Copper(II) acetate complexes, [CuLm(OAc)2]n (L = HNPPh3), stable in the solid state either as a dimer (m = 1, n = 2) or a monomer (m = 2, n = 1).
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Crystallography, X-Ray↗
Biomedical subjects
J C Stephens
Publications and source records attributed to J C Stephens.
Haplotype variation and linkage disequilibrium in 313 human genes.
Variation within genes has important implications for all biological traits. We identified 3899 single nucleotide polymorphisms (SNPs) that were present within 313 genes from 82 unrelated individuals of diverse ancestry, and we organized the SNPs into 4304 different haplotypes. Each gene had several variable SNPs and haplotypes that were present in all populations, as well as a number that were population-specific. Pairs of SNPs exhibited variability in the degree of linkage disequilibrium that was a function of their location within a gene, distance from each other, population distribution, and population frequency. Haplotypes generally had more information content (heterozygosity) than did individual SNPs. Our analysis of the pattern of variation strongly supports the recent expansion of the human population.
Alleles↗
Notes from the SNP vs. haplotype front.
Single nucleotide polymorphisms (SNPs) and haplotypes are commonly used genetic markers in clinical studies. We provide some broad guidelines for deciding which of the two is most appropriate in particular circumstances. Molecular haplotyping techniques are also briefly reviewed and contrasted with electronic approaches.
Genetic Markers↗
Genetic restriction of HIV-1 pathogenesis to AIDS by promoter alleles of IL10.
IL10 is a powerful TH-2 cell cytokine produced by lymphoid cells that limits HIV-1 replication in vivo, ostensibly by inhibiting macrophage/monocyte and T-cell lymphocyte replication and secretion of inflammatory cytokines (IL1, TNFalpha, IL6, IL8, and IL12). A genetic epidemiological scan of patients enrolled in AIDS cohorts for candidate gene-linked short tandem repeat polymorphisms revealed significant genotype associations for HIV-1 infection and progression to AIDS with markers adjacent to and tracking (by linkage disequilibrium) common single nucleotide polymorphic variants in the IL10 promoter region. Individuals carrying the IL10-5'-592A (IL10-5'A) promoter allele possibly were at increased risk for HIV-1 infection, and once infected they progressed to AIDS more rapidly than homozygotes for the alternative IL10-5'-592 C/C (IL10-+/+) genotype, particularly in the later stages of HIV-1 infection. An estimated 25-30% of long-term nonprogressors (who avoid clinical AIDS for 10 or more years after HIV-1 infection) can be attributed to their IL10-+/+ promoter genotype. Alternative IL10 promoter alleles are functionally distinct in relative IL10 production, in retention of an avian erythroblastosis virus transcription factor recognition sequence and in binding to specific putative nuclear transcription factors, suggesting a potential mechanism whereby IL10-5'A down-regulation of inhibitory IL10 facilitates HIV-1 replication in vivo, accelerating the onset of AIDS.
Acquired Immunodeficiency Syndrome↗
Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness.
The human beta(2)-adrenergic receptor gene has multiple single-nucleotide polymorphisms (SNPs), but the relevance of chromosomally phased SNPs (haplotypes) is not known. The phylogeny and the in vitro and in vivo consequences of variations in the 5' upstream and ORF were delineated in a multiethnic reference population and an asthmatic cohort. Thirteen SNPs were found organized into 12 haplotypes out of the theoretically possible 8,192 combinations. Deep divergence in the distribution of some haplotypes was noted in Caucasian, African-American, Asian, and Hispanic-Latino ethnic groups with >20-fold differences among the frequencies of the four major haplotypes. The relevance of the five most common beta(2)-adrenergic receptor haplotype pairs was determined in vivo by assessing the bronchodilator response to beta agonist in asthmatics. Mean responses by haplotype pair varied by >2-fold, and response was significantly related to the haplotype pair (P = 0.007) but not to individual SNPs. Expression vectors representing two of the haplotypes differing at eight of the SNP loci and associated with divergent in vivo responsiveness to agonist were used to transfect HEK293 cells. beta(2)-adrenergic receptor mRNA levels and receptor density in cells transfected with the haplotype associated with the greater physiologic response were approximately 50% greater than those transfected with the lower response haplotype. The results indicate that the unique interactions of multiple SNPs within a haplotype ultimately can affect biologic and therapeutic phenotype and that individual SNPs may have poor predictive power as pharmacogenetic loci.
Base Sequence↗
Significant admixture linkage disequilibrium across 30 cM around the FY locus in African Americans.
