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PubMed1998

Genetic variation of the Borrelia burgdorferi gene vlsE involves cassette-specific, segmental gene conversion.

The Lyme disease spirochete Borrelia burgdorferi possesses 15 silent vls cassettes and a vls expression site (vlsE) encoding a surface-exposed lipoprotein. Segments of the silent vls cassettes have been shown to recombine with the vlsE cassette region in the mammalian host, resulting in combinatorial antigenic variation. Despite promiscuous recombination within the vlsE cassette region, the 5' and 3' coding sequences of vlsE that flank the cassette region are not subject to sequence variation during these recombination events. The segments of the silent vls cassettes recombine in the vlsE cassette region through a unidirectional process such that the sequence and organization of the silent vls loci are not affected. As a result of recombination, the previously expressed segments are replaced by incoming segments and apparently degraded. These results provide evidence for a gene conversion mechanism in VlsE antigenic variation.

Animals↗
PubMed2006

Additive genetic variation of transcriptional regulation: metallothionein expression in the soil insect Orchesella cincta.

Field-selected metal tolerance in Orchesella cincta is correlated with overexpression of the single copy cadmium (Cd) inducible metallothionein (mt). Previously, we have demonstrated large phenotypic variation in mt gene expression, and a higher frequency of high-expression phenotypes in a tolerant population. Here, we describe midparent-offspring regression analysis of mt gene expression in a laboratory culture originating from a noncontaminated natural population. Families were either not exposed (n=47) or exposed to 0.5 micromol Cd per gram dry food (n=46). Mean mt gene expressions normalized to 28S rRNA and beta-actin RNA were generated using real-time RT-PCR applied to parents and offspring RNA and subjected to regression analysis. A significant heritability (h2) for mt gene expression was estimated between 0.36 (beta-actin normalized) and 0.46 (28S normalized) in Cd exposed families. Nontreated families did not yield a significant h2 value. Restriction Fragment Length Polymorphism analysis of the metallothionein promoter sequence revealed eight promoter alleles that show structural variation. Three alleles show increased frequencies in families with high mt expression. Another gene, croquemort (isolated from a differential screening for 1 micromole Cd treatment) showed no h2 of gene expression in response to 0.5 micromol Cd. This gene codes for a receptor-protein involved in recognition of apoptotic cells and may participate in the general stress response. The present data suggest that evolution of metal tolerance in O. cincta can occur in the field by selection for high mt expression due to structural changes in mt cis-regulation.

Adaptation, Physiological↗
PubMed2005

Genetic variation in adiponectin receptor 1 and adiponectin receptor 2 is associated with type 2 diabetes in the Old Order Amish.

Adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2) are newly identified receptors for adiponectin, an adipocytokine with anti-inflammatory and insulin-sensitizing properties. We screened for polymorphisms by performing sequence analysis on all eight exons, splice junctions, and approximately 2 kb of the 5' flanking regions of each receptor. We detected 5 single nucleotide polymorphisms (SNPs) in ADIPOR1 and 16 SNPs in ADIPOR2. We genotyped these SNPs in Amish subjects with type 2 diabetes (n = 137), impaired glucose tolerance (IGT) (n = 139), and normal glucose tolerance (n = 342) to test for association with type 2 diabetes. Three intronic SNPs in ADIPOR1 were significantly associated with type 2 diabetes (P = 0.014-0.007; odds ratio [OR] 1.61-1.65) and in high linkage disequilibrium (r2 = 0.97-1.0). In ADIPOR2, we found that five SNPs delineated one large haplotype block (r2= 0.9-1.0) spanning >98 kb of the gene and promoter region, which was strongly associated with the combined type 2 diabetes/IGT trait (P < or = 0.001; OR 1.64-1.71). To our knowledge, these data provide the first evidence for association between variation in the adiponectin receptors and type 2 diabetes.

Aged↗
PubMed2003

Protective association of genetic variation in alcohol dehydrogenase with alcohol dependence in Native American Mission Indians.

