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PubMed1994

Polymorphic pattern of the (AT)X(T)Y motif at -530 5' to the beta-globin gene in over 40 patients homozygous for various beta-thalassemia mutations.

Nucleotide sequence analysis of the 5' beta-globin gene flanking region has been carried out for numerous homozygous beta-thalassemia patients with different mutations and of various ethnic backgrounds. Four different rearrangements were found associated with numerous beta-thalassemia mutations. The (AT)X(T)Y repeat motif at -530 showed polymorphic patterns among these patients as follows: All ten IVS-II-1 (G-->A) chromosomes and the two with the -87 (C-->G) mutation are associated with the (AT)9(T)5 rearrangement, while the 30 IVS-I-6 (T-->C), the 16 codon 39 (C-->T), the six codon 8 (-AA) chromosomes, and 12 chromosomes with different promoter mutations had the (AT)7(T)7 motif. Six chromosomes with the promoter mutation at position -29 (A-->G) had the (AT)8(T)6 motif, while an (AT)8(T)4 motif appears characteristic for two IVS-I-5 (G-->A and G-->T). No direct association between any of the (AT)X(T)Y arrangements and an increased gamma gene expression [G gamma and fetal hemoglobin (Hb F)] levels could be demonstrated, suggesting that variations in the (AT)X(T)Y motif are common polymorphisms.

Adult↗
PubMedDate not supplied

Evidence against a major role of PEG1/MEST in Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is a heterogeneous disorder characterised by interauterine and postnatal growth retardation, with or without additional dysmorphic features. Most cases are sporadic but a few familial cases have been described. A subset of patients exhibit maternal uniparental disomy for chromosome 7 (mUPD7) strongly suggesting that genomic imprinting plays a role in the aetiology of the disease. We and others have recently characterised the human PEG1/MEST gene, the first imprinted gene known to be located on chromosome 7. Although the function of PEG1/MEST is unknown, the paternal-specific expression of this gene and its location at 7q32, render it a promising candidate for SRS. As a prerequisite for mutation screening in 49 patients with SRS and 9 with primordial growth retardation (PGR), we determined the complete genomic structure of the PEG1/MEST gene which consists of 12 exons. Apart from one silent mutation and two novel polymorphisms, nucleotide changes were not detected in any of these patients. Moreover, methylation patterns of the 5' region of PEG1/MEST were found to be normal in 35 SRS and 9 PGR patients and different from the pattern seen in patients with mUPD7. These findings strongly argue against a role of PEG1/MEST in the majority of Silver-Russell syndrome cases.

Abnormalities, Multiple↗
PubMed2001

A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes.

Point mutations can generate defective and sometimes harmful proteins. The nonsense-mediated mRNA decay (NMD) pathway minimizes the potential damage caused by nonsense mutations. In-frame nonsense codons located at a minimum distance upstream of the last exon-exon junction are recognized as premature termination codons (PTCs), targeting the mRNA for degradation. Some nonsense mutations cause skipping of one or more exons, presumably during pre-mRNA splicing in the nucleus; this phenomenon is termed nonsense-mediated altered splicing (NAS), and its underlying mechanism is unclear. By analyzing NAS in BRCA1, we show here that inappropriate exon skipping can be reproduced in vitro, and results from disruption of a splicing enhancer in the coding sequence. Enhancers can be disrupted by single nonsense, missense and translationally silent point mutations, without recognition of an open reading frame as such. These results argue against a nuclear reading-frame scanning mechanism for NAS. Coding-region single-nucleotide polymorphisms (cSNPs) within exonic splicing enhancers or silencers may affect the patterns or efficiency of mRNA splicing, which may in turn cause phenotypic variability and variable penetrance of mutations elsewhere in a gene.

Amino Acid Motifs↗
PubMed2000

Recombinational and mutational hotspots within the human lipoprotein lipase gene.

