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[Structural organization of the human genome: distribution of nucleotides, Alu-repeats and exons in chromosomes 21 and 22].

Analysis of DNA sequences of the human chromosomes 21 and 22 performed using a specially designed MegaGene software allowed us to obtain the following results. Purine and pyrimidine nucleotide residues are unevenly distributed along both chromosomes, displaying maxima and minima (Y waves phi) with a period of about 3 Mbp. Distribution of G + C along both chromosomes has no distinct maxima and minima, however, chromosome 21 contains considerably less G + C than chromosome 22. Both exons and Alu repeats are unevenly distributed along chromosome 21: they are scarce in its left part and abundant in the right part, while MIR elements are quite monotonously spread along this chromosome. The Alu repeats show a wave-like distribution pattern similar for both repeat orientations. The number of the Alu repeats of opposite orientations was equal for both studied chromosomes, and this may be considered a new property of the human genome. The positive correlation between the exon and Alu distribution patterns along the chromosome, the concurrent distribution of Alu repeats in both orientations along the chromosome, and the equal copy numbers for Alu in direct and inverted orientations within an individual chromosome point to their important role in the human genome, and do not fit the notion that Alu repeats belong to parasitic (junk) DNA.

Chromosomes, Human, Pair 21↗
PubMed1991

The subset of mouse B1 (Alu-equivalent) sequences expressed as small processed cytoplasmic transcripts.

B1 (Alu-equivalent) is a murine short interspersed element whose amplification probably involved an RNA intermediate. B1-homologous RNA comprise a population of heterogenous transcripts of questionable function. A cloned B1 is expressed in the injected frog oocyte by RNA polymerase III transcription, ribonucleoprotein formation, post-transcriptional 3'-processing, and nucleocytoplasmic transport. The present study characterizes small cytoplasmic B1 transcripts of mouse cells. Analyses of ten cDNA clones revealed a subset of a high degree of sequence identity (98%) from which a novel consensus was developed. Structural analyses of these RNAs demonstrated a conserved Alu domain originally identified as part of the 7SL RNA within the translational control domain of the signal recognition particle, while this structure was not conserved in the majority of B1s in the sequence database. Furthermore, it was demonstrated that 3'-processing occurred in only a subset of B1 transcripts in-vitro using homologous nuclear extracts, and in the injected oocyte. The data demonstrate that a limited set of B1 sequences are expressed as processed RNA polymerase III-transcripts of a high degree of structural conservation. Although this subset is transcriptionally active, the selective expression may be due to regulation at the levels of processing and cytoplasmic accumulation. Their lack of Poly-(A) or 3'-oligo-(U) tracts argue that these RNAs are unlikely to represent transposition intermediates. Rather, their cytosolic compartmentalization and conservation of a biologically recognized structure, suggests potential involvement in other aspects of cellular metabolism.

Animals↗
PubMed1991

Characterization of a third major SINE family of repetitive sequences in the galago genome.

In addition to the Alu family of short interspersed repetitive DNA elements (SINEs), we have previously characterized one other repetitive DNA family (Type II) in the prosimian, Galago crassicaudatus. We present here a detailed analysis of seventeen members of a third galago SINE family designated as the Monomer family. Both the Monomer and Type II families are shown to be specific for the galago genome as compared to other primates, including another prosimian, the lemur. Moreover, in vitro transcription of galago SINEs suggests that the Monomer and Type II families have appreciably stronger RNA polymerase III promoters than does the Alu family. This agrees with the promoter sequence for each of these SINE families, in that the Monomer and Type II family promoters are more closely related to the RNA polymerase III promoter consensus sequence than is the Alu family promoter. These promoter strength analyses also correlate with copy number and sequence divergence analyses, which suggests that the SINE families with the strongest promoters have been amplified most recently in the galago genome.

Amino Acid Sequence↗
PubMed1983

A family of oligo-adenylate-terminated transposable sequences in Drosophila melanogaster.