OBJECTIVE: Two alcohol dehydrogenase genes (ADH2 and ADH3 on chromosome 4) and one aldehyde dehydrogenase gene (ALDH2 on chromosome 12) exhibit functional polymorphisms. The goal of this study was to determine whether any associations exist between the ADH2, ADH3, and ALDH2 polymorphisms and alcohol dependence in a group of Native Americans. An additional goal was to determine if any associations exist between these polymorphisms and the endophenotype, maximum number of drinks ever consumed in a 24-hour period. METHOD: Mission Indian adults (N=340) were recruited for participation from reservations in southern California. Each participant completed an interview with the Semi-Structured Assessment for the Genetics of Alcoholism. A blood sample was collected from each participant for genotyping at the ALDH2, ADH2, and ADH3 loci. RESULTS: Sixty percent of all participants (72% of men and 53% of women) met lifetime DSM-III-R criteria for alcohol dependence. A significant difference in the ADH2 allele distributions was found between alcohol-dependent and non-alcohol-dependent participants. Those with alcohol dependence were significantly less likely to have the ADH2*3 allele (odds ratio=0.28) and significantly more likely to have the ADH2*1 allele (odds ratio=2.00) than those who were not alcohol dependent. Individuals with ADH2*3 reported a lower number of maximum drinks ever consumed in a 24-hour period, compared to those without this allele. CONCLUSIONS: These results are consistent with genetic linkage studies showing protective associations for alcohol dependence and related behavior on chromosome 4 and suggest that ADH2 polymorphisms may account for these findings. These results also highlight the utility of evaluating protective factors in populations with high rates of alcohol dependence.

Adolescent↗
PubMed2006

Hypoadiponectinemia is associated with progression toward type 2 diabetes and genetic variation in the ADIPOQ gene promoter.

OBJECTIVE: Adiponectin encoded by the ADIPOQ gene modulates insulin sensitivity and glucose homeostasis. The aim of the current study was to investigate whether ADIPOQ gene variants in the promoter region predict adiponectin levels and type 2 diabetes progression. RESEARCH DESIGN AND METHODS: A total of 550 subjects with increased risk of type 2 diabetes were investigated; they underwent a 75-g oral glucose tolerance test, repeated after 3 years. Adiponectin levels were analyzed, and two ADIPOQ promoter variant single nucleotide polymorphisms, -11391G>A and -11377C>G, were genotyped. RESULTS: Tertiles of the adjusted adiponectin levels were associated with single nucleotide polymorphism -11391G>A and -11377C>G haplotypes (P < 0.0001). Carriers of the intermediate/high-level haplotype combination showed a bisected diabetes risk at the 3-year follow-up and were characterized by a "regression" of glucose tolerance. Evolution of disease status correlates with preexisting low adiponectin levels at inclusion rather than with variation in adiponectin levels. CONCLUSIONS: We present data that gene variants in the ADIPOQ promoter region are associated with variations in adiponectin levels and thus with future type 2 diabetes and disease progression.

Adiponectin↗
PubMed1995

Genetics of male sterility in gynodioecious Plantago coronopus. II. Nuclear genetic variation.

Inheritance of male sterility was studied in the gynodioecious species Plantago coronopus using five plants and their descendants from an area of approximately 50 m2 from each of four locations. In each location, crosses between these five plants yielded the entire array of possible sex phenotypes. Both nuclear and cytoplasmic genes were involved. Emphasis is placed on the nuclear (restorer) genetics of two cytoplasmic types. For both types, multiple interacting nuclear genes were demonstrated. These genes carried either dominant or recessive restorer alleles. The exact number of genes involved could not be determined, because different genetic models could be proposed for each location and no common genetic solution could be given. At least five genes, three with dominant and two with recessive restorer allele action, were involved with both cytoplasmic types. Segregation patterns of partially male sterile plants suggested that they are due to incomplete dominance at restorer loci. Restorer genes interact in different ways. In most instances models with independent restorer gene action were sufficient to explain the crossing results. However, for one case we propose a model with epistatic restorer gene action. There was a consistent difference in the segregation of male sterility between plants from the two cytoplasmic types. Hermaphrodites of cytoplasmic type 2 hardly segregated male steriles, in contrast to plants with cytoplasmic type 1.

