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PubMed1993

Localization of a type I diabetes susceptibility locus to the variable tandem repeat region flanking the insulin gene.

A susceptibility gene for type I diabetes is present on chromosome 11p15.5, but its location, identity, and mechanism of action are unknown. We have sequenced 14 kilobases of DNA flanking the human insulin gene and found new DNA polymorphisms and determined their frequencies in the general population and in families of type I diabetic subjects. A DNA polymorphism located 3123 base pairs downstream from the initiation site of transcription of the insulin gene, when present in the homozygous state, provides a relative risk for type I diabetes of 5.2 (P = 0.006). However, this DNA polymorphism as well as other diabetes-associated 3' markers are in linkage-disequilibrium with the actual susceptibility region, because these polymorphisms are found on haplotypes both positively and negatively associated with type I diabetes susceptibility. Nucleotide sequence analysis of the variable tandem repeat region flanking the 5' end of the insulin gene shows variable tandem repeat elements associated with these haplotypes to differ greatly in composition, i.e., an ATAGGGGTGTGGGG repeat element is absent on a haplotype associated with type I diabetes susceptibility, but is found in 6-10 copies on two haplotypes negatively associated with the disease. These findings suggest that the type I diabetes susceptibility locus on chromosome 11p15.5 is probably located in the 5' variable tandem repeat region rather than in the 3' region of the insulin gene.

Base Sequence↗
PubMed1988

Evidence for preferential multiplication of the internal unit in tandem repeats of the mating factor alpha genes in Saccharomyces yeasts.

We have determined DNA sequences of the mating factor alpha genes of Saccharomyces uvarum and Saccharomyces italicus and compared them to that of the MF alpha 1 gene of S. cerevisiae. The DNA sequences of the mating factor genes in both species were almost completely identical to that of the MF alpha 1 gene of S. cerevisiae except for the number of tandem repeated units; these latter consisted of a spacer peptide and a mature mating factor and there were three units in S. uvarum and five units in S. italicus compared with four units in the MF alpha 1 of S. cerevisiae. From the detailed comparison of DNA sequences of the spacer peptide-mating factor units from these three species, the high sequence homology can be recognized in the internal units of the tandem repeats. This suggests that the internal units might be multiplied preferentially in the tandem repeated units of mating factor genes.

Amino Acid Sequence↗
PubMed1997

Multiple imprinted sense and antisense transcripts, differential methylation and tandem repeats in a putative imprinting control region upstream of mouse Igf2.

The mouse insulin-like growth factor 2 (Igf2) locus is a complex genomic region that produces multiple transcripts from alternative promoters. Expression at this locus is regulated by parental imprinting. However, despite the existence of putative imprinting control elements in the Igf2 upstream region, imprinted transcriptional repression is abolished by null mutations at the linked H19 locus. To clarify the extent to which the Igf2 upstream region contains autonomous imprinting control elements we have performed functional and comparative analyses of the region in the mouse and human. Here we report the existence of multiple, overlapping imprinted (maternally repressed) sense and antisense transcripts that are associated with a tandem repeat in the mouse Igf2 upstream region. Regions flanking the repeat exhibit tissue-specific parental allelic methylation patterns, suggesting the existence of tissue-specific control elements in the upstream region. Studies in H19 null mice indicate that both parental allelic methylation and monoallelic expression of the upstream transcripts depends on an intact H19 gene acting in cis. The homologous region in human IGF2 is structurally conserved, with the significant exception that it does not contain a tandem repeat. Our results support the proposal that tandem repeats act to target methylation to imprinted genetic loci.

Alleles↗
PubMed1993

Switch recombination breakpoints occur at nonrandom positions in the S gamma tandem repeat.

