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PubMed1999

Human identity testing with PCR-based systems.

Large numbers of repetitive stretches of DNA are present within the human genome that are associated with human individuality due to their polymorphic character. Approximately one-third of these repeat sequences is arranged as microsatellites or short tandem repeats (STRs) whose valuable application as state-of-the-art technique in human identity testing will be briefly summarized in this review. Prerequisites for successful DNA typing using STRs amplified by polymerase chain reaction (PCR) are outlined and particular attention is paid to the molecular structure of STRs from autosomes as well as from the Y chromosome. A comprehensive overview about current and emerging methods of STR analysis is given as well.

Genetic Variation↗
PubMed1992

Genetic and physical maps of human chromosome 4 based on dinucleotide repeats.

Characterization of inherited variations within tandem arrays of dinucleotide repeats has substantially advanced the construction of genetic maps using linkage approaches over the last several years. Using a backbone of 10 newly identified microsatellite repeats on human chromosome 4 and 6 previously identified short tandem repeat element polymorphisms, we have constructed several genetic maps and a physical map of human chromosome 4. The genetic and physical maps are in complete concordance with each other. The genetic maps include a 15-locus microsatellite-based linkage map, a framework map of high support incorporating a total of 39 independent loci, a 25-locus high-heterozygosity, easily used index map, and a gene-based comprehensive map that provides the best genetic location for 35 genes mapped to chromosome 4. The 16 microsatellite markers are each localized to one of nine regions of chromosome 4, delineated by a panel of somatic cell hybrids. These results demonstrate the utility of PCR-based repeat elements for the construction of genetic maps and provide a valuable resource for continued high-resolution mapping of chromosome 4 and of genetic disorders to this chromosome.

Base Sequence↗
PubMed2001

Genotyping of dinucleotide tandem repeats by MALDI mass spectrometry of ribozyme-cleaved RNA transcripts.

We describe a method for high-throughput typing of short tandem repeat (STR) polymorphisms. Current gel electrophoresis techniques allow only moderate throughput with long hands-on and analysis time, and the output is on a relative scale of electrophoretic mobility, prone to artifacts. Matrix-assisted laser- desorption/ionization mass spectrometry (MALDI-MS) enables an automated high throughput and delivers accurate data directly depicting the molecular nature of the analyte. Analysis of large DNA fragments, however, is limited by adduct formation and fragmentation, which result in peak broadening and low signal intensity. MALDI typing of polymorphic STRs has been reported for tri- and tetranucleotide repeats with sufficient resolution to distinguish alleles. For dinucleotide repeats, essential in animal genome studies, an enhanced resolution is necessary. Increased mass resolution was reported for RNA (ref. 7) and modified DNA (refs 8-10) due to substituents that disfavor intramolecular reactions leading to fragmentation. RNA transcripts can be synthesized enzymatically from PCR products containing a promoter sequence, requiring no specialty reagents or primer labels. Furthermore, RNA transcripts are single-stranded, a prerequisite for high-resolution mass spectrometry of nucleic acids. The 3' heterogeneities produced by viral RNA polymerases, however, impede exact sizing of RNA runoff transcripts. Non-templated multiple-base extensions as well as premature termination have been reported. PCR of dinucleotide repeats tends toward the deletion of repeat units, generating a complex pattern of interleaved extensions (from RNA polymerase) and deletions (from PCR) that obscure the true allele size. We overcome this obstacle by adding a 3' sequence encoding a catalytic RNA sequence, the so-called hammerhead ribozyme, that cleaves itself co-transcriptionally, creating a homogeneous 3' end.

Alleles↗
PubMed1992

Survey of human and rat microsatellites.

Length variations in simple sequence tandem repeats (microsatellite DNA polymorphisms) are finding increasing usage in mammalian genetics. Although every variety of short tandem repeat that has been tested has been shown to exhibit length polymorphisms, little information on the relative abundance of the different repeat motifs has been collected. In this report, summaries of GenBank searches for all possible human and rat microsatellites ranging from mononucleotide to tetranucleotide repeats are presented. In humans, the five most abundant microsatellites with total lengths for the runs of repeats of greater than or equal to 20 nucleotides contained repeat sequences of A, AC, AAAN, AAN, and AG, in order of decreasing abundance, where N is C, G, or T. These five groups comprised about 76% of all microsatellites. Many other human simple sequence repeats were found at low frequency. In the 745 kb of human genomic DNA surveyed, one microsatellite of greater than or equal to 20 nucleotides in length was found, on average, every 6 kb. Only 12% of the human microsatellites had total lengths greater than or equal to 40 nucleotides. Roughly 80% of the A, AAN, and AAAN microsatellites and 50% of the AT microsatellites, but few of the other human microsatellites, were found to be associated with interspersed, repetitive Alu elements. In rats, the five most abundant microsatellites contained AC, AG, A, AAAN, and AAGG sequences, respectively. Rat microsatellites were generally longer than human microsatellites, with 43% of the rat sequences greater than or equal to 40 nucleotides.