Here an analysis is presented of the roles of recombination and mutation in shaping previously determined haplotype variation in 9.7 kb of genomic DNA sequence from the human lipoprotein lipase gene (LPL), scored in 71 individuals from three populations: 24 African Americans, 24 Finns, and 23 non-Hispanic whites. Recombination and gene-conversion events inferred from data on 88 haplotypes that were defined by 69 variable sites were tested. The analysis revealed 29 statistically significant recombination events and one gene-conversion event. The recombination events were concentrated in a 1.9-kb region, near the middle of the segment, that contains a microsatellite and a pair of tandem and complementary mononucleotide runs; both the microsatellite and the runs show length variation. An analysis of site variation revealed that 9.6% of the nucleotides at CpG sites were variable, as were 3% of the nucleotides found in mononucleotide runs of >/=5 nucleotides, 3% of the nucleotides found </=3 bp from certain putative polymerase alpha-arrest sites, and 0. 5% of the remaining nucleotides. This nonhomogeneous distribution of variation suggests that multiple mutational hits at certain sites are common, an observation that challenges the fundamental assumption of the infinite-sites-mutation model. The nonrandom patterns of recombination and mutation suggest that randomly chosen single-nucleotide polymorphisms may not be optimal for disequilibrium mapping of this gene. Overall, these results indicate that both recombinational and mutational hotspots have played significant roles in shaping the haplotype variation at the LPL locus.

Black People↗
PubMed1997

Quinolone-resistant Salmonella typhi in Viet Nam: molecular basis of resistance and clinical response to treatment.

Nalidixic acid-resistant Salmonella typhi (NARST) was first isolated in Viet Nam in 1993. Analysis of the quinolone resistance-determining region of gyrA in 20 NARST isolates by polymerase chain reaction and single-stranded conformational polymorphism yielded two novel patterns: pattern II corresponding to a point mutation at nucleotide 87 Asp-->Gly (n = 17), and pattern III corresponding to a point mutation at nucleotide 83 Ser-->Phe (n = 3). In trials of short-course ofloxacin therapy for uncomplicated typhoid, 117 (78%) of 150 patients were infected with multidrug-resistant S. typhi, 18 (15%) of which were NARST. The median time to fever clearance was 156 hours (range, 30-366 hours) for patients infected with NARST and 84 hours (range, 12-378 hours) for those infected with nalidixic acid-susceptible strains (P < .001). Six (33.3%) of 18 NARST infections required retreatment, whereas 1 (0.8%) of 132 infections due to susceptible strains required retreatment (relative risk = 44; 95% confidence interval = 5.6-345; P < .0001). We recommend that short courses of quinolones not be used in patients infected with NARST.

4-Quinolones↗
PubMed1994

Neutral and non-neutral evolution of Drosophila mitochondrial DNA.

To test hypotheses of neutral evolution of mitochondrial DNA (mtDNA), nucleotide sequences were determined for 1515 base pairs of the NADH dehydrogenase subunit 5 (ND5) gene in the mitochondrial DNA of 29 lines of Drosophila melanogaster and 9 lines of its sibling species Drosophila simulans. In contrast to the patterns for nuclear genes, where D. melanogaster generally exhibits much less nucleotide polymorphism, the number of segregating sites was slightly higher in a global sample of nine ND5 sequences in D. melanogaster (s = 8) than in the nine lines of D. simulans (s = 6). When compared to variation at nuclear loci, the mtDNA variation in D. melanogaster does not depart from neutral expectations. The ND5 sequences in D. simulans, however, show fewer than half the number of variable sites expected under neutrality when compared to sequences from the period locus. While this reduction in variation is not significant at the 5% level, HKA tests with published restriction data for mtDNA in D. simulans do show a significant reduction of variation suggesting a selective sweep of variation in the mtDNA in this species. Tests of neutral evolution based on the ratios of synonymous and replacement polymorphism and divergence are generally consistent with neutral expectations, although a significant excess of amino acid polymorphism within both species is localized in one region of the protein. The rate of mtDNA evolution has been faster in D. melanogaster than in D. simulans and the population structure of mtDNA is distinct in these species. The data reveal how different rates of mtDNA evolution between species and different histories of neutral and adaptive evolution within species can compromise historical inferences in population and evolutionary biology.

