine 1224, exon 14 of the factor VIII gene, leading to a stop codon within the inserted sequence. This observation indicates that the retroposition of Alu elements is a continuing process possibly generating various human genetic defects.

Adolescent↗
PubMed2006

The first reported case of Menkes disease caused by an Alu insertion mutation.

We present the first reported case of Menkes disease caused by an Alu element insertion mutation that interfered with splicing regulatory elements. A whole young AluYa5a2 element, which was 382-bp long, was identified within exon 9 of the ATP7A gene, and all of exon 9 was aberrantly skipped in the cDNA, resulting in severely truncated proteins. To confirm whether the aberrant skipping resulted in Alu insertion, an exonic splicing enhancer finder was used. The Alu element created two new high-score exonic splicing enhancer sequences in the mutation located near the site of the insertion. Exon 9, which encodes the first and second transmembrane domains, is necessary for the normal function of the ATP7A protein.

Adenosine Triphosphatases↗
PubMed2003

Identification of CBL, a proto-oncogene at 11q23.3, as a novel MLL fusion partner in a patient with de novo acute myeloid leukemia.

We have shown that the CBL gene at 11q23.3, telomeric to MLL, was fused to MLL in an adult patient with de novo acute myeloid leukemia (FAB-M1). Southern blot analysis indicated that the MLL rearrangement was involved in the chromosomal abnormality. cDNA panhandle polymerase chain reaction identified the fusion transcript, in which MLL exon 6 was fused in-frame with CBL exon 8. Long-distance PCR amplified the genomic junction region, which involved the fusion of the 3' portion of an Alu element in intron 6 of MLL with the 5' portion of an Alu element in intron 7 of CBL. The absence of extensive sequence similarity at both breakpoints of MLL and CBL indicated that the recombination was not generated through homologous recombination. MLL and CBL are located between STS markers D11S939 and D11S924. Analysis of the sequence demonstrated that the transcriptional orientation of both genes at 11q23.3 is from centromere to telomere. The results of Southern blotting in conjunction with fluorescence in situ hybridization suggest that the MLL-CBL fusion was the result of an interstitial deletion. CBL, a proto-oncogene, functions as a negative regulator of several receptor protein-tyrosine-kinase signaling pathways and as an adaptor protein in tyrosine phosphorylation-dependent signaling. CBL is the second gene at 11q23.3 found to fuse with MLL.

Adult↗
PubMed2006

Complementary intron sequence motifs associated with human exon repetition: a role for intragenic, inter-transcript interactions in gene expression.

MOTIVATION: Exon repetition describes the presence of tandemly repeated exons in mRNA in the absence of duplications in the genome. The regulation of this process is not fully understood. We therefore investigated the entire flanking intronic sequences of exons involved in exon repetition for common sequence elements. RESULTS: A computational analysis of 48 human single exon repetition events identified two common sequence motifs. One of these motifs is pyrimidine-rich and is more common in the upstream intron, whilst the other motif is highly enriched in purines and is more common in the downstream intron. As the two motifs are complementary to each other, they support a model by which exon repetition occurs as a result of trans-splicing between separate pre-mRNA transcripts from the same gene that are brought together during transcription by complementary intronic sequences. The majority of the motif instances overlap with the locations of mobile elements such as Alu elements. We explore the potential importance of complementary intron sequences in a rat gene that undertakes natural exon repetition in a strain specific manner. The possibility that distant complementary sequences can stimulate inter-transcript splicing during transcription suggests an unsuspected new role for potential secondary structures in endogenous genes.

Chromosome Mapping↗
PubMed2000

Alu-mediated PCR artifacts and the constitutional t(11;22) breakpoint.