Alleles↗
PubMed1986

Genetic variation and plasma creatine kinase activity.

The distribution of plasma creatine kinase (CK; E.C.2.7.3.2) is known to be skewed, and this has made it difficult to analyse the sources of variation. We have studied plasma CK in 206 pairs of twins and have analysed the results after separating them into what appear to be two Gaussian frequency distributions. The results in the main distribution (CK less than 300 iu/1) are apparently affected by genetic factors common to both men and women, and by environmental factors which are of much greater effect in men. The tendency for some men to have very high CK values may also have a genetic basis.

Adult↗
PubMed1976

Genetic variation in serum low density lipoproteins and lipid levels in man.

Combined data from 10 different populations indicate that the serum cholesterol and triglyceride levels are higher in Ag(x-) than in Ag(x+) individuals. Although the differences were relatively small, they became more pronounced with increasing age. The Ag(x) antigen, which is associated with the serum low density lipoprotein, is genetically controlled and the present study therefore has revealed a small but significant effect of a single autosomal locus on lipids implicated in the pathogenesis of atherosclerosis. No explanation of the higher cholesterol and triglyceride levels in Ag(x-) than in Ag(x+) persons is apparent.

Age Factors↗
PubMed2001

Genetic variation in beta-adrenergic receptors and their relationship to susceptibility for asthma and therapeutic response.

Our early work focused on quantitative variation in traits related to beta-adrenergic signaling: lymphocyte levels of cAMP and the binding properties of the beta-adrenergic receptor. We confirmed the work of others that the major histocompatibility locus had an effect on cAMP levels in mice and in man. The latter result was presumably due to the influence of beta-adrenergic receptors, since it was the isoproterenol-stimulated lymphocyte cAMP level that was studied. We went on to directly study beta-adrenergic receptor levels in mouse hepatic plasma membranes using dihydroalprenolol binding. We discovered a strain variation, apparently controlled by a single locus, which determined a magnesium influence on measurable levels of dihydroalprenolol binding. More recently, our group's work has focused on the human single nucleotide polymorphisms (SNPs) in the human beta2-adrenergic receptor. We found that variation at amino acid position 16 had a very marked effect on the response of subjects to albuterol. Similar trends were observed for asthmatic and nonasthmatic children, and the results were independent of baseline lung function. Our results, and those of other groups relating SNPs in the beta-adrenergic receptor to a number of responses, mostly related to asthma, are reviewed in this article.

Animals↗
PubMed2002

Chagas disease: role of parasite genetic variation in pathogenesis.

Chagas disease, caused by the parasite protozoan Trypanosoma cruzi, is characterised by a variable clinical course, from symptomless cases to severe chronic disease with cardiac and/or gastrointestinal involvement. This variability has been attributed both to differences in the host response and to genomic heterogeneity of the parasite. This article reviews the evidence in favour of an important role of the genetic constitution of T. cruzi in determining the clinical characteristics of Chagas disease and discusses the basis of the 'Clonal-Histotropic Model' for the pathogenesis of this disease.

Animals↗
PubMed2006

Short-term impact of 1997/1998 ENSO-induced disturbance on abundance and genetic variation in a tropical butterfly.