Five members of the F family of transposable elements in Drosophila melanogaster have been characterized. Together with earlier work, these experiments lead to the following conclusions. There are about 50 copies of F elements in the genome located at about 25 euchromatic sites and in the chromocenter. Three of the cloned F elements have a length of 4.7 X 10(3) bases, the other two are truncated at their left ends by 0.4 X 10(3) and 1.3 X 10(3) bases, the other two are truncated at their left ends by 0.4 X 10(3) and 1.3 X 10(3) bases. The shortest F element has been found in a recently arisen revertant of the white ivory mutation. All F elements terminate at their right ends in a stretch of 12 to 30 A residues. A polyadenylation signal (A-A-T-A-A-A) precedes this terminus. Analysis of homologous DNA regions derived from two different strains of D. melanogaster containing F elements (filled sites) or lacking F elements (empty sites) showed that F insertions lead to the generation of target site duplications of 8 to 13 base-pairs. The five target sites analyzed differ in sequence but show a low level of homology. F elements do not contain internal repeats and, in particular, they lack the terminal redundancy characteristic of many other transposable elements. We compare F elements with other oligo(A)-terminated sequences, specifically the Alu sequences and processed pseudogenes of mammals. The presence of an oligo(A) stretch and of a polyadenylation signal raises the possibility that F elements transpose by a mechanism that involves transcription and reverse transcription followed by reinsertion into the genome.

Animals↗
PubMed2001

The association between HLA-A alleles and an Alu dimorphism near HLA-G.

The AluYb8 sequences are a subfamily of short interspersed Alu retroelements that have been amplified within the human genome during recent evolutionary time and are useful polymorphic markers for studies on the origin of human populations. We have identified a new member of the Yb8 subfamily, AluyHG, located between the HLA-H and -G genes and 88-kb telomeric of the highly polymorphic HLA-A gene within the alpha block of the major histocompatibility complex (MHC). The AluyHG element was characterised with a view to examining the association between AluyHG and HLA-A polymorphism and reconstructing the history of the MHC alpha block. A specific primer pair was designed for a simple PCR assay to detect the absence or presence (dimorphism) of the AluyHG element within the DNA samples prepared from a panel of 46 homozygous cell-lines containing complete or recombinant ancestral haplotypes (AH) of diverse ethnic origin and 92 Caucasoid and Asian subjects on which HLA-A typing was available. The AluyHG insertion was most strongly associated with HLA-A2 and, to a lesser degree with HLA-A1, -A3, -A11, and A-19. The gene frequency of the AluyHG insertion for 146 Caucasians and 94 Chinese-Han was 0.30 and 0.32 and there was no significant difference between the observed and expected frequencies. The results of the association studies and the phylogenetic analysis of HLA-A alleles suggest that the AluyHG sequence was integrated within the progenitor of HLA-A2, but has been transferred by recombination to other human ancestral populations. In this regard, the dimorphic AluyHG element is an important diagnostic marker for HLA association studies and could help in elucidating the evolution and functions of the MHC alpha block and polymorphism within and between ancestral haplotypes.

Alleles↗
PubMed2006

Molecular basis of Kindler syndrome in Italy: novel and recurrent Alu/Alu recombination, splice site, nonsense, and frameshift mutations in the KIND1 gene.

Kindler syndrome (KS) is a rare autosomal recessive disorder characterized by skin blistering in childhood followed by photosensitivity and progressive poikiloderma. Most cases of KS result from mutations in the KIND1 gene encoding kindlin-1, a component of focal adhesions in keratinocytes. Here, we report novel and recurrent KIND1 gene mutations in nine unrelated Italian KS individuals. A novel genomic deletion of approximately 3.9 kb was identified in four patients originating from the same Italian region. This mutation deletes exons 10 and 11 from the KIND1 mRNA leading to a truncated kindlin-1. The deletion breakpoint was embedded in AluSx repeats, specifically in identical 30-bp sequences, suggesting Alu-mediated homologous recombination as the pathogenic mechanism. KIND1 haplotype analysis demonstrated that patients with this large deletion were ancestrally related. Five additional mutations were disclosed, two of which were novel. To date, four recurrent mutations have been identified in Italian patients accounting for approximately approximately 75% of KS alleles in this population. The abundance of repetitive elements in intronic regions of KIND1, together with the identification of a large deletion, suggests that genomic rearrangements could be responsible for a significant proportion of KS cases. This finding has implications for optimal KIND1 mutational screening in KS individuals.

Adolescent↗
PubMed1983

A cluster of repetitive elements within a 700 base pair region in the mouse genome.

Approximately 39% of the clones from a BALB/c mouse genomic library hybridized with polyadenylated cytoplasmic RNA extracted from anemic mouse spleen. The DNA sequence of a portion of one such clone revealed the presence of three repetitive sequence elements within a 700 bp span. All three elements contain putative RNA polymerase III control regions oriented in the same direction and oligo(dA) tracts at their 3' ends. The first element is a member of the murine B1 family. A comparison of this element with other B1 family members indicates that the B1 family can be divided into two subclasses based on commonly held base changes and deletions. The second element within this 700 bp region may be a member of a new murine Alu family. Its structure is analogous to other murine Alu-equivalent sequences with respect to overall length, the presence of a 3' oligo(dA) tract and putative RNA polymerase III control regions. The third element is a murine type 2 Alu-equivalent sequence.