Scientists, to understand the importance of allelic polymorphisms on phenotypes that are quantitative and environmentally interacting, are now turning to population-association screens, especially in instances in which pedigree analysis is difficult. Because association screens require linkage disequilibrium between markers and disease loci, maximizing the degree of linkage disequilibrium increases the chances of discovering functional gene-marker associations. One theoretically valid approach-mapping by admixture linkage disequilibrium (MALD), using recently admixed African Americans-is empirically evaluated here by measurement of marker associations with 15 short tandem repeats (STRs) and an insertion/deletion polymorphism of the AT3 locus in a 70-cM segment at 1q22-23, around the FY (Duffy) locus. The FY polymorphism (-46T-->C) disrupts the GATA promoter motif, specifically blocking FY erythroid expression and has a nearly fixed allele-frequency difference between European Americans and native Africans that is likely a consequence of a selective advantage of FY-/- in malaria infections. Analysis of linkage disequilibrium around the FY gene has indicated that there is strong and consistent linkage disequilibrium between FY and three flanking loci (D1S303, SPTA1, and D1S484) spanning 8 cM. We observed significant linkage-disequilibrium signals over a 30-cM region from -4.4 to 16.3 cM (from D1S2777 to D1S196) for STRs and at 26.4 cM (AT3), which provided quantitative estimates of centimorgan limits, by MALD assessment in African American population-association analyses, of 5-10 cM.
Africa↗
Significant association of cagA positive Helicobacter pylori strains with risk of premature myocardial infarction.
OBJECTIVE: To investigate whether genetic diversity of Helicobacter pylori influences its association with coronary heart disease, and specifically whether the risk is confined to infection with the more virulent strains bearing the cytotoxin associated gene-A (cagA) antigen. DESIGN AND SETTING: Case-control study in hospital admitting unselected patients with myocardial infarction. METHODS AND SUBJECTS: Serological status for cagA and H pylori were determined in 342 cases of acute myocardial infarction and 214 population based control subjects free of clinical coronary heart disease. RESULTS: 38.0% of cases and 30.8% of controls were cagA seropositive (odds ratio 1.38, 95% confidence interval (CI) 0.94 to 2.01, p = 0.08). In subjects < 65 years old (153 cases, 153 controls), cagA seropositivity was associated with a 1.80-fold increase (95% CI 1.07 to 3.03, p = 0.02) in myocardial infarction risk, which increased further to 2.25-fold (95% CI 1.12 to 4.53, p = 0.01) in subjects < 55 years. There was no significant association of cagA status with classical coronary heart disease risk factors. H pylori seropositivity was present in 60.2% of cases and 53.7% of controls (odds ratio 1.12, 95% CI 0.83 to 1.51, p = 0.43). H pylori seropositivity was not increased in young cases and did not show any interaction with age. CONCLUSIONS: The association of chronic H pylori infection with risk of myocardial infarction appears to be restricted to cagA bearing strains. The association is age dependent and stronger in younger subjects. Genetic heterogeneity of H pylori may explain some of the discordant findings with regard to the association of H pylori with coronary heart disease.
Aged↗
The predictive power of haplotypes in clinical response.
A variety of approaches have been proposed to find genetic markers that can be used in a clinical setting. Single nucleotide polymorphisms (SNPs) are the basis of the most commonly used approaches. Here we describe an approach using gene-based haplotypes, which are collections of SNPs located throughout the ftinctional regions of candidate genes, and organised as they occur separately on an individual's two chromosomes. The main point of this review is that the haplotype has greater power than any individual SNP to track an unobsenrved, but evolutionarily linked, variable site.
Animals↗
Molecular genetic diversity and evolution at the MHC DQB locus in four species of pinnipeds.
Variation was investigated at exon 2 (including part of the putative peptide-binding region) of the class II major histocompatibility complex (MHC) DQB locus for two congeneric phocid seal species and two congeneric otariid seal species. Polymorphism in one phocid species, the southern elephant seal (Mirounga leonina), was comparable to that seen in human populations, while the other phocid, the northern elephant seal (Mirounga angustirostris), has been through a severe population bottleneck and exhibited much less variation at this locus. A phylogenetic comparison of the four species was consistent with the trans-specific pattern of evolution described for other taxa at this locus, and relative nonsynonymous and synonymous substitution rates suggest the maintenance of polymorphisms by natural selection. A comparison of sequence patterns also suggested that some variation could have been generated through recombinational events, primarily within genera. These results suggest a pattern of evolution of the immune response in pinnipeds similar to that in terrestrial mammal species.
Amino Acid Sequence↗
Single-nucleotide polymorphisms, haplotypes, and their relevance to pharmacogenetics.
