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PubMed1989

A negative regulatory element with properties similar to those of enhancers is contained within an Alu sequence.

A negative regulatory element has been found within a member of the African green monkey Alu family of interspersed repeated sequences. This "reducer" element decreased transcription in both directions from a cellular simian virus 40-like bidirectional promoter independently of both orientation and position. The reducer was not promoter specific since it also decreased expression from the simian virus 40 early and human beta-globin promoters. In addition, the reducer decreased transcription from a polymerase III promoter. The reducer was contained in 38 base pairs of an Alu family member and interacted specifically with a monkey cell nuclear protein.

Animals↗
PubMed1999

Organization of the gene for gelatin-binding protein (GBP28).

GBP28 is a novel human plasma gelatin-binding protein that is encoded by apM1 mRNA, expressed specifically in adipose tissue. Three overlapping clones (two lambda clones and one BAC clone) containing the human plasma gelatin-binding protein (GBP28) gene were isolated and characterized. The GBP28 gene spans 16kb and is composed of three exons from 18bp to 4277bp in size with consensus splice sites. The sizes of the two introns were 0.8 and 12kb, respectively. The gene's regulatory sequences contain putative promoter elements, but no typical TATA box. The third exon of this gene contains a long 3'-untranslated sequence containing three Alu repeats. The exon-intron organization of this gene was very similar to that of obese gene, encoding leptin. We also report the chromosome mapping of this gene by fluorescence in situ hybridization (FISH) using a genomic DNA fragment as a probe. The GBP28 gene was located on human chromosome 3q27. The nucleotide sequence data reported in this paper will appear in the DDBJ/EMBL/GenBank nucleotide sequence databases with the accession numbers ABO12163, ABO12164 or ABO12165.

Adiponectin↗
PubMed1993

Rh null phenotypes are not due to a gross deletion and can occur on different Rh genetic backgrounds.

Alu element-primed PCR was performed on genomic clones containing human RH blood group genes. When used as a probe, the Alu PCR product detected a restriction fragment-length polymorphism which is in complete linkage disequilibrium with the Rh C/c serological polymorphism, irrespective of the Rh D or E serological type it is coupled with. This provides the opportunity to type individuals for their RH C gene directly at the DNA level. RFLP analysis of two individuals with the amorph Rh null phenotype revealed that in one case this phenotype occurred on an RH C background, whereas in the other it was on an RH c background. Taken together these results indicate that the Rh C/c polymorphism has arisen only once, but that the amorph Rh null phenotype, although exceedingly rare, is the result of at least two independent mutations.

Alleles↗
PubMed1991

Integration site preferences of endogenous retroviruses.

Retroviruses have the ability to integrate into the genome of their host, in many cases with little apparent sequence or site specificity. However, relatively few studies have addressed more general features of chromosomal integration. In this study we directly visualized the chromosomal organization of three representative endogenous retroviruses by in situ hybridization. Because there are 50-1000 copies of each of these retroviruses in the genome, it was possible to evaluate repeated integration events. Each retroviral sequence exhibited a unique and markedly different integration pattern. In order to characterize more precisely the chromosomal domains targeted by each retrovirus, later replicating domains were differentially labeled. Additionally, prototypic SINES and LINES (short and long interspersed reiterated sequences), which are inhomogeneously distributed on chromosome arms, were simultaneously detected. Retroviral copies of greater than or equal to 2 kb were found (i) exclusively in a discrete set of later replicating domains, most of which have the staining characteristics of constitutive heterochromatin, (ii) widely represented in disparate types of chromosome domains, or (iii) almost completely confined to CpG Alu-rich regions that are known to be early replicating. Retroviral elements in Alu-rich domains would be expected to be actively transcribed in all cells. Surprisingly, hybridization to blots of brain RNA showed an approximately 25 fold lower level of transcripts from these Alu associated elements than from retroviral sequences restricted to later replicating, heterochromatic domains. Retroviral insertions may subvert more typical transcriptional characteristics of a domain. The present results indicate that there are highly specific integration patterns for each endogenous retrovirus that do not readily relate to their sequence or particle classification. Each host genome may utilize these elements for contrary, and possibly beneficial functions.

Adult↗
PubMed1992

Human repeat element-mediated PCR: cloning and mapping of chromosome 10 DNA markers.