The breakpoints of the recurrent t(11;22)(q23;q11) have recently been cloned. We identified palindromic AT-rich repeats (PATRRs) on 11q23 and 22q11 as the mechanism responsible for the rearrangement. Contradictory to our results, A.S. Hill et al. (Hum. Mol. Genet., 9, 1525-1532) suggested that Alu-mediated recombination is responsible. To clarify this discrepancy, the cloned 4.5 kb der(11) junction fragment has been completely sequenced. This sequence has been compared with that of an inverse PCR-generated der(11) junction fragment obtained by Hill et al. This reveals that the inverse PCR product has sustained a deletion between two Alu elements, such that the true breakpoint region is deleted from the PCR product. Utilizing PCR primers designed by Hill et al. to amplify across the der(11) breakpoint, we obtained a deleted PCR product even when our cloned der(11) junction fragment was used as template. Further, we find that the PCR primers that they utilized for amplification of the der(22) junction fragment are not located on the der(22). They are oriented in opposite directions within the region deleted from the der(11) PCR product, generating an artifact derived from the der(11) chromosome. Analysis of the truncated PCR products indicates a mixture of sequences from two distinct Alu elements, suggesting that the putative junction fragment described by Hill et al. is an Alu-mediated PCR artifact. These data suggest that caution should be exercised when analyzing PCR-based data, particularly when amplification is carried out in a region containing repeat structures with specific, difficult-to-amplify sequences.

Alu Elements↗
PubMed2025

Alu Overexpression Leads to an Increased Double-Stranded RNA Signature in Dermatomyositis.

OBJECTIVE: Dermatomyositis is an autoimmune condition characterized by a high interferon signature of unknown etiology. Because coding sequences constitute <1.2% of our genomes, there is a need to explore the role of the noncoding genome in disease pathogenesis. Our genomes include roughly 1.2 million Alu elements occupying approximately 10% of the genome, which can form double-stranded (ds) RNA capable of triggering MDA5 leading to interferon production. METHODS: We aligned muscle biopsy RNA sequencing data to the telomere-to-telomere reference genome and quantified short interspersed elements including Alus. Because Alus have a propensity to form dsRNA and are the major targets of both adenosine deaminase RNA specific and MDA5, we quantified adenosine to inosine (A-to-I) RNA editing, which reflects dsRNA in vivo. RESULTS: Dermatomyositis muscle (n = 39) showed a global elevation in Alu expression (including inverted-repeat Alus with high potential to form dsRNA) as well as an increased expression of unique Alu elements (n = 557, q < 0.05) compared with healthy controls (n = 34), in a pattern not seen in other myositis types (n = 81). Most (75.3%) of these Alus originated from genomic regions outside genes. A cluster of the uniquely overexpressed Alus (n = 167) correlated with interferon-stimulated genes and markers of myositis activity. Additionally, we found a uniquely expanded Alu A-to-I editome in dermatomyositis, reflecting an increase in dsRNA. Edited Alus clustered on chromosome 19, which is known to have the highest concentration of dsRNA. CONCLUSION: We hypothesize that overexpressed Alus in dermatomyositis form endogenous dsRNA that exceeds the capacity of RNA editing enzymes and triggers dsRNA sensors leading to interferon production.

Humans↗
PubMed2001

Nonrandom distribution of interspersed repeat elements in the BCR and ABL1 genes and its relation to breakpoint cluster regions.

The Philadelphia translocation, t(9;22)(q34;q11), is the microscopically visible product of recombination between two genes, ABL1 on chromosome 9 and BCR on chromosome 22, and gives rise to a functional hybrid BCR-ABL1 gene with demonstrated leukemogenic properties. Breakpoints in BCR occur mostly within one of two regions: a 5 kb major breakpoint cluster region (M-Bcr) and a larger 35 kb minor breakpoint cluster region (m-Bcr) towards the 3' end of the first BCR intron. By contrast, breakpoints in ABL1 are reported to occur more widely across a >200 kb region which spans the large first and second introns. The mechanisms that determine preferential breakage sites in BCR, and which cause recombination between BCR and ABL1, are presently unknown. In some cases, Alu repeats have been identified at or near sequenced breakpoint sites in both genes, providing indications, albeit controversial, that they may be relevant. For the present study, we carried out a detailed analysis of genomic BCR and ABL1 sequences to identify, classify, and locate interspersed repeat sequences and to relate their distribution to precisely mapped BCR-ABL1 recombination sites. Our findings confirm that Alu are the most abundant class of repeat in both genes, but that they occupy fewer sites than previously estimated and that they are distributed nonrandomly. r-Scan statistics were applied to provide a measure of repeat distribution and to evaluate extremes in repeat spacing. A significant lack of Alu elements was observed across the major and minor breakpoint cluster regions of BCR and across a 25-kb region showing a high frequency of breakage in ABL1. These findings counter the suggestion that occurrence of Alu at BCR-ABL1 recombination sites is likely by chance because of the high density of Alu in these two genes. Instead, as yet unidentified DNA conformation or nucleotide characteristics peculiar to the preferentially recombining regions, including those Alu elements present within them, more likely influence their fragility.

