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PubMed1995

Description of a 700-kb yeast artificial chromosome contig containing the BCL1 translocation breakpoint region at 11q13.

We screened two human yeast artificial chromosome (YAC) libraries by polymerase chain reaction (PCR) with oligonucleotides specific to the BCL1 major translocation breakpoint cluster region at 11q13. Five YACs were isolated. Two of them were chimeric. One of these and remaining three YACs were characterized by hybridization with various known 11q13 probes, Alu-PCR fingerprinting, in situ hybridization, and isolation of YAC ends. A map of this ca 700-kb YAC contig was obtained. This map was consistent with maps established from total human genomic DNA. Every YAC in this region was found unstable and gave rise to reproducibly deleted lineages. Analysis in detail of these deletions over many generations showed that more than a single sequence might be involved. The availability of cloned material will facilitate the search for the still elusive genetic elements responsible for amplifications, deletions and translocations observed at 11q13 in malignancies.

Base Sequence↗
PubMed1990

Genomic organization and chromosomal localization of the human nucleolin gene.

Nucleolin, a eukaryotic nucleolar phosphoprotein, is involved in the synthesis and maturation of ribosomes. To characterize the genomic organization and regulatory sequences of this gene, two overlapping lambda clones containing the human nucleolin gene plus flanking regions were isolated from a genomic library using human nucleolin cDNA. Southern blots of genomic DNA from human, several mammals, chicken, and yeast revealed that the nucleolin gene is well conserved across these species. The gene consists of 14 exons with 13 intervening sequences and spans approximately 11 kilobases of DNA. Analysis of the splice junctions indicated that the amino-terminal domain and the four RNA binding domains plus the nuclear localization signal are split into adjacent exons. Sequences from the 5'-flanking and the first intron contain a high content of GC residues which is consistent with nucleolin being a "housekeeping" gene. Promoter elements include an atypical TATA box (GTTA), one CCAAT box much further from the initiation site, three reverse compliments of CCAAT (ATTGG), and two pyrimidine-rich nucleotide stretches. In addition, this region and the first intron contain numerous potential Sp1, GCF, CRE-fos, GCN, AP-1, AP-2, UCE, and sequences similar to the glucocorticoid receptor binding site. The transcription start site was determined by primer extension and S1 nuclease mapping of RNA from human liver. One Kpn and three Alu repeats were found within two of the middle introns. The 3'-untranslated portion of the gene contains five homology blocks in a 100-base pair region that are highly conserved among human, mouse, and hamster genomes. Finally, we have determined that the human nucleolin gene is located on chromosome 2q12-qter and is present at one copy per haploid genome. A restriction fragment length polymorphism with EcoRI has been detected in the gene.

Amino Acid Sequence↗
PubMedDate not supplied

[Nucleotide sequence of the repetitive B2 region of the mouse genome].

Mouse genome contains two major families of short interspersed repeats in more than 10(5) copies and scattered throughout the whole genome. They were named as B1 and B2 sequences since they were first isolated from the genome library by means of a dsRNA-B probe. Three copies of B2 family were sequenced and compared with previously sequenced B1 repeat. B2 ubiquitous repeat is of ca. 180 bp long. The members of the family deviate by 5% of nucleotides from the consensus sequence. B2 contains the regions of homology to RNA polymerase III split promoter and to 4.5 S snRNA I. In contrast to B1, it does not contain clear homologies to exon-intron junctions, papova replication origins and human Alu-sequence. One side of B2 repeat is represented by a very AT-rich sequence (30 bp long) followed with an oligo(A) stretch 10-15 nucleotides long. This region of the repeat is the most variable one. The unit is flanked by 15-16 bp direct repeats different in sequenced copies of B2. The same is true for some copies of B1 family. The properties of B1 and B2 repeats suggest that they represent a novel class of transposon-like elements of eukaryotic genome. The possible role of B-type repeats in genome reorganization, DNA replication and pre-mRNA processing is discussed.

Animals↗
PubMed2000

Preferential cleavage sites for Sau3A restriction endonuclease in human ribosomal DNA.

