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PubMed1993

Towards covering immunological genes with highly informative markers: a trans-species approach.

To establish a highly informative screening system for immunologically relevant genes ("immunoprinting") we co-amplified via polymerase chain reaction (PCR) polymorphic exons plus adjacent intronic simple repetitive dinucleotide stretches in the T-cell receptor (Tcr) Vb6 and Major Histocompatibility Complex (MHC)-DRB loci in man and several ungulate species. In both gene families the basic structure of the simple repeat was found to be preserved for more than 70 x 10(6) years in all investigated species. The simple repeats exhibit extensive length variability. Distinct exon sequences are correlated with a defined repeat length and substructure. In addition, PCR and the oligonucleotides for typing were applicable to a broad range of species from different mammalian orders. Multiplex PCR of different members of the Tcr Vb6 family and MHC-DRB resulted in a complex pattern similar to an oligolocus fingerprint. Hence immunoprinting can be employed for searching for associations of immunologically relevant genes with diseases even across species barriers.

Animals↗

PubMed1994

Genes with triplet repeats: a new class of mutations causing neurological diseases.

Microsatellites, simple tamdem repeats of 2 to 4 nucleotide sequences, are widely distributed throughout the genome. Trinucleotide repeats are found every 300 to 500 kb. Recently, a new type of mutation was described involving a specific expansion of triplets within or in close proximity to a gene. Expanded triplets have been found in the genes causing six different neurological disorders: fragile X syndrome (FRAXA), spinal and bulbar muscular atrophy (SBMA), myotonic dystrophy (DM), Huntington's disease (HD), spinocerebellar ataxia type 1 (SCA1), and dentato-rubra-pallidoluysian atrophy (DRPLA). These neurological disorders have in common a variable age of onset and clinical severity, as well as a decrease in the age of onset over generations, known as anticipation. These unusual characteristics are related to the observation that expanded repeats are unstable both in meioses and mitoses. A younger age of onset and an increase in severity correlate with a higher number of repeats. Interestingly, particular haplotypes are in disequilibrium with the mutation for FRAXA, DM and HD, suggesting instability for selected chromosomes. How expanded triplets affect the expression and the function of genes is still unknown. Since neurodegenerative disorders are often variable in age of onset and clinical severity, the list of expanding triplet mutations should increase in the very near future.

DNA↗

PubMed1991

An improved microcomputer program for finding gene- or gene family-specific oligonucleotides suitable as primers for polymerase chain reactions or as probes.

We present here an easy-to-use computer program which finds oligonucleotides suitable as primers in polymerase chain reactions (PCR) or as probes for hybridization. In contrast to other programs used for this purpose, the additional advantage of this one is the possibility of directly detecting gene- as well as gene family-specific oligonucleotides. For this purpose, up to 200 different DNA sequences, of maximally 65,000 nucleotides each, can be scanned in a single search to ensure either single or multiple gene binding of the PCR primers or probes. Specific oligonucleotides for genes carrying internal repetitions and for single genes belonging to a set of highly conserved genes can also be detected. Many parameters such as exclusion of simple sequences, which are known to be highly repeated throughout various genomes or regions of stable secondary structures in both primer-primer and primer-template, can be taken into consideration and avoided. Furthermore, the G + C content and the length of the oligonucleotides can be changed in a broad range by the user.

Animals↗

PubMed2004

Telomeres and telomerase.

Telomeres are the protective DNA-protein complexes found at the ends of eukaryotic chromosomes. Telomeric DNA consists of tandem repeats of a simple, often G-rich, sequence specified by the action of telomerase, and complete replication of telomeric DNA requires telomerase. Telomerase is a specialized cellular ribonucleoprotein reverse transcriptase. By copying a short template sequence within its intrinsic RNA moiety, telomerase synthesizes the telomeric DNA strand running 5' to 3' towards the distal end of the chromosome, thus extending it. Fusion of a telomere, either with another telomere or with a broken DNA end, generally constitutes a catastrophic event for genomic stability. Telomerase acts to prevent such fusions. The molecular consequences of telomere failure, and the molecular contributors to telomere function, with an emphasis on telomerase, are discussed here.

DNA Damage↗

PubMed2004

Neurological proteins are not enriched for repetitive sequences.