Amino Acid Sequence↗
PubMed1986

Pig mitochondrial DNA: polymorphism, restriction map orientation, and sequence data.

Restriction endonuclease cleavage patterns of mitochondrial DNA (mtDNA) in pigs were analyzed using 18 enzymes which recognize six nucleotides and 1 four-nucleotide-recognizing enzyme. Pigs including Taiwan native breeds and miniature strains maintained in Japan were examined in this study; four commercial breeds of pigs and Japanese wild boars have been investigated earlier [Watanabe, T., et al. (1985). Biochem. Genet. 23:105]. mtDNA polymorphisms were observed in the cleavage patterns of five restriction enzymes, Bg1II, EcoRV, ScaI, StuI, and TaqI. The results support the previous hypothesis that pigs must be derived from two different maternal origins, European and Asian wild boars, and that a breed, Large White, arises from both European and Asian pigs. Two HindIII cleavage fragments were cloned into the HindIII site of M13mp10 and were partially sequenced by the dideoxynucleotide-chain termination method. Furthermore, DraI and StuI cleavage sites were newly determined on the restriction endonuclease map. On the basis of these results, the restriction endonuclease cleavage map of pig mtDNA was rewritten. Comparing sequence data of pig mtDNA at 237 positions with those of cow, human, mouse, and rat mtDNA, the sequence difference, silent and replacement changes, and transitions and transversions among mammalian species were estimated. The relationships among them are discussed.

Animals↗
PubMed1998

Role of mutation in the gyrA and parC genes of nalidixic-acid-resistant salmonella serotypes isolated from animals in the United Kingdom.

To answer the question as to whether isolates of salmonella from animals with decreased susceptibility to quinolones possess the same mechanism of resistance as isolates from humans, the polymerase chain reaction (PCR) was used to amplify a 347 base pair fragment equivalent to codons 39-159 covering the quinolone resistance determining region (QRDR) of the gyrA gene of Salmonella typhimurium NCTC 74, and 196 veterinary isolates of 26 serotypes of salmonella (109 from turkeys, 29 from chickens, the remainder from cattle, parrots, pigs, dogs, a pigeon, an exotic bird, a duck, a partridge, a sheep, a horse and environmental samples including litter, a nest and water). All PCR products were electrophoresed for single-stranded conformational polymorphism (SSCP). The DNA sequence of all eight novel SSCP patterns was determined. Nucleotide substitutions were identified in the gyrA gene of all except two isolates; all substitutions conferred a substitution at serine 83 or aspartate 87, as has previously been shown for isolates from humans. No mutations conferring an amino acid substitution in parC (the gene encoding the secondary target for quinolones) were revealed in the 48 isolates requiring 0.5-1 mg/L ciprofloxacin for inhibition, or the isolates for which no mutation in gyrA was revealed. The accumulation of enrofloxacin and ciprofloxacin was determined for 30 representative isolates (of which five were multiply drug resistant). Five isolates accumulated one-quarter to one-half the concentration achieved by the corresponding wild-type serotype. For two of these five isolates no mutation in gyrA was revealed, and one lacked OmpF.

Animals↗
PubMed1991

Detection of mutations in insulin-receptor gene in NIDDM patients by analysis of single-stranded conformation polymorphisms.