Previous studies of cloned ribosomal DNA (rDNA) variants isolated from the cosmid library of human chromosome 13 have revealed some disproportion in representativity of different rDNA regions (N. S. Kupriyanova, K. K. Netchvolodov, P. M. Kirilenko, B. I. Kapanadze, N. K. Yankovsky, and A. P. Ryskov, Mol. Biol. 30, 51-60, 1996). Here we show nonrandom cleavage of human rDNA with Sau3A or its isoshizomer MboI under mild hydrolysis conditions. The hypersensitive cleavage sites were found to be located in the ribosomal intergenic spacer (rIGS), especially in the regions of about 5-5.5 and 11 kb upstream of the rRNA transcription start point. This finding is based on sequencing mapping of the rDNA insert ends in randomly selected cosmid clones of human chromosome 13 and on the data of digestion kinetics of cloned and noncloned human genomic rDNA with Sau3A and MboI. The results show that a methylation status and superhelicity state of the rIGS have no effect on cleavage site sensitivity. It is interesting that all primary cleavage sites are adjacent to or entering into Alu or Psi cdc 27 retroposons of the rIGS suggesting a possible role of neighboring sequences in nuclease accessibility. The results explain nonequal representation of rDNA sequences in the human genomic DNA library used for this study.

Chromosomes, Human, Pair 13↗
PubMed1996

A population genetic study of the evolution of SINEs. II. Sequence evolution under the master copy model.

A transient population genetic model of SINE (short interspersed repetitive element) evolution assuming the master copy model is theoretically investigated. Means and variances of consensus frequency of nucleotides, nucleotide homozygosity, and the number of shared differences that are considered to have caused by mutations occurring in the master copy lineages are computed. All quantities investigated are shown to be monotone functions of the duration of the expansion period. Thus, they can be used to estimate the expansion period although their sampling variances are generally large. Using the theoretical results, the Sb subfamily of human Alu sequences is analyzed. First, the expansion period is estimated from the observed mean and variance of homozygosity. The expansion period is shown to be short compared to the time since the end of the expansion of the subfamily. However, the observed number of the shared differences is more than twice that expected under the master copy model with the estimated expansion period. Alternative models including that with multiple master copy loci to explain this observation are discussed.

Animals↗
PubMedDate not supplied

[Comparative analysis of B1- and B2-like repetitive sequences in DNA from different organisms].

Sequences homologous to short repeated elements of the mouse genome, B1 and B2, were detected in DNA of different organisms by dot-hybridization. The sequences B1 and B2 hybridized most efficiently with DNA of Myomorpha rodents and primates. The hybridization was also observed with DNA of all other eukaryotes studied, however, it is probably caused by an existence of short homologies with the B1 and B2 sequences only. The effective hybridization of the B1 sequence with DNA of primates is apparently explained by a presence of numerous copies of Alu sequence in their genomes. A repeated sequence of the human DNA that is able to hybridize with B2 sequence was cloned. It was designated as HsB2 sequence. There are about 5000 copies of this sequence in the human genome. To estimate the degree of homology, the melting temperature of hybrids of sequences B1 and B2 with DNA of rodents and some other mammals was measured. It was found that the degree of homology of B2 sequence (but not B1) correlated well with the phylogenetic relationship of the organisms. Perhaps, the difference of evolution of these sequences results from their structural and functional peculiarities.

Animals↗
PubMed1993

Characterization of human bone marrow-derived closed circular DNA clones.

Because of interest in mechanisms of recombination involved in chromosomal deletions in neoplastic disease, and their relation to possible rearrangements in normal tissues, we are studying circular DNA molecules from human tissue with a long-term goal of investigating them as possible by-products of physiologically relevant intrachromosomal recombination events. Covalently closed circular (ccc) DNA from human bone marrow was cloned in bacteriophage vectors, and fourteen clones chosen randomly from the cccDNA-derived library were characterized. Five clones originated from chromosome-specific centromeric alpha-satellite DNA; two clones carried highly repetitive sequences probably derived from interspersed repetitive elements; six clones were derived from single-copy chromosome-specific sequences which detected homologous rodent sequences; and one clone (EPM10) was derived from a small chromosome 11-specific sequence family which localized to chromosome regions 11cen and 11q14. Oligonucleotide primers derived from the cccDNA clones were used in polymerase chain reaction studies to show that (1) the EPM10 clone carried the circular junction, (2) several of the single-copy products could be detected in three different bone marrow cccDNA preparations, and (3) the Alu-PCR profile for bone marrow cccDNA showed distinct bands which were similar in four bone marrow cccDNA preparations.

Acute Disease↗
PubMed1996

Molecular characterization of the gene locus of the human cell proliferation-associated nuclear protein defined by monoclonal antibody Ki-67.