Proteins associated with disease and development of the nervous system are thought to contain repetitive, simple sequences. However, genome-wide surveys for simple sequences within proteins have revealed that repetitive peptide sequences are the most frequent shared peptide segments among eukaryotic proteins, including those of Saccharomyces cerevisiae, which has few to no specialized developmental and neurological proteins. It is therefore of interest to determine if these specialized proteins have an excess of simple sequences when compared to other sets of compositionally similar proteins. We have determined the relative abundance of simple sequences within neurological proteins and find no excess of repetitive simple sequence within this class. In fact, polyglutamine repeats that are associated with many neurodegenerative diseases are no more abundant within neurological specialized proteins than within nonneurological collections of proteins. We also examined the codon composition of serine homopolymers to determine what forces may play a role in the evolution of extended homopolymers. Codon type homogeneity tends to be favored, suggesting replicative slippage instead of selection as the main force responsible for producing these homopolymers.

Alanine↗

PubMed1984

Simple sequences are ubiquitous repetitive components of eukaryotic genomes.

Simple sequences are stretches of DNA which consist of only one, or a few tandemly repeated nucleotides, for example poly (dA) X poly (dT) or poly (dG-dT) X poly (dC-dA). These two types of simple sequence have been shown to be repetitive and interspersed in many eukaryotic genomes. Several other types have been found by sequencing eukaryotic DNA. In this report we have undertaken a systematical survey for simple sequences. We hybridized synthetical simple sequence DNA to genome blots of phylogenetically different organisms. We found that many, probably even all possible types of simple sequence are repetitive components of eukaryotic genomes. We propose therefore that they arise by common mechanisms namely slippage replication and unequal crossover and that they might have no general function with regards to gene expression. This latter inference is supported by the fact that we have detected simple sequences only in the metabolically inactive micronucleus of the protozoan Stylonychia, but not in the metabolically active macronucleus which is derived from the micronucleus by chromosome diminution.

Animals↗

PubMed2005

Sequential-context-dependent hippocampal activity is not necessary to learn sequences with repeated elements.

Learning sequences of events (e.g., a-b-c) is conceptually a simple problem that can be solved using asymmetrically linked cell assemblies [e.g., "phase sequences" (Hebb, 1949)], provided that the elements of the sequence are unique. When elements repeat within the sequence, however (e.g., a-b-c-d-b-e), the same element belongs to two separate "contexts," and a more complex sequence encoding mechanism is required to differentiate between the two contexts. Some neural structure must form sequential-context-dependent, or "differential," representations of the two contexts (i.e., b as an element of "a-b-c" as opposed to "d-b-e") to allow the correct choice to be made after the repeated element. To investigate the possible role of hippocampus in complex sequence encoding, rats were trained to remember repeated-location sequences under three conditions: (1) reward was given at each location; (2) during training, moveable barriers were placed at the entry and exit of the repeated segment to direct the rat and were removed once the sequence was learned; and (3) reward was withheld at the entry and exit of the repeated segment. In the first condition, hippocampal ensemble activity did not differentiate the sequential context of the repeated segment, indicating that complex sequences with repeated segments can be learned without differential encoding within the hippocampus. Differential hippocampal encoding was observed, however, under the latter two conditions, suggesting that long-term memory for discriminative cues present only during training, working memory of the most recently visited reinforcement sites, or anticipation of the subsequent reinforcement site can separate hippocampal activity patterns at the same location.

Acoustic Stimulation↗

PubMed1999

[Effect of simple repeats (AC)n and (AT)n on chloramphenicol acetyltransferase gene expression in Escherichia coli].

According to some published reports, simple repeats can modulate gene transcription. The ability of (AC)n and (AT)n sequences to modulate gene expression in E. coli was investigated. These repeats were inserted in the leader sequence, in its 3' uncoding region, and in both these sites. When simple sequences were inserted in the leader sequence, gene expression was the highest for constructions containing 40 bp insertion. An increase in the insertion length led to a decrease in the gene expression. The (AC)20 sequence insertions in a 3' uncoding site of cat gene did not notably change its expression. Gene expression was much more modified by inserting the simple sequences on both sites of cat gene. Cat gene expression depended on the ratio of simple sequence lengths in its 5' and 3' uncoding sites. It was the highest when (AC)n sequence in the gene leader sequence or its 3' uncoding region was 40 bp. Gene expression modulation by simple sequence is assumed to be associated with the DNA lability increase.