Recognition that there is a vast quantity of human genetic variation has had a pervasive impact on modern medicine, facilitating the identification of scores of genes that underlie monogenic clinical disorders, as well as genes involved in complex disease processes. The next logical step for human genetics is the exploration and elucidation of genes involved in differential pharmacological response: responders, nonresponders, and those with adverse side effects. An understanding of the role that genes have in pharmacological response is the cornerstone of personalized medicine. Pharmacogenetic activities have swiftly embraced these tenets, leading to a proliferation of resources and approaches meant to enable and expedite targeted drug discovery and development. To realize the potential of these efforts, it will be necessary to incorporate a better understanding of the population genetic and evolutionary processes that have shaped genetic variation in modern humans. This article introduces these concepts to provide context and guidelines for the use of this variation (primarily single-nucleotide polymorphisms and haplotypes) in pharmacogenetics.
Genetics, Population↗
Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes.
The CCR5-Delta32 deletion obliterates the CCR5 chemokine and the human immunodeficiency virus (HIV)-1 coreceptor on lymphoid cells, leading to strong resistance against HIV-1 infection and AIDS. A genotype survey of 4,166 individuals revealed a cline of CCR5-Delta32 allele frequencies of 0%-14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and two microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, we estimate the origin of the CCR5-Delta32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275-1,875 years. The geographic cline of CCR5-Delta32 frequencies and its recent emergence are consistent with a historic strong selective event (e.g. , an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations.
Acquired Immunodeficiency Syndrome↗
Helicobacter pylori cagA status, vacA genotypes and ulcer disease.
OBJECTIVE: Helicobacter pylori is the causative organism of peptic ulcer disease and has two putative virulence determinants: the cagA gene which encodes a protein of unknown function in 60% of strains, and the vacA gene, which is present in all strains, although active cytotoxin is produced in only about 50% of these. The relationship between genotypes of both cagA and vacA and resultant gastroduodenal pathology is unclear. The objective of this study was to correlate vacA genotype and cagA status with gastroduodenal pathology. METHODS: One hundred and six dyspeptic patients were studied (average age 56 years, range 19-86 years, 56 men) referred for routine endoscopy. Macroscopic evidence of gastroduodenal disease was noted and antral biopsies taken for culture and genotyping of H. pylori. The polymerase chain reaction (PCR) was used to detect the cagA and vacA genes of H. pylori using specific primers. RESULTS: Seventy eight of the 106 (73.6%) patients were cagA positive. Of those who had peptic ulcer disease 29/32 (90.6%) were cagA positive. The presence of the cagA gene was significantly associated with peptic ulcer disease (P = 0.006). The presence of the vacA s1 genotype was also significantly associated with peptic ulcer disease (P = 0.01). The presence of the cagA gene was significantly associated with the vacA s1 genotype (P < 0.001). There was no significant difference in the distribution of the s1/m1 and s1/m2 strains between ulcer and non-ulcer patients. CONCLUSION: There is a significant association of the cagA gene and vacA s1 signal sequence with gastroduodenal ulcer disease. The relationship of the various other vacA genotypes to gastroduodenal ulcer disease is less clear.
Adult↗
The significance of cagA and vacA subtypes of Helicobacter pylori in the pathogenesis of inflammation and peptic ulceration.
AIMS: To assess the significance of cagA and vacA subtypes of Helicobacter pylori in relation to inflammation and density of bacterial colonisation in vivo within a dyspeptic UK population. METHODS: Dyspeptic patients who were Helicobacter pylori positive had antral samples taken for histology and culture. Gastroduodenal pathology was noted. The grade of bacterial density and inflammation was assessed using the Sydney system. Bacterial DNA was extracted and the vacA alleles and the cagA/gene typed using PCR. RESULTS: 120 patients were studied. There was high rate of cagA positive strains in this population. Bacterial density did not correlate with the presence of peptic ulceration. There was a significant association between cagA positive strains and increased inflammation and bacterial density. The vacA s1 type independently correlated with extensive chronic inflammation but there was no association with bacterial density. The vacA m type did not correlate with extent of inflammation or bacterial density. CONCLUSIONS: The results suggest that cagA is important in the pathogenesis of inflammation and peptic ulceration. These findings are in keeping with the hypothesis that cagA acts as a marker for a cag pathogenicity island which encodes several genes involved in inflammation. The vacA s1 allele correlates with inflammation independently of cagA, possibly through its enhanced ability to produce the vacuolating cytotoxin.
Adult↗
Detection and typing of the virulence determinants cagA and vacA of Helicobacter pylori directly from biopsy DNA: are in vitro strains representative of in vivo strains?