Animals↗
PubMed2002

Mammalian retroelements.

The eukaryotic genome has undergone a series of epidemics of amplification of mobile elements that have resulted in most eukaryotic genomes containing much more of this 'junk' DNA than actual coding DNA. The majority of these elements utilize an RNA intermediate and are termed retroelements. Most of these retroelements appear to amplify in evolutionary waves that insert in the genome and then gradually diverge. In humans, almost half of the genome is recognizably derived from retroelements, with the two elements that are currently actively amplifying, L1 and Alu, making up about 25% of the genome and contributing extensively to disease. The mechanisms of this amplification process are beginning to be understood, although there are still more questions than answers. Insertion of new retroelements may directly damage the genome, and the presence of multiple copies of these elements throughout the genome has longer-term influences on recombination events in the genome and more subtle influences on gene expression.

Animals↗
PubMed2000

Complete genomic sequence of the human ABCA1 gene: analysis of the human and mouse ATP-binding cassette A promoter.

The ABCA1 gene, a member of the ATP-binding cassette A (ABCA1) transporter superfamily, encodes a membrane protein that facilitates the cellular efflux of cholesterol and phospholipids. Mutations in ABCA1 lead to familial high density lipoprotein deficiency and Tangier disease. We report the complete human ABCA1 gene sequence, including 1,453 bp of the promoter, 146,581 bp of introns and exons, and 1 kb of the 3' flanking region. The ABCA1 gene spans 149 kb and comprises 50 exons. Sixty-two repetitive Alu sequences were identified in introns 1-49. The transcription start site is 315 bp upstream of a newly identified initiation methionine codon and encodes an ORF of 6,783 bp. Thus, the ABCA1 protein is comprised of 2,261 aa. Analysis of the 1,453 bp 5' upstream of the transcriptional start site reveals multiple binding sites for transcription factors with roles in lipid metabolism. Comparative analysis of the mouse and human ABCA1 promoter sequences identified specific regulatory elements, which are evolutionarily conserved. The human ABCA1 promoter fragment -200 to -80 bp that contains binding motifs for SP1, SP3, E-box, and AP1 modulates cellular cholesterol and cAMP regulation of ABCA1 gene expression. These combined findings provide insights into ABCA1-mediated regulation of cellular cholesterol metabolism and will facilitate the identification of new pharmacologic agents for the treatment of atherosclerosis in humans.

ATP Binding Cassette Transporter 1↗
PubMed2003

Genomic characterization of MOZ/CBP and CBP/MOZ chimeras in acute myeloid leukemia suggests the involvement of a damage-repair mechanism in the origin of the t(8;16)(p11;p13).

The t(8;16)(p11;p13), which is strongly associated with acute myeloid leukemia (AML) displaying monocytic differentiation, erythrophagocytosis by the leukemic cells, and a poor response to chemotherapy, fuses the MOZ gene (8p11) with the CBP gene (16p13). Although genomic rearrangements of MOZ and CBP have been detected using fluorescence in situ hybridization and Southern blot analyses, characterization of the breakpoints at the sequence level has never been performed. We have sequenced the breakpoints in four t(8;16)-positive AML cases with the aim to identify molecular genetic mechanisms underlying the origin of this translocation. In addition, an exon/intron map of the MOZ gene was constructed, which was found to be composed of 17 exons. Long-range-PCR with CBP forward primers in exon 2 and MOZ reverse primers in exon 17 as well as with a MOZ forward primer in exon 16 and a CBP reverse primer in intron 2 successfully amplified CBP/MOZ and MOZ/CBP hybrid genomic DNA fragments in all four AMLs. The breaks clustered in both CBP intron 2 and MOZ intron 16, and were close to repetitive elements, and in one case an Alu-Alu junction for the CBP/MOZ hybrid was identified. Additional genomic events (i.e., deletions, duplications, and insertions) in the breakpoint regions in both the MOZ and CBP genes were found in all four cases. Thus, the t(8;16) does not originate through a simple end-to-end fusion. The findings of multiple breaks and rearrangements rather suggest the involvement of a damage-repair mechanism in the origin of this translocation.

Acetyltransferases↗
PubMed2002

Identification of mRNAs differentially-expressed between benign and malignant breast tumour cells.