Ig switch (S) recombination is clearly focused on S regions. It is possible that S-specific DNA binding proteins facilitate the alignment of these regions before recombination. The S gamma 3-specific DNA binding proteins, SNAP and SNIP/NF-kappa B, interact with two discrete regions of the S gamma 3 tandem repeat, the A and B sites. Recombination breakpoints in the S gamma 3 region were found to significantly correlate with the binding sites of the S gamma 3 binding proteins. We now report the conservation of the SNIP and SNAP binding sites in S gamma 2b and S gamma 1 DNA. SNIP/NF-kappa B interacts with its cognate sites in S gamma 2b and S gamma 1 DNA as determined by mobility shift assays, competition binding studies, and supershift analysis using an antiserum specific for the p50 component. SNAP binds specifically to S gamma 2b and S gamma 1 as measured by mobility shift assays and competition binding studies. SNAP is composed of two closely traveling mobilities that do not separate on partial purification. SNIP and SNAP are expressed in nuclear extracts derived from murine splenic B cell cultures stimulated with mitogen or mitogen and IL-4. No new DNA binding proteins specific for S gamma 1 tandem repeats are detectable in nuclear extracts from B cells stimulated with mitogen and IL-4. The sites at which recombination occurs in the S gamma 2b and S gamma 1 regions have been analyzed statistically and found to correlate with the SNIP/NF-kappa B and SNAP binding sites. Distinctions have been found regarding the use of DNA substrates within the tandem repeat between primary (mu-->gamma) and successive (gamma-->x) S recombination.

Animals↗
PubMed1999

[A preliminary study of human Y chromosome specific short tandem repeat loci]

OBJECTIVE: To understand the allele structure and reveal genetic polymorphism of Y chromosome specific short tandem repeat (Y-specific STR) loci in Chinese Han population. METHODS: The authors used a set of five Y-specific STR loci which were tetrameric tandem repeat loci chosen from the Genome Database. EDTA-blood specimens were collected from the unrelated individuals. DNA was extracted by Chelex method and amplified by the polymerase chain reaction (PCR). The PCR products were analyzed using both the PAGE horizontal electrophoresis with discontinuous buffer system and the automated fluorescence detection approach. RESULTS: The authors observed that the alleles at the five Y-specific STR loci were composed of some complex repeat structures. They successfully prepared a set of human allele ladders for the typing of the five Y-specific STRs and demonstrated the polymorphisms at the five Y-specific STR loci in Chinese Han population. CONCLUSION: Y-specific STRs are good genetic markers for the purpose of analysis of genetic relationship between populations. This preliminary study not only reveals allele frequencies and haplotype distribution of Y-specific STR in Chinese Han population, but also indicates a reference population for detecting male migration events and for reconstructing paternal history.

Journal Article↗
PubMed1996

Validation of highly discriminating multiplex short tandem repeat amplification systems for individual identification.

Short tandem repeat (STR) loci are routinely employed for individual identification. WE have examined the performance and reproducibility of a highly informative co-amplification system containing the tetranucleotide STR loci: HUMVWFA31/A, HUMTH01, D20S85, D8S1179, HUMFIBRA, D21S11, and D18S51, in conjunction with the amelogenin sex test, in addition to a modified system omitting the locus D20S85. Polymerase chain reaction (PCR) products were fluorescently detected on an automated sequencer and automatically sized against an internal size standard by Genescan software. Both systems were routinely able to type 500 pg of undegraded DNA. At DNA concentrations between 50-500 pg, partial profiles were produced, but no allelic drop-out was observed. Balanced amplification of all loci occurred over a wide range of DNA concentrations from 50 pg to 10 ng. Alteration of reagent concentrations and cycling parameters from optimal resulted in variation in the efficiency of individual locus amplification relative to the other loci within the system. This was also observed at high ionic strength or extreme pH. However, at all reagent concentrations and conditions, allelic drop-out was not observed. These multiplex systems have potential in both routine forensic and intelligence database applications.

Buffers↗
PubMed1988

Isolation and molecular characterization of a highly polymorphic centromeric tandem repeat in the family Falconidae.

An abundant tandem repeat has been cloned from genomic DNA of the merlin (Falco columbarius). The cloned sequence is 174 bp in length, and maps by in situ hybridization to the centromeric regions of several of the large chromosomes within the merlin karyotype. Complementary sequences have been identified within a variety of falcon species; these sequences are either absent or in very low copy number in the family Accipitridae. The cloned merlin repeat reveals highly polymorphic restriction patterns in the peregrine falcon (Falco peregrinus). These polymorphisms, which have been shown to be stably inherited within a family of captive peregrines, can be used to differentiate the Greenland and Argentina populations of this endangered raptor species.