Repeat element-mediated PCR can facilitate rapid cloning and mapping of human chromosomal region-specific DNA markers from somatic cell hybrid DNA. PCR primers directed to human repeat elements result in human-specific DNA synthesis; template DNA derived from a somatic cell hybrid containing the human chromosomal region of interest provides region specificity. We have generated a series of repeat element-mediated PCR clones from a reduced complexity somatic cell hybrid containing a portion of human chromosome 10. The cloning source retains the centromere and tightly linked flanking markers, plus additional chromosome 10 sequences. Twelve new inter-Alu, two inter-L1, and four inter-Alu/L1 repeat element-mediated PCR clones were mapped by hybridization to Southern blots of repeat element-mediated PCR products amplified from somatic cell hybrid DNA templates. Two inter-Alu clones mapped to the pericentromeric region. We propose that a scarcity of Alu elements in the pericentromeric region of chromosome 10 contributed to the low number of clones obtained from this region. One inter-Alu clone, pC11/A1S-6-c23, defines the D10S94 locus, which is tightly linked to MEN2A and D10Z1.

Animals↗
PubMed1995

Genomic sequence comparison of the human and mouse XRCC1 DNA repair gene regions.

The XRCC1 (X-ray repair cross complementing) gene is involved in the efficient repair of DNA single-strand breaks formed by exposure to ionizing radiation and alkylating agents. The human gene maps to chromosome 19q13.2, and the mouse homologue maps to the syntenic region on chromosome 7. Two cosmids (approximately 38 kb each) containing the human and mouse genes were sequenced to an average 8-fold clonal redundancy. The XRCC1 gene spans a genomic distance of 26 kb in mouse and 31.9 kb in human. Both genes contain 17 exons, are 84% identical within the coding regions, and are 86% identical at the amino acid sequence level. Intron and exon lengths are highly conserved. For the human cosmid, a total of 43 Alu repetitive elements are present, a density of 1.1 Alu/kb, but due to clustering, the local density is as high as 1.8 Alu/kb. In addition, we observed a statistically significant bias for insertion of these elements in the 3'-5' orientation relative to the direction of XRCC1 transcription, predominantly in the second and third introns. This bias may indicate that XRCC1 is more accessible to Alu retroposition events during transcription than genes not expressed during spermatogenesis. The density of B1 and B2 elements in the mouse is 0.4/kb, integrated primarily in the 5'-3' orientation. The human chromosome 19-specific minisatellite PE670 was present in the same orientation in 3 introns in the human gene, and a similar repeat was found at 3 different locations in the mouse cosmid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Modeling oncogenic translocations: distinct roles for double-strand break repair pathways in translocation formation in mammalian cells.

Reciprocal chromosomal translocations are implicated in the etiology of many tumors, including leukemias, lymphomas, and sarcomas. DNA double-strand breaks (DSBs) caused by various cellular processes and exogenous agents are thought to be responsible for the generation of most translocations. Mammalian cells have multiple pathways for repairing DSBs in the chromosomes: non-homologous end-joining (NHEJ), homologous recombination (HR), and single-strand annealing (SSA), which is a specialized pathway involving sequence repeats. In this review, we summarize the various reporters that have been used to examine the potential for each of these DSB repair pathways to mediate translocation formation in mammalian cells. This approach has demonstrated that NHEJ is very proficient at mediating translocation formation, while HR is not because of crossover suppression. Although SSA can efficiently mediate translocations between identical repeats, its contribution to translocation formation is likely very limited because of sequence divergence between repetitive elements in the genome.

Alu Elements↗
PubMed2002

Retroelement distributions in the human genome: variations associated with age and proximity to genes.