We used the recently described technique of single-stranded conformation-polymorphism (SSCP) analysis to examine the insulin-receptor locus. First, the ability of the method to detect known mutations and polymorphisms in the insulin-receptor coding sequence was assessed. Regions of the insulin-receptor sequence containing 16 different nucleotide changes, 9 in patient genomic DNA and 7 as cloned cDNA in plasmids, were analyzed. All 9 patient genomic DNA mutants and 5 of 7 plasmid mutants exhibited variant SSCP patterns. To investigate the potential of the technique for screening many patients, the 5 exons that encode the tyrosine kinase domain of the insulin receptor were examined in 30 unrelated white subjects with non-insulin-dependent diabetes mellitus (NIDDM). Exons 17-21 were amplified from genomic DNA with polymerase chain reaction and subjected to SSCP analysis. Exons 19, 20, and 21 revealed no bands of aberrant migration, suggesting a high degree of conservation of these sequences. One diabetic subject had an SSCP variant in exon 18. Direct sequencing of this subject's genomic DNA revealed a heterozygous missense mutation (Lys1068----Glu1068). Five different SSCP patterns were detected in exon 17. Based on direct sequencing, these patterns were explained by combinations of three different nucleotide substitutions, two of which were common silent polymorphisms. One subject had a heterozygous missense mutation Val985---- Met985. Allele-specific oligonucleotide hybridization confirmed the presence of these mutations in the appropriate diabetic subjects and also detected the Val985 mutation in heterozygous form in 1 of 13 nondiabetic white subjects. SSCP analysis is a sensitive rapid method for screening for mutations in the insulin-receptor gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed2001

Mitochondrial genomics flies high.

A new pair of papers reports the complete coding sequences for 28 mitochondrial DNAs in Drosophila. By examining the patterns of polymorphism and divergence among functionally distinct classes of synonymous and nonsynonymous nucleotide sites, Bill Ballard provides a comprehensive whole-genome picture of how mtDNA sequence evolution can depart from the strictly neutral and nearly neutral models of molecular evolution.

Journal Article↗
PubMed2025

Pedigree Painter (pepa): a tool for the visualization of genetic inheritance in chromosomal context.

MOTIVATION: Data visualization is increasingly important in genomics, enabling researchers to uncover inheritance and recombination patterns across generations. While most existing tools focus on ancestry prediction, they lack functionality for analyzing known ancestries in controlled settings, such as determining parental contributions to offspring genomes. To address this gap, I developed pepa, a lightweight, deterministic, modular tool that visualizes and quantifies genomic inheritance, designed for beginner and advanced users. RESULTS: pepa is a program for processing VCF files, assigning ancestries to homozygous SNPs, and clustering them into biologically meaningful regions. It generates human-readable comparison tables and visualizes inheritance patterns with chromosome paintings through R. Tested on fission yeast, pepa revealed non-uniform recombination patterns, with chromosomes largely inherited from one parent and seemingly random recombination. Quantitative analyses showed differences in parental contributions at the nucleotide and gene levels, with some offspring inheriting similar percentages from parents. However, the painted chromosomes revealed that even offspring with similar percentages from one parent rarely inherit the same genomic region, highlighting the importance of this tool in drawing biologically meaningful insights. pepa provides an accessible and powerful solution for analyzing genomic inheritance, bridging experimental and computational biology. Its modular design and minimal dependencies allow adaptation to diverse organisms, facilitating intuitive visualization and quantitative insights into recombination dynamics.

Pedigree↗
PubMed2000

Determination of X-chromosome inactivation status using X-linked expressed polymorphisms identified by database searching.

The large number of redundant sequences available in nucleotide databases provides a resource for the identification of polymorphisms. Expressed polymorphisms in X-linked genes can be used to determine the inactivation status of the genes, and polymorphisms in genes that are subject to inactivation can then be used as tools to examine X-chromosome inactivation status in heterozygous females. In this study, we have identified six new X-linked single-nucleotide polymorphisms and determined the inactivation status of these genes by examination of expression patterns in female cells previously demonstrated to have skewed inactivation, as well as by analysis of somatic cell hybrids retaining the inactive human X chromosome. Expression was seen from both alleles in females heterozygous for the RPS4X gene, confirming the previously reported expression from the inactive X chromosome. Expression of only a single allele was seen in females heterozygous for polymorphisms in the BGN, TM4SF2, ATP6S1, VBP1, and PDHA1 genes, suggesting that these genes are subject to X-chromosome inactivation.

Algorithms↗
PubMed1993

Molecular drift of the bride of sevenless (boss) gene in Drosophila.