In order to assess the short-term impact of habitat loss after disturbance, we studied Arhopala epimuta (Lepidoptera: Lycaenidae) populations in 5 landscapes in Borneo that were differentially affected by the 1997/1998 El Niño Southern Oscillation-induced drought and fire. Sampling was conducted before (1997) and after (1998 and 2000) disturbance. This study combined demographic and genetic data inferred from the analysis of 5 microsatellite loci and mitochondrial DNA (mtDNA) control region sequences. Over all 5 landscapes, a total of 313 A. epimuta were sampled over the 3-year survey. Butterfly abundance varied greatly both spatially and temporally (within disturbed landscapes). After the disturbance, a 4-fold population expansion was observed in a small unburned isolate, whereas population extinction was observed in one of the severely burned areas. The analysis of mtDNA sequences in a subsample of 106 A. epimuta revealed no significant spatial or temporal genetic structure. The analysis of 5 microsatellite loci revealed high frequencies of null alleles. Genetic evidence of recent change in population size was found in all 3 unburned landscapes using microsatellites. Congruent to mtDNA, microsatellites failed to detect significant genetic structure according to sampling year or landscapes. Our results suggest that, for mobile species within recently fragmented habitat, habitat loss after disturbance may lead to local population extinction but may augment genetic diversity in remnant local populations because of increased gene flow.

Animals↗
PubMed2005

Genetic variation in pure lines and crosses of large-bodied turkey lines. 3. Growth-related measurements on live birds.

An experimental line (F) selected over 34 generations for increased 16-wk BW was reciprocally crossed with a primary breeding sire line (C) from a large international turkey breeder to study the inheritance of growth-related traits measured on live birds. All genetic groups were grown intermingled in confinement with sexes reared in different houses. The traits measured included BW at 8, 16, and 20 wk of age and shank length, shank width, shank depth, breast width, and walking ability scores at 16 wk of age. Walking ability was rated from 1 to 5 with 1 representing birds with no leg defects and no difficulty walking and 5 indicating birds with extreme lateral deviations of the legs and great difficulty walking. Ratings of 2, 3, and 4 represented intermediate values. The F line had a different growth pattern than the C line with the F line being larger than the C line at 8 wk of age, but the reverse was true at 16 and 20 wk of age. The difference in BW between the C and F lines increased from 16 to 20 wk of age. The C line had wider breasts than the F line at 16 wk of age. The F line had longer shanks than the C line. Shank width was larger in the C line than the F line for females but not males. No line difference in shank depth was observed. Walking ability scores at 16 wk of age were lower (better) in the C line than in the F line for males but not females. Significant heterosis in BW of the crosses of the F and C lines was observed at all ages in males (range = 3.3 to 5.6%) and only at 8 wk of age in females (3.6%). These results were similar to an earlier study in which the F line was crossed with a primary-breeding sire line from 2 other international turkey breeders. No significant heterosis in the crosses of the C and F line was observed for breast width and shank measurements. Heterosis was significant for walking ability scores of females (-3.0%) but not males. Reciprocal effects, a measure of sex linkage and maternal influences, were noted only for shank length and the direction of the difference was not the same in the 2 sexes.

Animals↗
PubMed2006

Association of genetic variations in CCR5 and its ligand, RANTES with clearance of hepatitis B virus in Korea.

Immunogenetic factors may play a role in determining the susceptibility of an individual to viral infection. The aim of current study was to investigate the association of clearance of hepatitis B virus (HBV) with promoter polymorphisms within the CC chemokine receptor 5 (CCR5) and its major ligand, regulated upon activation, normal T cells expressed and secreted (RANTES) genes. Five chemokine system polymorphisms (CCR5 Delta32, CCR5 promoter 59029G/A, 59353C/T, RANTES -403G/A, and -28C/G) were studied in a total of 698 subjects. The carriage of each genetic variant was compared among "spontaneously recovered" group (n = 243), "chronic carrier" group (n = 349), and "unexposed" group (n = 106). CCR5 59029G promoter variant was associated with clearance of HBV infection in an acute phase (OR = 1.71, P = 0.006, dominant model; OR = 2.17, P < 0.001, recessive model) and amelioration of hepatic inflammation (P = 0.003) with the control of HBV replication (P = 0.04) in chronic carriers. Interestingly, CCR5 59029 was linked completely to CCR5 59353, and CCR5 Delta32 homozygosity or heterozygosity was not found in any Korean patient. No association was seen with RANTES polymorphisms at position -403 and -28. The CCR5 59029G/CCR5 59353T polymorphism may play a role in the clearance of HBV infection.