The human antigen defined by the monoclonal antibody Ki-67, the 'Ki-67 protein', is an ubiquitously expressed human nuclear protein strictly associated with cell proliferation and is widely used in routine pathology as a 'proliferation marker' to measure the growth fraction in human tumours. In immunoblots of proteins from proliferating cells, Ki-67 detects two bands with the apparent molecular weights of 345 and 395 kDa. Recently we reported on the cloning and sequencing of the complete cDNA of the Ki-67 protein. We found two isoforms of cDNA with full lengths of 11.4 and 12.5 kb, respectively, likely formed by the alternative splicing of exon 7. The remarkable exon 13 at the 'centre' of this gene contains 16 homologous segments of 366 bp (Ki-67 repeats), each including a highly conserved new motif of 66 bp (Ki-67 motif). Computer analyses confirmed that the cDNAs encode for a new class of nuclear proteins. The complete gene locus of the Ki-67 protein, comprising a 74 bp 5' region and a 264 bp 3' region, has been sequenced and aligned to a continuous sequence of 29,965 bp length located on chromosome 10q25-ter. The gene is organized in 15 exons with sizes from 67 to 6845 bp and in 14 introns with sizes from 87 to 3569 bp. Three introns contain homologue copies of 'Alu-repeats'. Interestingly, the introns flanking the alternative spliced exon 7 are free of any consensus donor and acceptor splicing signal. All other intron-exon transitions contained a potential branch site. The complete 5' region including the first two exons represents a CpG-rich island. We found the transcription initiation site in exon two adjacent to the consensus sequence of a cap site. Upstream of this cap site no TATA- or CCAAT-box could be located, but downstream we found two remarkable directly repeated elements of 24 bp lengths each containing a TATA box in inverse orientation.

Amino Acid Sequence↗
PubMed1996

Identification of promoter sequences in the 5' untranslated region of the baboon apolipoprotein[a] gene.

Like humans, baboons possess apolipoprotein[a] (apo[a]), a unique protein component of the atherogenic lipoprotein [a] (Lp[a]) particle. Baboon apo[a] also exhibits extensive variation with respect to size and serum levels. In this report, we have cloned the 5' flanking region of the baboon apo[a] gene (I isoform) and performed promoter mapping studies to identify sequences that control apo[a] transcription. The sequence of the baboon apo[a] 5' flanking region is similar to the human gene, and contains two Alu repeats that distinguish the apo[a] gene from plasminogen and other apo[a]-like genes. The transcription start site for the baboon apo[a]gene is located 85 bp upstream from the major start site for the human apo[a] gene. For promoter mapping studies, we constructed two sets of deletion clones (5' to 3' and 3' to 5') in luciferase reporter plasmids for transfection of hepatic cell lines (HepG2 and HUh7). These experiments showed that the 5' untranslated region (5' UTR) contains a positive promoter element with 85% identity to the consensus binding site for hepatocyte nuclear factor 1 alpha (HNF-1 alpha), and a negative element that is functional in HepG2 cells, but not Huh7 cells. Transfection assays with HeLa cells showed that the positive promoter element acts in an hepatocyte-specific manner. We also cloned the 5' flanking region from a baboon carrying a null allele that produced no detectable hepatic transcripts or serum isoforms in vivo. Surprisingly, the 5' flanking regions of the null allele possessed a promoter that was functional in transfection assays. We conclude that the baboon apo[a] gene 5'UTR contains hepatocyte-specific promoter elements, but that other unknown sequences must influence apo[a] expression in vivo.

Alleles↗
PubMed1982

Ubiquitous transposon-like repeats B1 and B2 of the mouse genome: B2 sequencing.

Mouse genome contains two major families of short interspersed repeats in more than 10(5) copies scattered throughout the whole genome. They are referred to as B1 and B2 sequences since they were first isolated from the genome library by means of a dsRNA-B probe /1/. In this work, two copies of the B2 family were sequenced and compared with the previously sequenced B1 repeat /2/. A B2 ubiquitous repeat is ca. 190 bp long. The members of the family deviate in 3-5% of nucleotides from the consensus sequence. B2 contains regions of homology to the RNA polymerase III split promoter and to 4.5S snRNA I. Both B1 and B2 contain regions which resemble junctions between exons and introns. In contrast to B1, B2 does not contain apparent homologies to papova viral replication origins and a human Alu sequence. One side of the B2 repeat is represented by a very AT-rich sequence (ca. 30 bp long) followed with an oligo (dA) stretch 10-15 nucleotides long. This region of the repeat is the most variable one. The whole unit is flanked with 15-16 bp direct repeats different in sequenced copies of B2. The same is true of some copies of the B1 family. The properties of B1 and B2 repeats suggest that they may represent a novel class of transposon-like elements in eukaryotic genome. A possible role of B-type repeats in genome reorganization, DNA replication and pre-mRNA processing is discussed.