Alu Elements↗
PubMed2003

Comprehensive analysis of Alu-associated diversity on the human sex chromosomes.

A comprehensive analysis of the human sex chromosomes was undertaken to assess Alu-associated human genomic diversity and to identify novel Alu insertion polymorphisms for the study of human evolution. Three hundred forty-five recently integrated Alu elements from eight different Alu subfamilies were identified on the X and Y chromosomes, 225 of which were selected and analyzed by polymerase chain reaction (PCR). From a total of 225 elements analyzed, 16 were found to be polymorphic on the X chromosome and one on the Y chromosome. In line with previous research using other classes of genetic markers, our results indicate reduced Alu-associated insertion polymorphism on the human sex chromosomes, presumably reflective of the reduced recombination rates and lower effective population sizes on the sex chromosomes. The Alu insertion polymorphisms identified in this study should prove useful for the study of human population genetics.

Alu Elements↗
PubMed1997

Identification and characterization of two polymorphic Ya5 Alu repeats.

Two new polymorphic Alu elements (HS2.25 and HS4.14) belonging to the young (Ya5/8) subfamily of human-specific Alu repeats have been identified. DNA sequence analysis of both Alu repeats revealed that each Alu repeat had a long 3'-oligo-dA-rich tail (41 and 52 nucleotides in length) and a low level of random mutations. HS2.25 and HS4.14 were flanked by short precise direct repeats of 8 and 14 nucleotides in length, respectively. HS2.25 was located on human chromosome 13, and HS4.14 on chromosome 1. Both Alu elements were absent from the orthologous positions within the genomes of non-human primates, and were highly polymorphic in a survey of twelve geographically diverse human groups.

Animals↗
PubMed1988

Human plasminogen activator inhibitor-1 gene. Promoter and structural gene nucleotide sequences.

We have determined the nucleotide sequence of the human plasminogen activator inhibitor-1 (PAI-1) gene and significant stretches of DNA which extend into its 5'-and 3'-flanking DNA regions; a total sequence of 15,867 base pairs (bp) is presented. The sequenced 5'-flanking DNA (1,520 bp) contains the essential eukaryotic cis-type proximal regulatory elements CCAAT and TATAA; the more distal 5'-flanking DNA region, as well as some introns, contain sequence elements which share identities with known eukaryotic enhancer elements. A major finding is the identification of a large region of shared nucleotides (comprising of about 520 bp) between the 5'-flanking DNAs of PAI-1 and tissue-type plasminogen activator genes. The length of the PAI-1 5'-untranslated region was found to be 145 bp as determined by nuclease analysis. The remaining PAI-1 structural gene consists of amino acid coding regions (containing a total of 1,206 bp, coding for the 23 amino acids of the signal peptide and 379 amino acids of the mature PAI-1 protein), 8 intron regions (a total of 8,978 bp), and a long 3'-untranslated region of about 1,800 bp which contains several polyadenylation sites. Two types of repetitive DNA elements are located within the PAI-1 structural gene and flanking DNAs: we have found 12 Alu elements and 5 repeats of a long poly (Pur) element. These Alu-Pur elements may represent a subset of the more abundant Alu family of repetitive sequence elements.

Amino Acid Sequence↗
PubMed1998

Identification of Alu-mediated deletions in the Fanconi anemia gene FAA.