Animals↗
PubMed1995

The gene for the peroxisomal targeting signal import receptor (PXR1) is located on human chromosome 12p13, flanked by TPI1 and D12S1089.

Mutations in the PXR1 gene can cause a generalized peroxisome biogenesis disorder (complementation group 2). Fluorescence in situ hybridization with the PXR1 cDNA and two cosmids containing the PXR1 gene was used for the cytogenetic assignment of the gene to chromosome 12p13. Analysis of a radiation hybrid panel for chromosome 12 with a PXR1 gene-based sequence-tagged site (STS) mapped the PXR1 gene between TPI1 and D12S1089. The STS also detects an unusual, highly polymorphic, short tandem repeat (heterozygosity, 0.82). This repeat shows one set of short alleles containing a pentanucleotide repeat and one set of long alleles containing a complex array of different pentanucleotides.

Alleles↗
PubMed1996

Evaluation of tetranucleotide repeat locus D7S809 (wg1g9) in the Japanese population.

The tetrameric short tandem repeat (STR) locus (D7S809) has been evaluated in the Japanese population. In order to detect the alleles, PCR was carried out using primers, one of which was end labelled with 32P, and PCR products were separated by electrophoresis on a denaturing polyacrylamide gel. Using this method, accurate genotypes could be determined from as little as 0.5 ng of genomic DNA. Thirteen different alleles were identified on 256 chromosomes tested. All alleles differed in size by one (4 bp) repeat unit, and no "interalleles' were found. The estimated heterozygosity and the polymorphism information content (PIC) were 0.86 and 0.83, respectively. We observed 42 of the 91 possible different genotypes. The power of discrimination (PD) was 0.96, and no significant deviations from the Hardy-Weinberg equilibrium were found. We retyped all apparently homozygous samples using an alternative pair of flanking primers in order to confirm homozygosity. We also demonstrated a typing result involving sexual assault. D7S809 appears to be a very useful STR locus for forensic practice in Japanese.

Base Sequence↗
PubMed1995

A collection of tri- and tetranucleotide repeat markers used to generate high quality, high resolution human genome-wide linkage maps.

We report a collection of tri- and tetranucleotide repeat sequence polymorphic markers used to construct genome-wide human linkage maps. Using a strategy of marker selection to create libraries highly enriched for the presence of specific tandem repeat elements, we have developed over 2000 high heterozygosity, easy-to-use tri- and tetranucleotide short tandem repeat polymorphisms (STRPs). To date, over 1300 of these markers have been genotyped on the CEPH reference families. Additional STRPs were assigned to chromosomes using human monochromosomal somatic cell hybrids. The linkage maps constructed with these markers have been integrated with other CEPH genotypes into a comprehensive high density linkage map. These STRPs have been shown to be robust for genotyping in a variety of laboratories using a variety of methods. The high quality of these STRPs makes them ideal candidates for use in genome-wide linkage searches. The integration of these markers with physical mapping reagents and other genetic markers will create a resource for moving from genome-wide linkage searches to rapid sublocalization of disease loci.

Base Sequence↗
PubMed1998

Tandem repeat structure of the duplicated Y-chromosomal STR locus DYS385 and frequency studies in the German and three Asian populations.

The Y-chromosomal short tandem repeat (STR) locus DYS385 can be typed using PCR amplification and separation of the resulting polymorphic fragments by non-denaturing high resolution polyacrylamide gel electrophoresis followed by silver staining. The PCR primers amplify a duplicated repeat sequence on the Y chromosome revealing a two-band pattern in male individuals. To determine the internal repeat structure as a basis for a consensus nomenclature, DNA sequence analysis was carried out after subcloning of PCR-amplified fragments revealing the uniform 4-bp repeat structure 'GAAA'. The shortest allele observed consisted of 10 repeat units thus providing the basis for the designation 'allele 10'. Except for isolated point mutations, no systematic differences could be observed either in the repeat sequence or in the flanking regions between the two fragments of a given individual. Thus it was not possible to discriminate between the two loci of the DYS385 system. Four population samples of German (n = 146), Chinese (n = 100), Japanese (n = 100), and Thai (n = 95) origin were studied. In the four groups, alleles 10 to 24 could be observed and genotype frequencies differed significantly. In Germans only one common genotype was present (11-14; 33.8% frequency). In the Asian populations, the frequencies were more evenly distributed with the 13-13 genotype (9%) in Chinese, the 13-17 genotype (14%) in Japanese and the 14-18 genotype (7%) in Thai being the most common. Overall, 69 different genotypes were found, of these 36 were observed in Germans, 36 in Chinese, 33 in Japanese and 44 in Thai. No mutations were detected in 62 father-son pairs. Thus DYS385 is a highly polymorphic STR system with population-specific genotype distributions.