Animals↗
PubMed1997

A dedicated internal standard in fragment length analysis of hyperpolymorphic short tandem repeats.

Some of the most polymorphic short tandem repeats (STRs) have alleles differing in size by as little as one basepair. Since sizing precision with commercially available internal standards ordinarily does not allow safe discrimination at this level, typing is accomplished through comparisons with allelic ladders run on each gel. Here we introduce the use of optimally spaced sequenced alleles as a dedicated internal standard for measurement and typing of hyperpolymorphic STRs. We have constructed such a dedicated internal standard for HUMACTBP2 ([1]; Moos and Gallwitz, EMBO I., 5 (1983) 757-761) typing, including 25 sequenced, ROX labelled HUMACTBP2 alleles spanning the size range for alleles at this locus (233-333 basepairs (bp)). Comparisons of inter-gel runs of selected alleles with this dedicated standard and the commercial GS500 internal standard demonstrate that only the presently described internal standard is suited for direct typing based on fragment length measurements only. Obvious advantages of this typing procedure are that fragment measurements are precise and in accordance with sequenced lengths, and that the typing procedure via an external allelic ladder is avoided. Sequences of the alleles used in the internal standard as well as of selected alleles for allelic ladders in two other hyperpolymorphic AAAG-repeat STRs, D11S554 (Phromchotikul et al., Hum. Mol. Genet., 3 (1991) 21) and HUMAPOA11 (Kimpton et al., PCR Methods Appl., 3 (1993) 13-22) are also presented. To allow fragment length analysis of these two STRs, five D11S554 alleles, spanning from 176 to 225 basepairs, were added to the dedicated internal standard. Performing similar comparisons as for HUMACTBP2, it is demonstrated that even if sizing accuracy is not as good as with HUMACTBP2, typing based on measured fragment size only may be achieved with both other STRs as well. Selecting different colours for the three STRs, triplex electrophoretic runs were performed of a Norwegian population database of 300 unrelated individuals. The probability that two unrelated individuals have the same type in all three STRs is 5 x 10(-7), and the combined paternity exclusion power 99.77%, indicating that this STR selection may represent a good choice for forensic genetic casework.

Base Composition↗
PubMed1992

Comparison of five tandem repeat loci between humans and chimpanzees.

Five tandem repeat loci were studied in humans and chimpanzees using VNTR probes derived from human DNA. Shared alleles were found at three loci and were often the modal allele in one species but never in both. There was no difference in the mean number of alleles per locus. However, these species exhibited substantially different levels of gene diversity, with chimpanzees monomorphic at two loci. Evidence of reduced variability in chimpanzees corroborates earlier comparisons using isozymes and plasma proteins. Molecular mechanisms, population dynamics, or both may be responsible for these differences. Equal numbers of alleles per locus may reflect high mutation rates. By one test, chimpanzees were out of equilibrium at one locus, which may reflect a typing error or population substructure. The long divergence time, and the high probability of backward mutations, precludes accurate estimation of genetic distance between these species.

Alleles↗
PubMed1991

Forensic applications of molecular genetic analysis: an Italian collaborative study on paternity testing by the determination of variable number of tandem repeat DNA polymorphisms.

Several variable number of tandem repeat (VNTR) DNA polymorphisms detecting different loci (YNH24/MspI or TaqI, CMM101/MspI or MLJ14/MspI, EFD64.2/RsaI or HinfI, YNZ22/TaqI, AW101/EcoRI, EKMDA2.1/PvuII and 3'-HVR/PvuII) were used in the analysis of 27 cases of disputed paternity in the Italian population. Fourteen exclusions and 17 attributions were performed. The results were compared with those obtained with immunohematologic analyses. Four exclusions and 2 attributions were made possible only by the combined use of several DNA polymorphisms, as the analyses of red-blood-cell antigens and isoenzymes, serum proteins and HLA group determinants were inconclusive. With the DNA test, 10 exclusions and 15 attributions were confirmed, with increased overall probability. In conclusion, VNTR polymorphisms were more informative, accurate and sensitive than the immunohematologic tests. Therefore, DNA analysis is the method of choice for testing genetic relationships.