Adult↗
PubMed1993

Genetic variation in thymidylate synthase confers resistance to 5-fluorodeoxyuridine.

The human colorectal tumor cell line HCT 116 was resident to the cytotoxic effects of 5-fluorodeoxyuridine (FdUrd). The response to FdUrd was increased only slightly by the presence of 10 microM folinic acid (CF). HCT 116 formed FdUMP and CH2H4PteGlu polyglutamates after exposure to FdUrd and CF. The sensitivity to FdUrd correlated well with the extent of TS inhibition. The role of TS in the resistance of the cells to FdUrd was examined. HCT 116 expresses two TS enzymes, which differ in pI. The more basic TS has been detected in only HCT 116 cells. The other TS is identical in pI to the enzymes detected in other human cells. The variant TS differs from the common by His replacement of Tyr at residue 33. The variant TS exhibited a 3-fold lower affinity for FdUMP than the common TS. The enzymes co-expressed in HCT 116 exhibited an FdUMP binding constant similar to that of the variant TS. TS-deficient cells were transfected with cDNAs encoding the two TS polypeptides. Transfectants expressing the variant TS were more resistant to FdUrd cytotoxicity than cells expressing the common TS. Thus, the structural variation in TS reduced enzyme affinity for FdUMP and conferred resistance to FdUrd.

Colorectal Neoplasms↗
PubMed2003

Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations.

Many areas of biomedical research depend on the analysis of uncommon variations in individual genes or transcripts. Here we describe a method that can quantify such variation at a scale and ease heretofore unattainable. Each DNA molecule in a collection of such molecules is converted into a single magnetic particle to which thousands of copies of DNA identical in sequence to the original are bound. This population of beads then corresponds to a one-to-one representation of the starting DNA molecules. Variation within the original population of DNA molecules can then be simply assessed by counting fluorescently labeled particles via flow cytometry. This approach is called BEAMing on the basis of four of its principal components (beads, emulsion, amplification, and magnetics). Millions of individual DNA molecules can be assessed in this fashion with standard laboratory equipment. Moreover, specific variants can be isolated by flow sorting and used for further experimentation. BEAMing can be used for the identification and quantification of rare mutations as well as to study variations in gene sequences or transcripts in specific populations or tissues.

Base Sequence↗
PubMed2001

[Genetic variation of the core and E1 region of hepatitis C virus in serum collected from patients with chronic hepatitis].

OBJECTIVE: To study the association of the core and E1 region variation of hepatitis C virus (HCV) with the chronicity of HCV infection. METHODS: Acute-phase plasma samples from two drug-injection users who acquired HCV infection during six-month follow-up and ten patients with chronic hepatitis C were obtained. A 1-kb fragment containing the 3' half of core, completed E2 and 3' half of E2 were amplified by nested reverse transcription polymerase chain reaction (RT-PCR). For each 30 cloned cDNAs were examined by a method that combined heteroduplex (HD) analysis and a single-stranded conformational polymorphism (SSCP) assay to assess quasispecies complexity and optimize selection of clones with unique gel shift patterns for sequenceing. Amino acid sequences were analyzed for signature patterns and glycosylation signals. RESULTS: There was obvious difference between the SSCP bands of cloned cDNAs representing core-E1 region, but not obvious distance between heteroduplexes and the homoduplex. There was no change in the sequence of each clonotype from acutely HCV-infected subjects, whereas the rate of nonsynonymous substitution was 1.32% in amino acid sequence of E1 from persistently HCV-infected subjects with except for functional patterns. CONCLUSIONS: The variation of the E1 gene of HCV is in the presence of quasispecies population but might not related with its immunologic escape.

Chronic Disease↗