Asia, Southeastern↗
PubMed1995

A tandemly repeated DNA family originated from SINE-related elements in the European plethodontid salamanders (Amphibia, Urodela).

We have characterized a highly repetitive family, named Hy/Pol III, in the genome of the European salamanders Hydromantes (Plethodontidae). This family consists of short, tandemly repeated sequences organized in clusters, scattered through the genome as shown both by in situ hybridization to chromosomes and by Southern blot hybridization. The repeat unit is about 200 bp in length and it is a composite element since it contains a SINE-like retroposon with a tRNA structure, flanked by two short direct repeats. The whole element itself is bordered by two other direct repeats. The sequence data suggest that two elements, presumably derived from polymerase III transcripts, have been inserted one into the other, giving rise to the observed composite structure. During evolution the Hy/Pol III family was then amplified by tandem duplication at the DNA level. The inferred relationships between Hy/Pol III members from three representative species of the European Hydromantes suggests that a subfamily structure characterizes the evolutionary history of this family.

Animals↗
PubMed1998

Catalonian population study of the tetranucleotide repeat loci D3S1358, D8S1179, D18S51 and D19S253.

Allele frequencies for four short tandem repeat loci were determined in a population sample from Catalonia (NE Spain). After denaturing PAGE electrophoresis, 8 alleles were identified for D3S1358 (n=201), 10 alleles for D8S1179 (n=198), 13 alleles for D18S51 (n=197) and 11 alleles for D19S253 (n=201). No deviation from Hardy-Weinberg equilibrium was found. Complete and relative uniformity in Caucasoid populations has been observed for D18S51 and D8S1179 respectively. Pronounced differences were found between different ethnic groups for both systems. Catalonia and Portugal do not differ for D3S1358 locus. Multiplex PCR amplifications of three loci (D3S1358, D18S51 and D19S253) without overlapping fragment size ranges could be interesting for monochrome automated laser fluorescence devices.

Alleles↗
PubMedDate not supplied

Polymorphism at the tetranucleotide repeat locus DYS389 in 10 populations reveals strong geographic clustering.

Several short tandem repeat polymorphism loci at the non-recombining part of the Y chromosome have been described recently and are now widely used for the investigation of the history and the diversity of man. The tetranucleotide repeat polymorphism at the DYS389 locus consists of two repetitive stretches with different numbers of (TCTG)n (TCTA)m repeat units. To study the overall variability of this locus, 768 alleles from males from 10 human populations (two sub-Saharan African, four Caucasoid and four Asian/Amerind populations) were investigated. The alleles found in the populations of different geographic origin exhibited remarkable differences in the number and arrangement of repeats in the two repetitive stretches and up to nine different sequence variants for a single fragment length have been detected. So far 53 different alleles, i.e. haplotypes, have been observed. Analysis of molecular variance (AMOVA) indicates that at least 24.5% of the total genetic variance was found between the populations and that these differences were significant in most pairwise comparisons. We propose a model, in which both founder effects and genetic drift together with single step replication slippage mutations explain the picture of haplotype diversity observed with this single locus.

Alleles↗
PubMed1991

Avian tandem repeats: nuclear protein binding sites and the origins of short tandem repetitive DNAS.

A 14 bp repeat isolated from the genome of a Mallard duck (Anas platyrhynchos) and a 13 bp repeat isolated from the genome of a Muscovy duck (Cairina moschata) were both tandem and genus-specific. There were 2.1 x 10(6) copies of the 14 bp repeat in the Mallard duck genome and 1.3 x 10(6) copies of the 13 bp repeat in the Muscovy duck genome. These two repeats were not obviously homologous but each contains different transcription protein binding sites. Experimentally, the two repeats were also observed to bind nuclear proteins specifically. A sequence-selective mechanism for the expansion of short tandem repeats from single ancestral sequences containing nuclear protein binding sites is presented.

Animals↗
PubMed1995

Bovine gall-bladder mucin contains two distinct tandem repeating sequences: evidence for scavenger receptor cysteine-rich repeats.