3' Untranslated Regions↗

PubMed1994

Different types of structural variation in STRs: HumFES/FPS, HumVWA and HumD21S11.

Alleles of the STR systems HumFES/FPS, HumVWA and HumD21S11 were sequenced and analyzed. Sequence data revealed 3 different systems concerning the complexity of their sequence structure. HumFES/FPS belongs to the STR polymorphism with a simple repeat structure. Only 2 subtypes were found with a base substitution in the 5'-flanking region and no variation in the repeat region. In the STR system HumVWA the sequence structure of the repeat region is more complex, because 2 tetranucleotide units TCTA and TCTG were present. Additionally allele 14 revealed a completely different sequence structure leading to a different electrophoretic mobility. The repeat region of HumD21S11 is compound in structure. The possibility of variation at 3 positions leads to the occurrence of microheterogeneities in fragments of apparent length. In the upper allele range alleles arise with an additional incomplete TA-repeat.

Alleles↗

PubMed2000

Microsatellite instability of dinucleotide tandem repeat sequences is higher than trinucleotide, tetranucleotide and pentanucleotide repeat sequences in prostate cancer.

In order to investigate whether the change in length of simple repetitive genomic sequences (microsatellite instability) is associated with prostate cancer, we analyzed 40 prostate cancer samples with 44 microsatellite loci markers on chromosomes 1, 3, 5, 6, 8, 9, 11, 13, 16, 17 and X. DNA was extracted from normal and tumor cells of 40 microdissected cancer samples, amplified by PCR and analyzed for microsatellite instability using 44 primers for dinucleotide, trinucleotide, tetranucleotide and pentanucleotide repeat sequences. The results of this study demonstrate that 45% of the prostate cancer specimens (18 out of 40) showed microsatellite instability (MSI) at a minimum of one locus using dinucleotide repeat sequences. Two out of 40 samples (5%) showed MSI at a minimum of one locus using three different trinucleotide repeat primers (AR, SR and TBP). Ten out of 40 (25%) samples showed MSI at a minimum of one locus using five different tetranucleotide repeat primers (HPRT1, HPRTII, MYCL1, RB, REN). There were no MSI observed in samples using pentanucleotide repeat sequences. There were no MSI in benign prostatic hyperplasia samples (25 samples). These experiments suggest that the microsatellite instability of dinucleotide tandem repeat sequences is much higher than trinucleotide, tetranucleotide and pentanucleotide repeat sequences in prostate cancer. The MSI with different lengths of nucleotide repeat sequences did not correlate with the stage and grades of prostate cancer.

Dinucleotide Repeats↗

PubMedDate not supplied

Early detection of bone marrow engraftment by amplification of hypervariable DNA regions.

BACKGROUND AND OBJECTIVE: After allogeneic bone marrow transplantation (BMT) it is important to be able to distinguish between the host and donor origin of cells in order to monitor the engraftment process. However, identifying whether the hematopoietic stem cells are of donor or recipient origin may be a difficult task. DNA studies using Southern blotting techniques or the amplification by PCR of regions in the human genome with high polymorphic neutral sequence variation showing Mendelian inheritance as variable number of tandem repeats (VNTR) can detect the origin of host bone marrow after BMT. We have tried to apply these sensitive systems of detection to the early stages of BMT when small numbers of regenerated cells are available for analysis. METHODS: We used in vitro polymerase chain reaction (PCR) amplification of three single-locus simple repetitive DNA sequences, all of which vary extensively in their repeat number among different individuals (VNTR D1S80, ApoB, and D17S5), to evaluate post transplant engraftment in six patients who showed no signs of peripheral blood engraftment at 2-3 weeks after transplant. We tested 2 patients with chronic myelogenous leukemia (CML), 2 with B-acute lymphoblastic leukemia (B-ALL), 1 with T-acute lymphoblastic leukemia (T-ALL), and 1 with aplastic anemia (SAA), all in prolonged aplasia following allogeneic bone marrow transplantation (BMT). RESULTS: In a sequential analysis protocol with the different loci, the donor was distinguishable from the recipient in all pairs with at least one of the three markers used. After 16 days (median 16.2; range 15 to 20 days) we found that complete chimerism was present in 5 patients: 4 of donor origin (= engraftment) and one of host origin (= rejection), this last case being one of mixed chimerism. In the 2 cases in which the presence (one complete and one partial) of host DNA was detected, rejection of the donor bone marrow followed, and in 1 patient a second BMT was necessary. The other 4 patients with complete chimerism of donor origin achieved hematological reconstitution and we documented complete engraftment of donor bone marrow a few months later. INTERPRETATION AND CONCLUSIONS: Utilizing PCR to document early post-transplant engraftment and chimerism in the first month after BMT has the advantage over Southern blotting of being more sensitive and requiring small amounts of sample. It may also be useful for guiding subsequent therapeutic decisions.