DNA sequences were determined for three to five alleles of the bride-of-sevenless (boss) gene in each of four species of Drosophila. The product of boss is a transmembrane receptor for a ligand coded by the sevenless gene that triggers differentiation of the R7 photoreceptor cell in the compound eye. Population parameters affecting the rate and pattern of molecular evolution of boss were estimated from the multinomial configurations of nucleotide polymorphisms of synonymous codons. The time of divergence between D. melanogaster and D. simulans was estimated as approximately 1 Myr, that between D. teissieri and D. yakuba as approximately 0.75 Myr, and that between the two pairs of sibling species as approximately 2 Myr. (The boss genes themselves have estimated divergence times approximately 50% greater than the species divergence times.) The effective size of the species was estimated as approximately 5 x 10(6), and the average mutation rate was estimated as 1-2 x 10(-9)/nucleotide/generation. The ratio of amino acid polymorphisms within species to fixed differences between species suggests that approximately 25% of all possible single-step amino acid replacements in the boss gene product may be selectively neutral or nearly neutral. The data also imply that random genetic drift has been responsible for virtually all of the observed differences in the portion of the boss gene analyzed among the four species.

Alcohol Dehydrogenase↗
PubMed1990

Rapid HLA-DPB typing using enzymatically amplified DNA and nonradioactive sequence-specific oligonucleotide probes.

A simple and rapid method for characterizing the polymorphism at the HLA-DPB1 locus has been developed. The procedure involves the selective amplification of the polymorphic second exon of the DPB1 locus by the polymerase chain reaction (PCR), followed by hybridization of the amplified DNA with 15 nonisotopic sequence-specific oligonucleotide probes. There are no sequences within the second exon of the DPB1 locus that uniquely define an allele; rather, each allele appears to arise from the shuffling of a limited number of polymorphic nucleotide sequences in six regions of variability. Consequently, individual alleles are identified by the pattern of hybridization of the 15 probes. Two formats for typing are described. In Format I (the dot-blot), the amplified DNA is ultraviolet (UV) cross-linked to a nylon membrane and hybridized with the oligonucleotide probes which are covalently labeled with horseradish peroxidase (HRP). In Format II (the reverse dot-blot), the oligonucleotides, which have poly-T tails, are bound to the membrane and the immobilized array of probes is hybridized to the PCR product which has incorporated biotinylated primers during the amplification process. In both formats, hybridization is detected by a simple colorimetric reaction. The application of this technology to the fields of tissue typing and individual identity is discussed.

Alleles↗
PubMed2001

CD81 nucleotide mutation in hepatocellular carcinoma and lack of CD81 polymorphism in patients at stages of hepatitis C virus infection.

Mechanisms determining the chronicity or the pattern of clinical course of hepatitis C virus (HCV) infections have not been clarified. Recently, CD81 was reported to bind the E2 protein of HCV and was suggested to function as a cellular receptor for HCV. Accordingly, the hypothesis was examined that CD81 polymorphism, if it exists, might correlate with certain clinical courses of HCV infection. CD81 cDNA sequences were determined from peripheral blood mononuclear cells (PBMCs). Twenty-four Japanese subjects were enrolled initially as follows: patients with chronic hepatitis C without cirrhosis (n = 3), patients with cirrhosis (n = 3), patients with cirrhosis complicated by hepatocellular carcinoma (HCC) (n = 3), patients with persistent HCV viremia without ALT elevation (n = 3), those with positive anti-HCV antibodies without evidence of HCV viremia (n = 3), and healthy volunteers (n = 9). In all PBMCs samples analyzed, no polymorphism was found in the CD81 cDNA sequence. The sequence was different, however, from the one reported previously at three nucleotide positions: a transversion to thymine instead of cytosine at nt 1130, a deletion at nt 1206, and a guanine insertion at nt 71. Subsequently, CD81 cDNA sequences from PBMCs and HCC tissue were compared among the other 6 patients with chronic hepatitis C bearing HCC. A comparative study of the CD81 sequences from HCC and PBMCs revealed that various nucleotide mutations existed only in the HCC samples in 3 out of 6 patients. Several mutations in the 3' non-coding region of CD81 cDNA were observed exclusively in HCC tissue suggesting its possible role in hepatocarcinogenesis. Because of the absence of polymorphisms, however, CD81 is unlikely to affect the progression of chronic hepatitis C in terms of chronicity, hepatitis activity, or disease stage.