Two suppression subtracted cDNA libraries have been constructed, one containing cDNAs to mRNAs present at a higher level in a benign human breast tumour-derived cell line relative to the malignant mammary cell line, MCF-7, and the other containing cDNAs present at a higher level in the MCF-7 cells relative to the benign cells. Randomly-picked cloned DNAs have been sequenced yielding 29 and 128 different cDNAs from the benign and malignant libraries, respectively. Using reverse Northern hybridisation, 76% and 83% of the cDNAs were differentially expressed by greater than two-fold, whilst 14% and 11% of cDNAs in the respective libraries were differentially expressed by more than 15-fold. Amongst these were oestrogen-responsive cDNAs and expressed sequence tags. One such oestrogen-responsive expressed sequence tag, M41, is transcribed from a gene located on chromosome 21q22.3, within an intron of a larger gene. The M41 gene contains oestrogen response elements, one of which is associated with alu repeats. M41 mRNA is expressed at a statistically significantly higher level in human breast cancer specimens than in normal human breast and benign lesions. In carcinomas, its up-regulation is associated with the development of the malignant cell.

Breast↗
PubMed2003

Stimulation of Tat-independent transcriptional processivity from the HIV-1 LTR promoter by matrix attachment regions.

The chromatin environment and the sites of integration in the host genome are critical determinants of human immunodeficiency virus (HIV) transcription and replication. Depending on the chromosomal location of provirus integration within the genome, HIV-1 long terminal repeat (LTR)-mediated transcription may vary from 0- to 70-fold. Cis-elements such as topoisomerase II cleavage sites, Alu repeats and matrix attachment regions (MARs) are thought to be targets for retroviral integration. Here we show that a novel MAR sequence from the T-cell receptor beta locus (MARbeta) and the IgH MAR mediate transcriptional augmentation when placed upstream of the HIV-1 LTR promoter. The effect of transcriptional augmentation is seen in both transient and stable transfection, indicating its effect even upon integration in the genome. MAR-mediated transcriptional elevation is independent of Tat, and occurs synergistically in the presence of Tat. Further, we show that MAR-mediated transcriptional elevation is specific to the HIV-1 LTR and the Moloney murine leukemia virus LTR promoter. In a transient transfection assay using over-expressed IkappaB, the inhibitor of NF-kappaB, we show that MAR-induced processive transcription is NF-kappaB dependent, signifying the role of local enhancers within the LTR promoter. Furthermore, by RNase protection experiments using proximal and distal probes, we show that MAR-mediated transcriptional upregulation is more prominent at the distal rather than the proximal end, thus indicating the potential role of MARs in promoting elongation.

Animals↗
PubMed1982

Long internal direct repeat in Epstein-Barr virus DNA.

The nucleotide sequence of the long internal reiteration. IR1, of Epstein-Barr Virus DNA has been determined. The repeat unit is 3,071 base pairs which are 66.8% guanine plus cytosine. There is a CCAAT sequence 39 nucleotides 5' to a TATAA, which could indicate a promotor for transcription. The longest open reading frame is 1,124 base pairs. Also within IR1 is a sequence homologous to the papovavirus origin of DNA replication. The ori-like sequence is within a long palindromic region which is 500 base pairs overall. The palidromic region shares common features with the Alu family members and with eucaryotic transposable elements. The juncture between the short unique region (U1) and IR1 is also sequenced. The transition occurs in BamHI-C at 1,214 base pairs before the BamHI site in the first repeat of IR1. The transition from IR1 to the rightward unique region (U2) has been reported to be at 636 base pairs after the BamHI site in the last repeat of IR1. Thus, relative to the start of IR1 at the juncture with U1, the last copy of IR1 is a partial repeat which contains only the beginning 1,850 base pairs.

Base Composition↗
PubMed1996

Specific cloning of human DNA as yeast artificial chromosomes by transformation-associated recombination.

DNA molecules undergoing transformation into yeast are highly recombinogenic, even when diverged. We reasoned that transformation-associated recombination (TAR) could be employed to clone large DNAs containing repeat sequences, thereby eliminating the need for in vitro enzymatic reactions such as restriction and ligation and reducing the amount of DNA handling. Gently isolated human DNA was transformed directly into yeast spheroplasts along with two genetically marked (M1 and M2) linearized vectors that contained a human Alu sequence at one end and a telomere sequence at the other end (Alu-CEN-M1-TEL and Alu-M2-TEL). Nearly all the M1-selected transformants had yeast artificial chromosomes (YACs) containing human DNA inserts that varied in size from 70 kb to > 600 kb. Approximately half of these had also acquired the unselected M2 marker. The mitotic segregational stability of YACs generated from one (M1) or two (M1 and M2) vector(s) was comparable, suggesting de novo generation of telomeric ends. Since no YACs were isolated when rodent DNAs or a vector lacking an Alu sequence was used, the YACs were most likely the consequence of TAR between the repeat elements on the vector(s) and the human DNA. Using the BLUR13 Alu-containing vector, we demonstrated that human DNA could be efficiently cloned from mouse cells that contained a single human chromosome 16. The distribution of cloned DNAs on chromosome 16 was determined by fluorescence in situ hybridization. We propose that TAR cloning can provide an efficient means for generating YACs from specific chromosomes and subchromosome fragments and that TAR cloning may be useful for isolating families of genes and specific genes from total genome DNA.