Biomarkers↗

PubMed1990

Repetition structure of mammalian nuclear DNA.

We have used Fragmentation Sequencing logic to analyse the repetition structure of several large human genomic genes. The method, based on a proposed laboratory scheme for DNA sequencing, detects short sequences which are repeated near, but not necessarily adjacent, to each other (cryptically simple DNA). We find a low frequency of such repeats. There is a slight excess of such repeats in introns over exons, and a slight but significant excess in genomic DNA over random DNA, confirming that cryptically simple sequences are over-represented in the genome. The analysis suggests that Fragmentation Sequencing will be a suitable method for sequencing large mammalian genes.

Animals↗

PubMed1975

A mechanism for initiation of genetic recombination.

A mechanism for the initiation of genetic recombination is proposed. Its key features are the pairing, nicking, and cross-annealing of palindromic loops, i.e., structures formed by DNA with sequences of inverted complementary repeats. This mechanism may provide a simple, yet specific means of producing crossed strand connections between homologous DNA duplexes to form structures which can be intermediates in the process of genetic recombination.

Base Sequence↗

PubMed1996

Characterization of Mycobacterium tuberculosis complex direct repeat sequence for use in cycling probe reaction.

Cycling probe technology (CPT) is a unique and simple method for the detection of specific target sequences. CPT utilizes a chimeric DNA-RNA-DNA probe providing an RNase H-sensitive scissile linkage when bound to a complementary target sequence. For this study a diagnostic assay based on CPT was developed for the detection of the 36-bp direct repeat (DR) region in Mycobacterium tuberculosis. To determine the feasibility of using the DR for detecting M. tuberculosis by CPT, a wide variety of mycobacteria were tested by Southern blot hybridization with three DR probes to verify their specificity. The entire DR region of Mycobacterium bovis 401 was sequenced, and the data were used to design a PCR assay that would allow us to estimate the number of DRs present in a variety of strains. A CPT assay which uses a probe complementary to the DR region was developed and evaluated with synthetic targets and genomic DNA from mycobacteria. In summary, the 36-bp DR provides an attractive target for detecting M. tuberculosis because the sequence is present in high copy numbers in the genome, is specific for the M. tuberculosis complex, and is found in strains that lack IS6110.

Animals↗

PubMed1995

Refined physical map of the spinal muscular atrophy gene (SMA) region at 5q13 based on YAC and cosmid contiguous arrays.

The gene for the autosomal recessive neurodegenerative disorder spinal muscular atrophy has been mapped to a region of 5q13 flanked proximally by CMS-1 and distally by D5S557. We present a 2-Mb yeast artificial chromosome (YAC) contig constructed from three libraries encompassing the D5S435/D5S629/CMS-1-SMA-D5S557/D5S112 interval. The D5S629/CMS-1-SMA-D5S557 interval is unusual insofar as chromosome 5-specific repetitive sequences are present and many of the simple tandem repeats (STR) are located at multiple loci that are unstable in our YAC clones. A long-range restriction map that demonstrates the SMA-containing interval to be 550 kb is presented. Moreover, a 210-kb cosmid array from both a YAC-specific and a chromosome 5-specific cosmid library encompassing the multilocus STRs CATT-1, CMS-1, D5F149, D5F150, and D5F153 has been assembled. We have recently reported strong linkage disequilibrium with Type I SMA for two of these STRs, indicating that the gene is located in close proximity to or within our cosmid clone array.

Base Sequence↗

PubMed1996

Long, polymorphic microsatellites in simple organisms.