Animals↗
PubMed1993

Identification of an Alu retrotransposition event in close proximity to a strong candidate gene for Huntington's disease.

Huntington's disease (HD) is a late-onset autosomal dominant neuropsychiatric disorder presenting in mid-adult life with personality disturbance and involuntary movements, cognitive and affective disturbance, and inexorable progression to death. The underlying genetic defect has been mapped to chromosomal band 4p16.3 (refs 2, 3). Analysis of specific recombination events in some families with HD has further refined the location of the HD defect to a 2.2 megabase DNA interval. Using a direct complementary DNA selection strategy we have identified at least seven transcriptional units within the minimal region believed to contain the HD gene. Screening with one of the cDNA clones identified an Alu insertion in genomic DNA from two persons with HD which showed complete cosegregation with the disease in these families but was not found in 1,000 control chromosomes. Two genes including the previously identified alpha-adducin gene and another that encodes for a 12-kilobase transcript, map in close proximity to the Alu insertion site. The 12-kilobase transcript should be regarded as a strong candidate for the HD gene.

Base Sequence↗
PubMed1987

A composite transposon 3' to the cow fetal globin gene binds a sequence specific factor.

Two unusual sequence organizations were found within the beta-globin locus of the cow. Each was a composite, consisting of closely linked Alu-type repeats with a short stretch of genomic non-repetitive sequence, called a lagan, sandwiched between. One lagan was found 3' to the fetal globin gene, while the second lay between the adult globin gene and a globin pseudogene. Southern blot analysis indicated that both lagans appeared twice within the cow haploid genome, with the second copies lying outside the cow beta-globin locus. One of these non-globin locus homologues was cloned and subjected to sequence analysis. Comparison of the DNA sequence data showed that the lagan-Alu composite was transposed as a unit. The lagan 3' to the cow fetal globin gene contains the recognition site for a sequence specific DNA binding factor. This factor was present in extracts from fetal, but not from adult cow tissues.

Animals↗
PubMed1990

Novel families of interspersed repetitive elements from the human genome.

Six novel families of interspersed repetitive elements have been detected in the available human DNA sequences using computer-assisted analyses. The estimated total number of elements in the reported six families is over 17,000. Sequences representative for each family range from approximately 150 to 650 base pairs (bp) in length and are predominantly (A + T)-rich. Sequences from four families contain stretches of patchy complementarity up to 45 bp long. Member of one of the families is likely be directly involved in a multigene deletion on chromosome 14. Two of the six sequence families are homologous to 'low reiteration frequency sequences' from monkey cells, detected first in defective variants of simian virus 40. Like Alu and L1 families, the newly discovered families are probably composed of pseudogenes derived from functional genes.

Animals↗
PubMed1989

The organization and the complete nucleotide sequence of the human NADH-cytochrome b5 reductase gene.

The organization and the complete nucleotide (nt) sequence of the b5R gene encoding human NADH-cytochrome b5 reductase (b5R; EC 1.6.2.2) have been determined by a combination of restriction mapping and nt sequence analysis of overlapping genomic DNA clones. The entire gene is about 31 kb in length and contains nine exons and eight introns. Exon 2 contains the junction of the membrane-binding domain and the catalytic domain of b5R, indicating that two forms of b5R, a soluble and a membrane-bound form, are generated by post-translational processing. The 5' portion of the b5R gene lacks the canonical 5' transcriptional regulatory elements, but contains five copies of the GC box sequence G-G-G-C-G-G. While the average G + C content of the b5R gene is 55%, that of the 5' portion of the gene is extraordinarily high (86%). The CpG dinucleotide sequence was found at a very high frequency in this G + C-rich region. These structural features are very similar to those of the regulatory regions of constitutively expressed 'housekeeping' genes. Several transcription start points were identified by the primer extension experiment. Seventeen complete and twelve incomplete Alu family sequences were found in introns. An uncanonical polyadenylation signal was detected in the 3'-untranslated region of the gene as A-G-T-A-A-A instead of A-A-T-A-A-A.

Amino Acid Sequence↗
PubMed2000

Conserved protein motifs and structural organization of a fish gene homologous to mammalian apolipoprotein E.