Remnants of more than 3 million transposable elements, primarily retroelements, comprise nearly half of the human genome and have generated much speculation concerning their evolutionary significance. We have exploited the draft human genome sequence to examine the distributions of retroelements on a genome-wide scale. Here we show that genomic densities of 10 major classes of human retroelements are distributed differently with respect to surrounding GC content and also show that the oldest elements are preferentially found in regions of lower GC compared with their younger relatives. In addition, we determined whether retroelement densities with respect to genes could be accurately predicted based on surrounding GC content or if genes exert independent effects on the density distributions. This analysis revealed that all classes of long terminal repeat (LTR) retroelements and L1 elements, particularly those in the same orientation as the nearest gene, are significantly underrepresented within genes and older LTR elements are also underrepresented in regions within 5 kb of genes. Thus, LTR elements have been excluded from gene regions, likely because of their potential to affect gene transcription. In contrast, the density of Alu sequences in the proximity of genes is significantly greater than that predicted based on the surrounding GC content. Furthermore, we show that the previously described density shift of Alu repeats with age to domains of higher GC was markedly delayed on the Y chromosome, suggesting that recombination between chromosome pairs greatly facilitates genomic redistributions of retroelements. These findings suggest that retroelements can be removed from the genome, possibly through recombination resulting in re-creation of insert-free alleles. Such a process may provide an explanation for the shifting distributions of retroelements with time.

Alu Elements↗
PubMed1991

A de novo Alu insertion results in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with a high mutation rate and variable expression, characterized by neurofibromas, café-au-lait spots, Lisch nodules of the iris, and less frequent features including bone deformities and learning disabilities. The recently cloned NF1 gene encodes a transcript of 13 kilobases from a ubiquitously expressed locus on chromosome 17. Most NF1 patients are expected to have unique mutations, but only a few have so far been characterized, restricting genetic and functional information and the design of DNA diagnostics. We report an unusual NF1 mutation, that of a de novo Alu repetitive element insertion into an intron, which results in deletion of the downstream exon during splicing and consequently shifts the reading frame. This previously undescribed mechanism of mutation indicates that Alu retrotransposition is an ongoing process in the human germ line.

Adult↗
PubMed2006

Methylation of endogenous human retroelements in health and disease.

Retroelements constitute approximately 45% of the human genome. Long interspersed nuclear element (LINE) autonomous retrotransposons are predominantly represented by LINE-1, nonautonomous small interspersed nuclear elements (SINEs) are primarily represented by ALUs, and LTR retrotransposons by several families of human endogenous retroviruses (HERVs). The vast majority of LINE and HERV elements are densely methylated in normal somatic cells and contained in inactive chromatin. Methylation and chromatin structure together ensure a stable equilibrium between retroelements and their host. Hypomethylation and expression in developing germ cells opens a "window of opportunity" for retrotransposition and recombination that contribute to human evolution, but also inherited disease. In somatic cells, the presence of retroelements may be exploited to organize the genome into active and inactive regions, to separate domains and functional regions within one chromatin domain, to suppress transcriptional noise, and to regulate transcript stability. Retroelements, particularly ALUs, may also fulfill physiological roles during responses to stress and infections. Reactivation and hypomethylation of LINEs and HERVs may be important in the pathophysiology of cancer and various autoimmune diseases, contributing to chromosomal instability and chronically aberrant immune responses. The emerging insights into the pathophysiological importance of endogenous retroelements accentuate the gaps in our knowledge of how these elements are controlled in normal developing and mature cells.

Alu Elements↗
PubMed2004

Mobile elements: drivers of genome evolution.

Mobile elements within genomes have driven genome evolution in diverse ways. Particularly in plants and mammals, retrotransposons have accumulated to constitute a large fraction of the genome and have shaped both genes and the entire genome. Although the host can often control their numbers, massive expansions of retrotransposons have been tolerated during evolution. Now mobile elements are becoming useful tools for learning more about genome evolution and gene function.

Alu Elements↗
PubMed2006

The human growth hormone gene contains a silencer embedded within an Alu repeat in the 3'-flanking region.