BACKGROUND: The relationship of Helicobacter pylori genotypes to gastrointestinal disease has relied on cultured isolates. This assumes that cultured strains are representative of in vivo strains. OBJECTIVE: To detect and type the cagA status and the vacA genotypes directly from biopsy DNA without the need for culture, and to further define the relationship between H. pylori genotypes and gastroduodenal pathology. METHODS: Fifty-two Caucasian patients undergoing routine endoscopy for dyspepsia had additional biopsies taken from four gastric sites and one duodenal site for biopsy DNA preparation. An antral sample was taken for biopsy culture. All recruited patients were H. pylori-positive on rapid urease test for Campylobacter-like organisms (CLO test) and/or histology. By polymerase chain reaction (PCR), the cagA status and the vacA s and m types were detected directly from biopsy DNA. RESULTS: H. pylori isolates were cultured from 28/52 patients in whom infection was detected by PCR. Two isolate types differed from biopsy types. Fifty of the 52 patients, strains were typable from all four gastric sites and in 51/52 the same strain predominated throughout. The cancer strains were all cagA-positive/vacA s1 type. There was a correlation between cagA positivity and vacA s1 (41/43). There was no difference between the cagA-positive/vacA s1 strains and the presence or absence of ulcers. There were only 5/52 vacA s2 m2 and four were in the non-ulcer dyspeptic group. CONCLUSION: cagA status and the vacA genotyping was successful with tissue samples taken directly from gastric and duodenal biopsies. Discrepancies between isolate and biopsy strain types stress the need for caution when interpreting in vitro strain types and suggest that direct PCR of biopsies is the preferred typing technique. The cagA status and the s1 vacA allele are unreliable as single markers in determining the risk of developing peptic ulcer disease.
Antigens, Bacterial↗
Rates of nuclear and cytoplasmic mitochondrial DNA sequence divergence in mammals.
Differential rates of nucleotide substitution among different gene segments and between distinct evolutionary lineages is well documented among mitochondrial genes and is likely a consequence of locus-specific selective constraints that delimit mutational divergence over evolutionary time. We compared sequence variation of 18 homologous loci (15 coding genes and 3 parts of the control region) among 10 mammalian mitochondrial DNA genomes which allowed us to describe different mitochondrial evolutionary patterns and to produce an estimation of the relative order of gene divergence. The relative rates of divergence of mitochondrial DNA genes in the family Felidae were estimated by comparing their divergence from homologous counterpart genes included in nuclear mitochondrial DNA (Numt, pronounced "new might"), a genomic fossil that represents an ancient transfer of 7.9 kb of mitochondrial DNA to the nuclear genome of an ancestral species of the domestic cat (Felis catus). Phylogenetic analyses of mitochondrial (mtDNA) sequences with multiple outgroup species were conducted to date the ancestral node common to the Numt and the cytoplasmic (Cymt) mtDNA genes and to calibrate the rate of sequence divergence of mitochondrial genes relative to nuclear homologous counterparts. By setting the fastest substitution rate as strictly mutational, an empirical "selective retardation index" is computed to quantify the sum of all constraints, selective and otherwise, that limit sequence divergence of mitochondrial gene sequences over time.
Animals↗
Identification of a novel TAP2 allele in a Colombian black population: gene conversion, ancestral intermediate or convergent change?
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ATP Binding Cassette Transporter, Subfamily B, Mem↗
Genetic individualization of domestic cats using feline STR loci for forensic applications.
A group of ten short tandem repeat (STR) loci suitable for PCR typing from DNA of domestic cats is evaluated for genetic individualization using blinded samples of eight putative feline blood specimens. The ten loci were also typed in a 70 member cat pedigree to demonstrate Mendelian inheritance and independent assortment. A "match window" or measurement precision estimate was empirically established by determining the maximum gel migration difference among alleles identical by descent in different individuals of the pedigree. Hardy-Weinberg equilibrium and abundant heterozygosity was observed for each locus in cat population samples from Canada and the USA. The probabilities of two unrelated individuals matching by chance (Pm) at all ten loci was estimated as 1.35 x 10(-10). We present a conservative approach to compute, for forensic consideration, the mathematical likelihood of a chance genotypic match between DNA evidence from a crime scene and the suspect composite STR genotypes for species or populations when genotype frequency information is not available.
Animals↗
Production of a monoclonal antibody against the 128 kDa (CagA) protein of Helicobacter pylori.
Helicobacter pylori is recognised as an important factor in gastroduodenal pathology. The 128 kDa CagA protein has been established as a useful marker of H. pylori strains associated with more severe forms of disease. A mouse monoclonal antibody raised against the CagA protein has been produced and characterised as belonging to the IgG1 subtype. It identified the protein in all clinical isolates (10/10) from this laboratory and in two NCTC reference strains (NCTC 11637 and NCTC 11961). No cross-reacting proteins were detected in H. pylori L2, a well characterised strain known not to contain the cagA gene, or in four Helicobacter sp. from non-human sources (H. canis, H. mustelidae, H. muridarum and H. acinonyx). The monoclonal antibody was used to develop an antigen capture ELISA system for detecting the presence of antibodies to the CagA protein in human serum samples.
Animals↗