Gall-bladder mucin is a densely glycosylated macromolecule which is the primary secretory product of the gall-bladder epithelium. It has been shown to bind cholesterol and other biliary lipids and to promote cholesterol crystal nucleation in vitro. In order to understand the molecular basis for mucin-lipid interactions, bovine gall-bladder mucin cDNAs were identified by expression cloning and were isolated and sequenced. The nucleotide sequences of these cDNAs revealed two distinct tandem repeating domains. One of these domains contained a 20-amino acid tandem repeating sequence enriched in threonine, serine and proline. This sequence was similar to, but not identical with, the short tandem repeating sequences identified previously in other mammalian mucins. The other domain contained a 127-amino acid tandem repeating sequence enriched in cysteine and glycine. This repeat displayed considerable sequence similarity to a family of receptor- and ligand-binding proteins containing scavenger receptor cysteine-rich repeats. By analogy with other proteins containing these cysteine-rich repeats, it is possible that, in gall-bladder mucin, this domain serves as a binding site for hydrophobic ligands such as bilirubin, cholesterol and other biliary lipids.

Amino Acid Sequence↗
PubMed1999

The STR polymorphisms in intron 8 may provide information about the molecular evolution of RH haplotypes.

We identified simple-sequence repeat polymorphisms in intron 8 of the RHD and RHCE genes, both of which contained the 5-bp repeat unit (AAAAT)n. We analyzed the polymorphisms of this short tandem repeat (STR) in 104 Japanese RhD-positive and 124 RhD-negative (87 RHD gene negative and 37 nonfunctional RHD gene positive) donors by the polymerase chain reaction (PCR) and subsequent typing by electrophoresis and silver staining. We found five alleles (10, 11, 12, 13, and 14 repeats) in the RHD gene and four (7, 8, 9, and 10 repeats) in the RHCE gene. The Rh phenotypes were closely associated with polymorphisms of the STR. The Ce allele had 12 repeats in the RHD gene and 9 repeats in the RHCE gene at high frequency. The cE allele frequently had 10-12 repeats in the RHD gene and 10 repeats in the RHCE gene. The 10 repeats in the RHCE gene were identified exclusively in the 87 RHD gene-negative donors and 9 repeats were identified only in those with the RhC antigen. These results indicate that both haplotypes of dce and dcE arose from single RHD gene deletion and recombination events, respectively. In the 37 RhD-negative donors with a nonfunctional RHD gene, 12 repeats in the RHD gene and 9 repeats in the RHCE gene were frequently observed. Thus, the RhD-negative with a nonfunctional RHD gene combination might have arisen from the DCe haplotype via a mutation that abolished RHD gene expression. These findings suggest that the STR polymorphisms might shed light upon the molecular evolution of RH haplotypes.

Alleles↗
PubMed2004

Mono-nucleotide repeats (MNRs): a neglected polymorphism for generating high density genetic maps in silico.

Short, tandemly repeated DNA motifs, termed SSRs (simple sequence repeats) are widely distributed throughout eukaryotic genomes and exhibit a high degree of polymorphism. The availability of size-based methods for genotyping SSRs has made them the markers of choice for genetic linkage studies in all higher eukaryotes. These genotyping methods are not efficiently applicable to mononucleotide repeats (MNRs). Consequently, MNRs, although highly frequent in the genome, have generally been ignored as genetic markers. In contrast to single nucleotide polymorphisms (SNPs), SSRs can be identified in silico once the genomic sequence or segment of interest is available, without requiring any additional information. This makes possible ad-hoc saturation of a target chromosomal region with informative markers. In this context, MNRs appear to have much to offer by increasing the degree of marker saturation that can be obtained. By using the human genome sequence as a model, computational analysis demonstrates that MNRs in the size of 9-15 bp are highly abundant, with an average appearance every 2.9 kb, exceeding di- and tri-nucleotide SSRs frequencies by two- and five-fold, respectively. In order to enable practical, high throughput MNR genotyping, a rapid method was developed, based on sizing of fluorescent-labeled primer extension products. Genotyping of 16 arbitrarily chosen non-coding MNR sites along human chromosome 22 revealed that almost two-thirds (63%) of them were polymorphic, having 2-5 alleles per locus, with 20% of the polymorphic MNRs having more than two alleles. Thus, MNRs have potential for in silico saturation of sequenced eukaryote genomes with informative genetic markers.

Chromosome Mapping↗
PubMed2000

DXYS267: DYS393 and its X chromosome counterpart.