Alu family sequences are middle repetitive short interspersed elements (SINEs) dispersed throughout vertebrate genomes that can modulate gene transcription. The human (h) GH locus contains 44 complete and four partial Alu elements. An Sx Alu repeat lies in close proximity to the hGH-1 and hGH-2 genes in the 3'-flanking region. Deletion of the Sx Alu repeat in reporter constructs containing hGH-1 3'-flanking sequences increased reporter activity in transfected pituitary GC cells, suggesting this region contained a repressor element. Analysis of multiple deletion fragments from the 3'-flanking region of the hGH-1 gene revealed a strong orientation- and position-independent silencing activity mapping between nucleotides 2158 and 2572 encompassing the Sx Alu repeat. Refined mapping revealed that the silencer was a complex element comprising four discrete entities, including a core repressor domain (CRD), an antisilencer domain (ASE) that contains elements mediating the orientation-independent silencer activity, and two domains flanking the CRD/ASE that modulate silencer activity in a CRD-dependent manner. The upstream modulator domain is also required for orientation-independent silencer function. EMSA with DNA fragments representing all of the silencer domains yielded a complex pattern of DNA-protein interactions indicating that numerous GC cell nuclear proteins bind specifically to the CRD, ASE, and modulator domains. The silencer is GH promoter dependent and, in turn, its presence decreases the rate of promoter-associated histone acetylation resulting in a significant decrease of RNA polymerase II recruitment to the promoter. The silencer may provide for complex regulatory control of hGH gene expression in pituitary cells.

Alu Elements↗
PubMed2003

Translocation and gross deletion breakpoints in human inherited disease and cancer I: Nucleotide composition and recombination-associated motifs.

Translocations and gross deletions are important causes of both cancer and inherited disease. Such gene rearrangements are nonrandomly distributed in the human genome as a consequence of selection for growth advantage and/or the inherent potential of some DNA sequences to be frequently involved in breakage and recombination. Using the Gross Rearrangement Breakpoint Database [GRaBD; www.uwcm.ac.uk/uwcm/mg/grabd/grabd.html] (containing 397 germ-line and somatic DNA breakpoint junction sequences derived from 219 different rearrangements underlying human inherited disease and cancer), we have analyzed the sequence context of translocation and deletion breakpoints in a search for general characteristics that might have rendered these sequences prone to rearrangement. The oligonucleotide composition of breakpoint junctions and a set of reference sequences, matched for length and genomic location, were compared with respect to their nucleotide composition. Deletion breakpoints were found to be AT-rich whereas by comparison, translocation breakpoints were GC-rich. Alternating purine-pyrimidine sequences were found to be significantly over-represented in the vicinity of deletion breakpoints while polypyrimidine tracts were over-represented at translocation breakpoints. A number of recombination-associated motifs were found to be over-represented at translocation breakpoints (including DNA polymerase pause sites/frameshift hotspots, immunoglobulin heavy chain class switch sites, heptamer/nonamer V(D)J recombination signal sequences, translin binding sites, and the chi element) but, with the exception of the translin-binding site and immunoglobulin heavy chain class switch sites, none of these motifs were over-represented at deletion breakpoints. Alu sequences were found to span both breakpoints in seven cases of gross deletion that may thus be inferred to have arisen by homologous recombination. Our results are therefore consistent with a role for homologous unequal recombination in deletion mutagenesis and a role for nonhomologous recombination in the generation of translocations.

Alu Elements↗
PubMed2001

Repetitive elements in the 5' untranslated region of a human zinc-finger gene modulate transcription and translation efficiency.

A substantial proportion of the human genome consists of repetitive sequences. Although most of these sequences are nonessential for the organism, retroelements, such as Alu sequences, L1s, and HERVs (human endogenous retroviruses), have recently been implicated in the regulation of various genes. Our laboratory previously identified a novel, alternatively spliced zinc-finger gene, ZNF177, which incorporates Alu L1, and HERV segments into the 5' untranslated region (UTR) of transcripts. In this study, we investigated the genomic structure and functional significance of the repetitive sequences in the 5' UTR of ZNF177 mRNAs. Using luciferase and GFP reporter constructs, we assessed the effect of the HERV, Alu, and L1 sequences on gene expression levels. Our results indicate that the presence of the retroelement sequences, particularly the Alu and L1 segments which form one 5' UTR exon, modifies the expression level of both reporter genes. We present evidence that the Alu and L1 sequences alter both the RNA and protein levels of reporter genes by increasing transcription efficiency while decreasing translation efficiency. Our findings indicate that the Alu and L1 repeats in the 5' UTR of ZNF177 exert a positive transcriptional enhancer effect, but repress translation of the zinc finger gene. In addition, our analysis of a 5' UTR database suggests that 4% of human 5' UTRs harbor Alu sequences, indicating that the expression of many genes might be influenced by Alu repeats. These results illustrate the complex regulatory effects that retroelements can have on human gene expression.