Alleles↗
PubMed1997

["SPELT1"--a new family of tandem repeats in grasses].

A novel family of tandemly repeated DNA in the cereal genome, "Spelt1," was isolated and described. This family accounts for about 2% of the DNA of Aegilops speltoides, one of the putative donors of B genome of hexaploid wheat. Genomes of fifteen other cereal species studied, including those with AB, AG, and ABD genome formulas, contain significantly lower amounts of Spelt1 repeats. RFLP analysis revealed three different types of Spelt1 sequence organization in the wheat and aegilops genomes studied. Data indicating that Spelt1 is a specific marker of Ae. speltoides-chromosomes are presented.

Base Sequence↗
PubMed1998

Development and population study of an eight-locus short tandem repeat (STR) multiplex system.

Amplification of short tandem repeat (STR) loci has become a useful tool for human identification applications. To improve throughput and efficiency for such uses, the polymorphic STR loci CSF1PO, TPOX, TH01, vWA, D16S539, D7S820, D13S317, D5S818, F13A01, FESFPS, F13B, and LPL have been evaluated, developed, and configured into fluorescently labeled multiplex systems. Eight of these STR loci were combined to generate the PowerPlex System, a two-color multiplex system that supports rapid, accurate, reliable analysis and designation of alleles. The remaining four loci comprise the FFFL System, a one-color multiplex system. The PowerPlex System may be evaluated alternatively as two one-color, four-locus multiplex systems, CTTv Multiplex and GammaSTR Multiplex. The products of multiplex amplification may be analyzed with a variety of fluorescence detection instruments. Determination of genotypes of over 200 individuals from each of three different population/ethnic groups revealed independence of inheritance of the loci and allowed calculation of matching probability, typical paternity index, and power of exclusion for each multiplex.

Alleles↗
PubMed1992

Mutation of leucine-57 to phenylalanine in a platelet glycoprotein Ib alpha leucine tandem repeat occurring in patients with an autosomal dominant variant of Bernard-Soulier disease.

The primary sequences of the three individual glycoprotein (GP) chains, GPIb alpha, GPIb beta, and GPIX, comprising the normal platelet GPIb/IX receptor for von Willebrand factor (vWF) have recently been determined, opening the possibility for characterization of disorders of this receptor at the molecular level. The presence of a leucine tandem repeat in each of these chains is of particular interest, because such repeats may be involved in associations between polypeptide segments. We now report an autosomal dominant variant of Bernard-Soulier disease associated with the heterozygous substitution of phenylalanine for a highly conserved leucine residue within the GPIb alpha leucine tandem repeat. Affected individuals experienced a moderate bleeding tendency, thrombocytopenia, and an increased mean platelet volume. Platelet aggregation was decreased only in response to ristocetin or to asialo-vWF. The kd for 125I-vWF binding to patients platelets was significantly increased over control values at 0.5 mg/mL ristocetin, but was normal at 1.0 or 1.5 mg/mL ristocetin. While sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed an essentially normal complement of all components of the GPIb/IX complex, a minor amount of a putative proteolytic fragment was identified that migrated faster than GPIb and was immunoreactive with polyclonal anti-GPIb alpha antibody, but not with a monoclonal antibody directed against the 45-Kd amino-terminal region of GPIb alpha. However, because the great majority of patient GPIb alpha comigrates with normal GPIb alpha, the major functional abnormalities of the patient platelets are most likely a consequence of the altered structure of the nonproteolyzed protein. Full concordance within the studied family between phenotypic expression and a heterozygous single nucleotide substitution in genomic DNA coding for a phenylalanine in place of the wild-type leucine at residue 57 of the mature GPIb alpha, absence of this substitution in 266 alleles from the normal population, and the lack of any other abnormality of patient DNA throughout the entire coding sequence for GPIb alpha provide strong support that this substitution may constitute a pathologic point mutation responsible for the observed phenotypic abnormalities. While the roles that leucine tandem repeats may normally play within the GPIb/IX complex are not yet known, the perturbation of such a repeat in GPIb alpha may impair interaction with other components of the complex and/or with the binding of vWF.