Fanconi anemia (FA) is an autosomal recessive syndrome associated with hypersensitivity to DNA cross-linking agents and predisposition to neoplasia. Eight complementation groups (A-H) have been described, but the only FA genes cloned so far are FAC and FAA. We have recently identified 40 different germline mutations, including microdeletions, microinsertions, and point mutations in genomic DNA from 97 FA patients from the International Fanconi Anemia Registry (IFAR) by single-strand conformational polymorphism (SSCP) analysis. Interestingly, only one mutant allele was identified in many of these patients. Haplotype analysis with intragenic polymorphisms, as well as cDNA analysis of some patients suggested the presence of large deletions that would not be detected by SSCP analysis. In this study, we report the occurrence of Alu-mediated genomic deletions in FAA. Two different deletions of 1.2 kb and 1.9 kb were found. Both deletions include exons 16 and 17 and remove a 156-bp segment from the transcript causing a shorter in-frame message. Sequence analysis revealed that introns 15 and 17 are rich in partial and complete Alu repeats. There are at least four head-to-tail arranged Alu elements in intron 17 and one in intron 15, all oriented in the 3'-->5' direction. Sequence analysis of the deletions showed that the 5' breakpoints occurred at different sites in the same Alu element in intron 15, while the 3' breakpoints were located in different Alu repeats in intron 17. Numerous Alu repeats are present in FAA, suggesting that Alu-mediated recombination might be an important mechanism for the generation of FAA mutations.

Base Sequence↗
PubMed1993

The topographic organization of repetitive DNA in the human nucleolus.

The nucleolus is a highly specialized nuclear domain where ribosomal DNA (rDNA) is transcribed and preribosomes are assembled. We investigated the molecular organization of the human lymphocyte nucleolus by fluorescence in situ hybridization and confocal laser scanning microscopy and found that transcribed rDNA and nontranscribed ribosomal intergenic spacer (IGS) sequences colocalized to discrete regions frequently on the nucleolar periphery of phytohemagglutinin-stimulated cells. The 5S rDNA gene cluster located on the long arm of chromosome 1 was not regularly associated with the nucleolus. Short interspersed (SINE) Alu elements detected by BLUR 11 were distributed diffusely throughout the nucleus but were severely underrepresented in the nucleolus, whereas an Alu element subcloned from the IGS detected sequences enriched in the nucleolus but sparsely represented in the remainder of the nucleus. In contrast, long interspersed (LINE) Kpn elements, which were located at the nucleolus, were not found in rDNA but were identified outside the ribosomal gene complex on the short arm of at least one acrocentric chromosome. A human chromosome 21-derived alphoid sequence that hybridized to the centromere was localized outside but near the nucleolus, and nonribosomal DNA consisting of a tandemly repeated simple sequence cluster derived from the short arm of chromosome 15 was organized in a compact fashion in the nucleolus. Our study provides new insight into the content and structure of the human nucleolus and illustrates that the unique organization of repetitive DNA on the acrocentric chromosome short arms is reflected in the topographic organization of the nucleolus.

Blotting, Southern↗
PubMed1991

Inactivation of the cholinesterase gene by Alu insertion: possible mechanism for human gene transposition.

The human cholinesterase (ChE) gene from a patient with acholinesterasemia was cloned and analyzed. By using ChE cDNA as a probe, four independent clones were isolated from a genomic library constructed from the patient's DNA. Sequencing analysis of all of the four clones revealed that exon 2 of the ChE gene was disrupted by a 342-base-pair (bp) insertion of Alu element, including a poly(A) tract of 38 bp, which showed 93% sequence homology with a current type of human Alu consensus sequence. Southern blot analysis showed that the Alu insertion occurred in both alleles of the patient and was inherited in the patient's family. This Alu insertion was flanked by 15-bp of target site duplication in exon 2 corresponding to positions 1062-1076 of ChE cDNA, indicating that an Alu element could have been integrated by retrotransposition. Thus, this case provides an important clue to the mechanism of inactivation of a gene by integration of a retrotransposon.

Acetylcholinesterase↗