5' Untranslated Regions↗
PubMed1987

Cloning and 5' end nucleotide sequences of two juvenile hormone-inducible vitellogenin genes of the African migratory locust.

Screening of lambda libraries prepared with locust (Locusta migratoria) genomic DNA yielded overlapping clones containing two complete vitellogenin genes, designated A and B, along with extensive 3'- and 5'-flanking sequences. Genes A and B are about 12 kb and 10.5 kb long, respectively, and both hybridize on Northern blots with 6300-nucleotide RNAs previously identified as vitellogenin mRNAs. Each gene contains a large intron near the 5' end and must also contain other introns. Repetitive "Lm1 elements," similar to the human Alu repetitive DNA elements, and other repeated sequences occur within the large intron and in the 3'- and 5'-flanking regions of each gene. Southern blots showed no cross-hybridization between the major portions of mRNA-coding sequences of genes A and B. DNA sequences have been determined for the 5' terminal exons and flanking regions of both genes. Both genes contain short (56-58 nucleotide) 5' leader exons, which, unlike the rest of the coding region, are highly conserved in sequence (87% identical) and code for amino acids that resemble the amino-terminal sequences of vertebrate vitellogenins. The upstream 5'-flanking sequences of the two genes contain several short stretches of similarity that may be involved in juvenile hormone regulated expression.

Animals↗
PubMed1988

RNA polymerase III promoter elements enhance transcription of RNA polymerase II genes.

Using transient expression assays in cultured human cells we have observed that RNA Polymerase III promoter sequences exert a positive cis-acting enhancer effect on RNA Polymerase II transcription. A DNA segment containing a copy of the Alu repeated element enhances transcription of the liver specific Haptoglobin related (Hpr) promoter in Hepatoma cell lines but not in HeLa cells. A tRNA(pro) gene acts as enhancer of the SV40 promoter both in Hepatoma and in HeLa cell lines. Transcription from the SV40 promoter is also enhanced by DNA segments containing only the box A or the box B of the tRNA(pro) promoter.

Carcinoma, Hepatocellular↗
PubMed1995

Insertion of an Alu sequence in the Ca(2+)-sensing receptor gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

Missense mutations in the calcium-sensing receptor (CaR) gene have previously been identified in patients with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). We studied family members of a Nova Scotian deme expressing both FHH and NSHPT and found, by PCR amplification of CaR gene exons, that FHH individuals were heterozygous and NSHPT individuals were homozygous for an abnormally large exon 7. This is due to an insertion at codon 877 of an Alu-repetitive element of the predicted-variant/human-specific-1 subfamily. It is in the opposite orientation to the CaR gene and contains an exceptionally long poly(A) tract. Stop signals are introduced in all reading frames within the Alu sequence, leading to a predicted shortened mutant CaR protein. The loss of the majority of the CaR carboxyl-terminal intracellular domain would dramatically impair its signal transduction capability. Identification of the specific mutation responsible for the FHH/NSHPT phenotype in this community will allow rapid testing of at-risk individuals.

Base Sequence↗
PubMed2005

Analysis of newly identified low copy AluYj subfamily.

Human specific AluY elements were investigated by comparative analysis between human chromosome 21 and chimpanzee chromosome 22. Human specific AluY element was identified on human chromosome 21q22 (accession no. AL163282), and then that was a new member of AluYj subfamily. From the bioinformatic analysis, AluYj subfamily was investigated in human whole genome using AluYj4 consensus sequence (accession no. AL163282). Thirteen members of the AluYj4 elements (4 diagnostic mutations) and eight members of the AluYj3 elements (3 diagnostic mutations) were identified with distinct diagnostic mutation from AluY consensus sequence. The results of the molecular clock calculation of non-CpG region substitution indicated that, AluYj4 elements (2.1 million years old) may be proliferated more recent time than AluYj3 elements (14.1 million years old). For the verification of recent insertion time, four of AluYj4 elements (ch2-AC017101, ch10-AC044786, ch12-AC007656 and ch21-AL163282) from human chromosomes 2, 10, 12, 21 were analyzed by PCR amplification using various human and primate DNA samples. Though, no polymorphism was detected in human population, we identified the new AluYj4 subfamily as the human specific elements.

Alu Elements↗