The GATA repeat DYS393 was reported in 1987 among other Y-specific short tandem repeats. It has since been used for forensic and evolutionary studies. We decided to test its Y-specificity when we found that female DNA gave amplicons, in agreement with recent GDB-recorded experiences on radiation hybrids. Parent-child triplets revealed that heterozygous daughters always carried the same paternally derived amplicon which, however, was not amplified in their fathers' DNAs. The X-assignment was verified in larger families. A half-new primer set with a new reverse DYS393 primer, outside the old one, resulted in X amplicons in females as well as Y and X amplicons in males. This new primer set defines the new DXYS267 (GDB Data Curation). DNA-sequencing revealed four base pair differences between the Y- and the X-sequences. Two are within the reverse primer site sequence, thus probably causing preferential hybridization to the Y sequence when using the conventional primers. The two others are within the repeat array, giving the regular repeat GATA in the Y-sequence, and TATA and GACA, respectively, in the X-sequence. Allele frequency distribution in DYS393 was studied in 300 unrelated Norwegian males, allele distribution in the X-locus in 48 Norwegian women. Even if allele repeat numbers are overlapping between the loci, leading to identical fragment lengths, the allele distribution is different between DYS393 and the X-chromosome locus. The differences between the two homologous loci on the Y and X indicate a considerable lap of time since common ancestry. To avoid co-amplification of the X-locus in DYS393 typing, primer A was elongated to include one of the sequence differences between the two loci. This to a considerable extent improved the specificity of the DYS393 primers.

Adenine↗
PubMed2001

Four year follow-up of a case of fucosidosis treated with unrelated donor bone marrow transplantation.

Fucosidosis is a rare autosomal recessive lysosomal disorder caused by alpha-fucosidase deficiency. We report a child with fucosidosis, second daughter of non-consanguineous parents, for whom biochemical diagnosis followed clinical evidence of the disease in her older sister. Based on previous experiences, the indication to transplant was considered. Since she lacked a matched sibling, an unrelated marrow donor was found. At pre-hematopoietic stem cell transplantation evaluation, first signs of neurological involvement were clinically detectable. MRI showed diffuse hypomyelination and auditory brainstem responses and somatic-sensorial evoked potentials were altered. Visual evoked potentials were normal, tortuosity in the retinal veins and peripapillary hemorrhages were detected. Bone marrow transplantation conditioning was with a regimen of busulphan, thiotepa and cyclophosphamide; in vivo Campath 1G, cyclosporin A and short course methotrexate were given to prevent graft-versus-host disease. The patient engrafted rapidly and her post-transplant course was complicated by moderate graft-versus-host disease, transient episodes of idiopathic thrombocytopenic purpura, repeated septic complications and recurrent episodes of Sweet's syndrome. Sequential short tandem repeat polymorphisms on peripheral blood and bone marrow cells documented the persistence of donor engraftment. Follow-up showed a progressive rise of enzymatic levels. Psychomotor development improved, as confirmed by evaluation of evoked potentials and by MRI scanning.

Bone Marrow Transplantation↗
PubMed1996

Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D).

Clinical, electrophysiological and genetic linkage studies were performed on a large autosomal dominant family with Charcot-Marie-Tooth axonal neuropathy type 2 (CMT2) with 38 members of which 14 were affected. Onset of the disease was between 16 and 30 years of age with weakness and atrophy of the hands more severe than of the feet with slow progressive course in 12 patients. Deep tendon reflexes were absent in the upper extremities and decreased in the lower extremities. There was distal hypesthesia for touch, proprioception and vibration sense for the hands more than for the feet. Motor nerve conduction velocities showed normal values (48-53 M/s) with normal latencies (2-3 msec) and electromyography revealed signs of denervation. Genetic linkage analysis used 167 short tandem repeat markers (STRPs) spaced throughout the 22 autosomes. Linkage to the short arm of chromosome 7 at 7p14 was found using the marker D7S435 (Z = 4.83 at theta = 0). Flanking markers were D7S1808 and D7S1806 and the genetic distance between them was 6.8 cM. The multipoint linkage analysis gave a peek multipoint lod score of 6.89 between the markers D7S1808 and D7S435. Linkage analysis showed significantly negative lod scores (with values less than -2) with markers of chromosomes 1 and 3 where CMT axonal forms have been previously mapped. PFGE analysis indicated the absence of the CMT1A duplication. Our findings are consistent with a new genetic type of axonal CMT neuropathy designated by us as CMT2D. Potential candidate genes are multiple T-cell gamma receptor genes which map to the same cytogenetic interval as CMT2D neuropathy.

Charcot-Marie-Tooth Disease↗