Adolescent↗
PubMed1994

Analysis of short tandem repeat (STR) HUMVWA in the Spanish population.

Amplification by polymerase chain reaction (PCR) of variable number of tandem repeat (VNTR) loci and subsequent typing by electrophoresis and silver staining has become a useful tool for identity testing. One viable group of genetic markers amenable to amplification by PCR is the short tandem repeat (STR) loci. A horizontal discontinuous polyacrylamide gel electrophoresis (PAGE) method was used to type the amplified products of the STR HUMVWA. Typing for VWA of 120 unrelated Spanish Caucasians was done. Six alleles were observed with frequencies in the range 0.096-0.242. The genotype distribution meets Hardy-Weinberg expectations (0.25 < P < 0.50). The heterozygosity was 73.3% and the discrimination power (DP) 0.94. Simultaneously, in a small sample of families (n = 24) no new mutations could be found.

Alleles↗
PubMed2004

Evolution of the tandem repeats in thymidylate synthase enhancer region (TSER) in primates.

The upstream regulatory region of the human thymidylate synthase gene (thymidylate synthase enhancer region, TSER) is length polymorphic, attributable to variable numbers of tandemly repeated copies of a 28-bp fragment. It has been found that TSER length polymorphism is correlated to malignancy risk. To further our understanding of the origin and evolution of TSER, this region was investigated among different primates, including hominoids, two subfamilies of the Old World monkeys (OWMs): colobines and cercopithecines, and two species of the New World monkeys (NWMs). In addition to humans, our results show that length polymorphism in TSER is also present in some primate populations, although it appears that this region is length monomorphic in many other primates. We identified three unique repeat motifs in TSER and defined them as R1, R2, and R3, respectively, starting from the 3' end. The same repeat motifs from different species are more similar to each other than different repeat motifs within same species are. Such a paraphyletic pattern suggests that divergence of the three repeat motifs predated divergence of the OWMs/hominoids and the NWMs. The most recent common ancestor (MRCA) of hominoids and the OWMs probably possessed triple repeats but now double and triple repeats are two dominant types in hominoids and the OWMs. In addition, our results show that each of the three repeat motifs may be lost independently. We have also found clues that recombination was involved in formation of tandem repeat polymorphism in TSER.

Alleles↗
PubMed1988

Porcine submaxillary gland apomucin contains tandemly repeated, identical sequences of 81 residues.

A lambda gt11 cDNA library, prepared from porcine submaxillary gland mRNA, was screened with anti-apomucin IgG, and five antibody-reactive phage were isolated. The phage with the largest cDNA insert, designated lambda PSM103, was further characterized. Its fusion protein reacted with anti-apomucin IgG and was used to affinity purify antibodies that specifically reacted with apomucin, indicating that the protein shares antigenic determinants with apomucin. The nucleotide sequence of 1510 bases in the 3.7-kilobase cDNA insert of lambda PSM103 has been established, thereby giving a deduced amino acid sequence of 503 residues in apomucin, or about 45% of the molecule. The deduced sequence of the apomucin polypeptide was found to contain 4.8 tandemly repeated, identical sequences of 81 residues each. The presence of these uniquely repeated sequences was confirmed by restriction endonuclease digestion of DNA derived from lambda PSM103. The repeat sequence was also confirmed in apomucin by the isolation of an 81-residue tryptic peptide with an amino acid composition and an amino-terminal amino acid sequence (up to 44 residues) identical to those of the tandem repeat. Moreover, the peptide was isolated in 760% yield, indicating that the tandem repeat occurs at least eight times in apomucin. The presence of such a long repetitive region in the gene for apomucin raises the possibility for considerable polymorphism in the gene and a corresponding size heterogeneity of apomucin. The predicted secondary structure of the 503 residues confirms the earlier proposal that apomucin is an extended, nonglobular polypeptide. Although the sequences around 192 serine and threonine residues have been established in apomucin, a recognition sequence for the N-acetylgalactosaminyltransferase that initiates glycosylation of apomucin is not evident, except that the glycosylated residues occur in turns.