Apolipoprotein E (apoE) plays a central role in lipid metabolism from its ability to interact with lipoprotein receptors. Besides its role in cardiovascular diseases, apoE polymorphism contributes to susceptibility to neurodegenerative diseases, such as Alzheimer's disease. The statistical significance of the combined match scores obtained after apoE motif-based protein sequence database searches, the structural features of the deduced protein, and the phylogenetic analysis, support the evidence that a homologue to mammalian apoE can be found in teleost fish. Isolation and characterization of the first nonmammalian APOE revealed that the zebrafish gene spans 2555/2692 bp instead of 3597 bp in human and has the same splice junctions and exon/intron organization as found in mammals, except that there is an additional intron that splits the last exon (exon 4) into two exons (exons 4 and 5). Enlargement of APOE size in the mammalian lineage occurs mainly by Alu repeats insertion. The additional intron found in zebrafish gene was also identified at the same splicing site in trout APOE and is located in the corresponding linker region following the conserved low density lipoprotein receptor binding domain. Primer extension and reverse transcriptase PCR (RT-PCR) assays demonstrated that two transcription start sites are located 26 and 28 bp upstream of the first intron and 22 or 24 bp downstream from a canonical TATA box. Sequence inspection of the 5'-flanking region upstream of the TATA box revealed potential regulatory DNA elements. These results will serve as a basis for comparative studies on transcriptional and post-transcriptional mechanisms of APOE regulation in vertebrates.

Amino Acid Motifs↗
PubMed1994

A model for systemic lupus erythematosus based on chromatin disruption by polyamines.

Here it is hypothesized that some autoimmune disorders, such as systemic lupus erythematosus, result in part from overexpression of polyamines which leads to disruption of chromatin structure. Disruption of inactive chromatin, such as the inactive X chromosome, exposes sites of unrepaired DNA damage. Repair is then hampered by the polyamines. Disruption also facilitates transcription at previously sequestered sites. Especially interesting are RNA polymerase III sites in highly repeated sequences such as the Alu sequence. Transcription and translation from these sites could create RNA and polypeptides not normally expressed. These could be antigenic either individually or in association with other cellular components. Interactions of polyamines in the nucleus and with the membrane could also lead to polyamine facilitated apoptosis.

Antibodies, Antinuclear↗
PubMed2004

SINEs of speciation: tracking lineages with retroposons.

The value of short interspersed elements (SINEs) for diagnosing common ancestry is being expanded to examine the differential sorting of lineages through the course of speciation events. Because most SINEs are neutral markers of identical descent, are not precisely excised from the genome and have a known ancestral condition, they are advantageous for reconciling gene trees and species trees with minimal phylogenetic error. A population perspective on SINE evolution combined with coalescence theory provides a context for investigating the phenomenon of ancestral polymorphism and its role in producing incongruent SINE insertion patterns among multiple loci. Studies of human Alu repeats demonstrate the value of young polymorphic SINEs for assessing human genomic diversity and tracking ancient demographics of human populations, whereas incongruent insertion patterns revealed by older fixed SINE loci, such as those in African cichlid fishes, contain information that might help identify ancient radiations that are otherwise obscured by accumulated mutations in sequence data. Here, we review the utility of retroposons for inferring common ancestry, discuss limits to the method, and clarify confusion by providing examples from the literature that illustrate how discordant multi-locus insertion patterns of retroelements can indicate lineage-sorting events that should not be misinterpreted as phylogenetic noise.

Journal Article↗
PubMed1989

The current source of human Alu retroposons is a conserved gene shared with Old World monkey.

A significant fraction of human Alu repeated sequences are members of the precise, recently inserted class. A cloned member of this class has been used as a probe for interspecies hybridization and thermal stability determination. The probe was reassociated with human, mandrill, and spider monkey DNA under conditions such that only almost perfectly matching duplexes could form. Equally precise hybrids were formed with human and mandrill DNA (Old World monkey) but not with spider monkey DNA (New World). These measurements as well as reassociation kinetics show the presence in mandrill DNA of many precise class Alu sequences that are very similar or identical in quantity and sequence to those in human DNA. Human and mandrill are moderately distant species with a single-copy DNA divergence of about 6%. Nevertheless, their recently inserted Alu sequences arise by retroposition of transcripts of source genes with nearly identical sequences. Apparently a gene present in our common ancestor at the time of branching was inherited and highly conserved in sequence in both the lineage of Old World monkeys and the lineage of apes and man.

Animals↗