We have examined the phylogenetic distribution of the longest, perfect microsatellites in GenBank. Despite the large contributions of model higher-eukaryotic organisms to GenBank, the selective cloning of long microsatellites from these organisms as genetic markers, and the relative lack of concentration on the microsatellites in lower eukaryotes and prokaryotes, we found that simple organisms, defined here as slime molds, fungi, protists, prokaryotes, viruses, organelles and plasmids, contributed 78 of the 375 examined sequences. These 78 simple-organism microsatellites are characterized predominantly by trinucleotide repeats, nearly half of which lie in exons, and in general show a bias towards A+T rich motifs. Simple-organism microsatellites represented more than once in GenBank displayed length polymorphisms when independent clones were compared. These facts collectively raise speculation as to the role of these 'junk' sequences in such highly economical genomes, especially when precise changes in long microsatellites are known to regulate critical virulence factors in several prokaryotes. Regardless of their biological significance, simple-organism microsatellites may provide a general source of molecular markers to track disease outbreaks and the evolution of microorganisms in unprecedented detail.

Animals↗

PubMed2000

Switching of flagellar motility in Helicobacter pylori by reversible length variation of a short homopolymeric sequence repeat in fliP, a gene encoding a basal body protein.

The genome of Helicobacter pylori contains numerous simple nucleotide repeats that have been proposed to have regulatory functions and to compensate for the conspicuous dearth of master regulatory pathways in this highly host-adapted bacterium. H. pylori strain 26695, whose genomic sequence was determined by The Institute for Genomic Research (TIGR), contains a repeat of nine cytidines in the fliP flagellar basal body gene that splits the open reading frame in two parts. In this work, we demonstrate that the 26695(C9) strain with a split fliP gene as sequenced by TIGR was nonflagellated and nonmotile. In contrast, earlier isolates of strain 26695 selected by positive motility testing as well as pig-passaged derivatives of 26695 were all flagellated and highly motile. All of these motile strains had a C(8) repeat and consequently a contiguous fliP reading frame. By screening approximately 50,000 colonies of 26695(C9) for motility in soft agar, a motile revertant with a C(8) repeat could be isolated, proving that the described switch is reversible. The fliP genes of 20 motile clinical H. pylori isolates from different geographic regions possessed intact fliP genes with repeats of eight cytidines or the sequence CCCCACCC in its place. Isogenic fliP mutants of a motile, C(8) repeat isolate of strain 26695 were constructed by allelic exchange mutagenesis and found to be defective in flagellum biogenesis. Mutants produced only small amounts of flagellins, while the transcription of flagellin genes appeared unchanged. These results strongly suggest a unique mechanism regulating motility in H. pylori which relies on slipped-strand mispairing-mediated mutagenesis of fliP.

Amino Acid Sequence↗

PubMed1988

Identification of a repeated sequence in the genome of the sea urchin which is transcribed by RNA polymerase III and contains the features of a retroposon.

A repeated sequence element which is located about 200 nucleotides upstream from the protein-coding portion of the muscle actin gene (probably within a large 5' intron) in the genome of the sea urchin, Strongylocentrotus purpuratus has been characterized, and shown to contain the sequence features which indicate that it has been transposed by means of an RNA intermediate. This retroposon-like sequence, SURF1-1, is a member of a family which is dispersed and repeated about 800 times in the genome, referred to as SURF1 (sea urchin retroposon family 1). In vitro transcription of this sequence by RNA polymerase III defines a 300 nucleotide transcription unit which is bounded by a short direct repeated sequence. The 3' end of this unit contains a simple 21 nucleotide A+T-rich sequence characteristic of retroponons, and a consensus B box portion of an internal RNA polymerase III promotor is located 60 to 80 nucleotides downstream from the two sites of transcription initiation. This sequence also contains a 40 nucleotide region that is related to several tRNA sequences (containing the B box), and a 79 nucleotide sequence which is homologous to a repeated sequence previously shown to be present within the 3' untranslated portions of the Spec1 and Spec2 mRNAs of this species (1). Analysis of transcripts of this sequence family in RNA from several embryonic stages indicates that its expression is highest at 11 hours postfertilization (about 128 cells) and drops as development proceeds. Furthermore, most or all, transcription of this sequence family in nuclei isolated from 11 hour embryos is by RNA polymerase III, and is from the same strand which is transcribed in vitro.

Actins↗