Adult↗
PubMed2000

Sequence alterations can mask each other's presence during screening with SSCP or heteroduplex analysis: BRCA genes as examples.

For mutation detection, various screening techniques are widely used because DNA sequencing, the gold-standard method, is still considered to be expensive and laborious for high-throughput screening. Single-strand conformation polymorphism (SSCP) analysis, heteroduplex analysis (HA) and their variant techniques are popular and frequently used for this purpose. It is widely accepted that when searching for unknown sequence variations, any revealed distinct pattern should always be sequenced. We give examples here of the BRCA1 and BRCA2 genes where the SSCP/HA techniques can produce ambiguous predictions if used to detect known genetic variants compared to positive controls. Using direct DNA sequencing, we provide evidence that in such cases, mutations or polymorphisms can mask each other's presence. This phenomenon can often influence the results of any DNA testing because genetic variations such as single-nucleotide polymorphisms occur frequently in the human genome. We suggest that even in the case of known electrophoretic patterns of well-characterized genetic alterations, every sequence alteration should be confirmed by direct DNA sequencing, especially if genetic testing is carried out for diagnostic purposes.

BRCA2 Protein↗
PubMed1999

Identification of two single nucleotide polymorphisms in exon 8 of PAX2.

We estimate the allele frequencies of two single nucleotide polymorphisms (1410 C --> T) and (1521 A --> C) in the coding region of PAX2. The coding region single nucleotide polymorphisms (cSNPs) were identified by sequencing of amplimers of PAX2 exon 8 exhibiting variant migration patterns in the course of genomic DNA mutation screening from patients with renal-coloboma syndrome. Allele frequencies of the two polymorphisms were 0.94 for 1410C and 0.72 for 1521A. Cosegregation analyses of both alleles suggest that they are each in Hardy-Weinberg equilibrium and jointly in linkage equilibrium and may represent ancient polymorphisms. Characterization of PAX2 exon 8 cSNPs will serve as useful tools for mapping at the PAX2 locus.

Abnormalities, Multiple↗
PubMed1995

Analysis of the hexokinase II gene in subjects with insulin resistance and NIDDM and detection of a Gln142-->His substitution.

Hexokinase II (HKII) is the predominant hexokinase isozyme expressed in insulin-responsive tissues. Since defects involving glucose transport and/or its phosphorylation to glucose-6-phosphate are present in muscle of insulin-resistant humans, HKII should be viewed as a candidate gene for inherited insulin resistance and susceptibility to non-insulin-dependent diabetes mellitus (NIDDM). To investigate the prevalence of potential mutations in the gene encoding HKII, we used the polymerase chain reaction (PCR) to amplify each of the 18 exons of the HKII gene from genomic DNA derived from 59 subjects: 25 insulin-resistant probands with clinical features of the type A syndrome and 34 NIDDM subjects enrolled in the United Kingdom Prospective Study of Therapies of NIDDM (UKPDS) who represented the highest percentile of fasting hyperinsulinemia in the UKPDS population of 5,098 subjects. PCR products corresponding to individual HKII exons derived from each subject were screened for the presence of nucleotide variation using a sensitive nonradioactive single-strand conformation polymorphism (SSCP) protocol. Variant SSCP patterns indicative of genetic variation were detected only in PCR amplimers containing exons 4-7, 10, 15, and 17. Direct sequencing of amplified DNA from individuals affected with variant SSCP patterns revealed the presence of the following silent polymorphisms: Asp251 (GAT/C) in exon 7 and Asn692 (AAT/C) in exon 15. SSCP variants detected in PCR products containing exons 5, 10, and 17 were due to single base substitutions in flanking intronic sequences. A polymorphic GGA repeat was identified within intron 5.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