Animals↗
PubMed1996

A novel 5'-upstream mutation in the factor XII gene is associated with a TaqI restriction site in an Alu repeat in factor XII-deficient patients.

The factor XII gene from factor XII-deficient patients was screened for mutations at the genomic level. In patients negative for cross-reacting material, a T to C transition 224 bp upstream of exon 3 was identified (exon 3-224 (T --> C)) that creates an additional TaqI restriction site in intron B. This mutation is located within a putative hormone responsive element and within a B box promoter of an Alu repeat of the Sb0 family. The TaqI site is associated with a G to C transversion upstream of the transcription initiation site (exon 1-8 (G --> C)). We discuss the possible roles of these elements in factor XII gene regulation.

Adult↗
PubMed1991

Elements which stimulate gene amplification in mammalian cells: role of recombinogenic sequences/structures and transcriptional activation.

HSAG-1 is a 3.4 kb mammalian genomic element which has been shown to stimulate the amplification of the pSV2DHFR expression vector in cis when transfected into a variety of cell lines (1). This amplification stimulatory activity requires the interaction of multiple positive acting elements that include sequence features associated with recombination 'hotspots', such as Alu-like repetitive sequences and A/T rich regions (2). We demonstrate here that two other members of the HSAG family of elements, HSAG-2 and HSAG-5, also stimulate vector amplification. By analysis of the HSAG-2 nucleotide sequence and of the amplification activity of HSAG-2 and HSAG-5 subfragments, we show that this activity also involves the interaction of multiple positive acting elements. The autonomous replication of the HSAG containing vectors is not responsible for this effect. We also show that the orientation of HSAG elements in pSV2DHFR has a profound effect on their amplification stimulatory activity, and present evidence that the transcription of these elements in pSV2DHFR is necessary for the effect.

Animals↗
PubMed1994

Sequence analysis of the breakpoint cluster region in the ALL-1 gene involved in acute leukemia.

DNA rearrangements caused by chromosome translocations between band 11q23 and various chromosomes can be detected by a single probe, B859, an 859-base pair complementary DNA fragment derived from the human ALL-1 gene. To try to understand why band 11q23 becomes a frequent target of the translocations, we have sequenced the entire breakpoint cluster region, a 8342-base pair BamHI genomic fragment delineated by B859. We found eight Alu repeats located within this region in the same orientation as the ALL-1 gene. We have also analyzed the sequences of the breakpoints in 10 patients with 6 different types of 11q23 aberration. In five patients the breaks coincided with Alu sequences on chromosome 11, but not on the partner chromosomes. Also, seven of the breaks occurred in the region delineated by exons 6 and 7, which is composed mainly of Alu sequences. In three patients topoisomerase II recognition site-like sequences, at different stringency levels, were identified at the breakpoints on chromosome 11. We conclude that while there is no specific sequence element present at all the breakpoints, the high density of Alu sequences in the breakpoint cluster region possibly makes the latter more prone to recombination events.

Acute Disease↗
PubMed1996

Integration of retroposable elements in mammals: selection of target sites.

Genomic DNA fragments generated by the reverse transcription of cellular RNA are called retroposons. Because they are flanked by short repeats, mammalian retroposons are believed to integrate at staggered chromosomal breaks. Recently, a significant sequence pattern associated with the integration of Alu and ID repeats was identified (Jurka 1996). It is represented by the 5' TTAAAA consensus sequence around the 5' ends of flanking repeats of Alu, ID, as well as, of B1 and B2 retroposed elements as shown in this paper. This consensus is a potential target for enzymatic nicking which probably occurs in the complementary strand between 3' AA and the following 3' TTTT bases. The first four bases of the flanking repeats corresponding to the 3' TTTT consensus sequence show some sequence variations that may be affected by complementary base pairing between the A-rich RNA tails and the DNA target sequences prior to nicking and reverse transcription. We discuss potential evidence for such base pairing based on correlated variations in nucleotide composition of different tail and target regions.

Animals↗