Amino Acid Sequence↗
PubMed2000

Model peptide studies of sequence repeats derived from the intracrystalline biomineralization protein, SM50. II. Pro,Asn-rich tandem repeats.

In the biomineralization process, a number of Pro-rich proteins participate in the formation of three-dimensional supramolecular structures. One such protein superfamily, the Pro,Gly-rich sea urchin intracrystalline spicule matrix proteins, form protein-protein supramolecular assemblies that modify the microstructure of the inorganic mineral phase (calcite) within embryonic sea urchin spicules and adult sea urchin spines. These proteins represent a useful model for understanding Pro sequence usage and the resulting generation of extended or "open" structures for protein-protein and/or protein-crystal recognition. In the sea urchin spicule matrix protein, SM50 (Strongylocentrotus purpuratus), there exists an unusual 20-residue Pro,Asn-containing repeat, &bond;PNNPNNPNPNNPNNPNNPNPbond which links the upstream 15-residue C-terminal domain and the downstream 211-residue beta-spiral repeat domain. To define the structural preferences of this 20-residue repeat, we created a 20-residue N- and C-terminal "capped" peptidomimetic of this sequence. Using far-uv CD dichroism, CH(alpha) and alpha-(15)N conformational shifts, (3)J(NH-CHalpha) coupling constants, sequential d(NN(i, i + 1)) rotating frame nuclear Overhauser effect connectivities, d(alphaN(i, i + 1))/d(NN(i, i + 1)) intensity ratios, amide temperature shift coefficients, amide solvent exchange, and simulated annealing refinement protocols, we have determined that this 20-residue repeat motif adopts an extended "twist" structure consisting of turn- and coil-like regions. These findings are consistent with previous studies, which have shown that Pro-rich tandem repeats adopt extended, flexible structures in solution. We hypothesize that this 20-residue repeat may fulfill the role of a mineral-binding domain, a protein-protein docking domain, or as an internal "molecular spacer" for the SM50 protein during spicule biocomposite formation.

Amino Acid Motifs↗
PubMed1995

Monoclonal antibody BW835 defines a site-specific Thomsen-Friedenreich disaccharide linked to threonine within the VTSA motif of MUC1 tandem repeats.

mAb BW835 (IgG1) has been generated to breast cancer cell lines by alternating injections of MCF-7 or SW-613 cells and has been demonstrated to be of value in the serodiagnosis of mammary carcinoma. BW835 defines a carbohydrate epitope on integrated or secreted MUC1 glycoforms from carcinoma cells and human milk. To identify BW835-reactive glycopeptides on MUC1, proteolytic fragments of the mucin obtained by digestion with the Gly-C-specific endopeptidase IV from papaya corresponding to low molecular mass fragments (< 10 kilodaltons) of the tandem repeat domain were screened. A glycosylated fragment (glycopeptide 17) containing the mAb HMFG-2-defined epitope was highly reactive to BW835 antibody, while nonglycosylated tandem repeat peptide TAP25 or its in vitro-glycosylated N-acetylgalactosamine (GalNAc) derivatives were unreactive. Glycopeptide 17 bound to peanut agglutinin and to a Thomsen-Friedenreich antigen (TF alpha)-specific mAb (A78-G/A7). Binding of BW835 to glycopeptide 17 or to MUC1 was competitively inhibited by peanut agglutinin and by the synthetic glycopeptides TF alpha Ser or TF alpha Thr but not by their beta-anomers. Evidence for site specificity of binding by BW835 to glycopeptide 17 was revealed by demonstrating nonreactivity of the antibody to other TF alpha-expressing glycoproteins with peptide moieties lacking MUC1-specific motifs at putative glycosylation sites. The epitope of BW835 was localized to threonine within the VTSA-peptide motif by site-specific enzymatic beta-galactosylation of the synthetic tandem repeat peptide TAP25-GalNAc1 TAPPAHGVT(-O-alpha GalNAc)SAPDTRPAPGSTAPPA. This is the first report on a TF alpha-specific mAb that shows a strict peptide sequence dependency of binding.

Amino Acid Sequence↗