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Results for “Genetic Variation”

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PubMed1984

Purification and characterization of the rat liver microsomal cytochrome P-450 involved in the 4-hydroxylation of debrisoquine, a prototype for genetic variation in oxidative drug metabolism.

Genetic polymorphism in oxidative drug metabolism is perhaps best exemplified in the case of debrisoquine 4-hydroxylase activity, where the incidence of deficient metabolism ranges from 1% to 30% in various populations and this defect is also linked to an impaired ability to metabolize a number of other drugs effectively. Sprague-Dawley (SD) rats possess this activity, but females of the DA strain do not, although total cytochrome P-450 (P-450) levels are similar. We have purified, by using debrisoquine 4-hydroxylase activity as an assay, a minor P-450 to electrophoretic homogeneity from male SD rats and designate this as P-450UT-H. P-450UT-H differs from eight other purified rat liver P-450s as judged by peptide mapping and immunochemical analysis and thus appears to be isozymic with these other P-450s. P-450UT-H exhibited considerably more debrisoquine 4-hydroxylase activity than any of the other purified P-450s and, on a total P-450 basis, more than total microsomal P-450. Antibodies raised against P-450UT-H specifically recognized P-450UT-H and inhibited more than 90% of the debrisoquine hydroxylase activity present in SD rat liver microsomes. The level of P-450UT-H in SD rat liver microsomes accounted for less than 10% of the total P-450, as judged by immunochemical quantitation. These assays also indicated that the level of P-450UT-H in female DA rat liver microsomes is only about 5% of that in male or female SD rat liver microsomes, consonant with the view that deficiency of this form of P-450 is responsible for the defective debrisoquine 4-hydroxylase activity in the former animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2007

Genetic variation in tumor necrosis factor and lymphotoxin-alpha (TNF-LTA) and breast cancer risk.

Tumor necrosis factor (TNF) is critical to regulation of inflammation. Genetic variation in the promoter region of TNF has been associated with expression differences, and a range of auto-immune, infectious, and oncologic diseases. We analyzed eight common single nucleotide polymorphisms (SNPs) (rs746868, rs909253, rs1799964, rs1800630, rs1800750, rs1800629, rs361525, and rs1800610) to capture most of the genetic variation in TNF in addition to SNPs in lymphotoxin-alpha (LTA), a pro-inflammatory cytokine in linkage disequilibrium with the TNF promoter region. SNPs were genotyped in a USA population-based case-control study (3,318 cases, 2,841 controls). Promising results were followed-up in an independent population-based case-control study in Poland (2,228 cases, 2,378 controls). In both studies, women carrying the variant allele of rs361525 were at elevated breast cancer risk compared to the GG genotype (per allele OR = 1.18, 95% CI 1.04-1.35; P for trend = 0.008). Other SNPs were not significantly associated with breast cancer risk. Haplotype analyses did not reveal any additional associations between TNF and breast cancer risk. Data from 5,269 cases and 4,982 controls suggested that the rs361525 A allele, located in the TNF promoter region, was associated with a modest increase in breast cancer risk. Additional studies are required to replicate these findings and to determine whether rs361525 is a causative SNP or is a marker of a causative SNP.

Adult↗

PubMed2006

Genetic variation in myosin IXB is associated with ulcerative colitis.

BACKGROUND & AIMS: Common germline genetic variation in the 3' region of myosin IXB (MYO9B) has been associated recently with susceptibility to celiac disease, with a hypothesis that MYO9B variants might influence intestinal permeability. These findings suggested the current study investigating a possible further role for MYO9B variation in inflammatory bowel disease. METHODS: Eight single-nucleotide polymorphisms (SNPs) were selected to tag common haplotypes from the 35-kb 3' region of MYO9B. These included the strongest celiac disease-associated variants reported in a Dutch cohort. These SNPs were studied in 3 independently collected and genotyped case-control cohorts of European descent (UK, Dutch, and Canadian/Italian), comprising in total 2717 inflammatory bowel disease patients (1197 with Crohn's disease, 1520 with ulcerative colitis) and 4440 controls. RESULTS: Common variation in MYO9B was associated with susceptibility to inflammatory bowel disease in all 3 cohorts examined (most associated SNP, rs1545620; meta-analysis P = 1.9 x 10(-6); odds ratio, 1.2), with the same alleles showing association as reported for celiac disease. CONCLUSIONS: MYO9B genetic variants predispose to inflammatory bowel disease. Interestingly, rs1545620 is a nonsynonymous variant leading to an amino acid change (Ala1011Ser) in the third calmodulin binding IQ domain of MYO9B. Unlike previous variants (in other genes) reported to predispose to inflammatory bowel disease, the association at MYO9B was considerably stronger with ulcerative colitis, although weaker association with Crohn's disease also was observed. These data imply shared causal mechanisms underlying intestinal inflammatory diseases.

Adolescent↗

PubMed2000

Historical biogeography in a linear system: genetic variation of sea rocket (Cakile maritima) and sea holly (Eryngium maritimum) along European coasts.

The exclusively coastal Cakile maritima and Eryngium maritimum represent a linear biogeographical system. Genetic variation among 25 individuals of C. maritima and 16 individuals of E. maritimum, from the coasts of Europe, North Africa and the Canary Islands, was analysed using random amplified polymorphic DNAs (RAPDs) and intersimple sequence repeats (ISSRs). Genetic distances (Dice) were calculated and used to investigate the correlation between genetic and geographical distances, to construct Neighbour Joining (NJ) trees, and to compare mean genetic distances between areas within and across species. Genetic distances and geographical distances measured along the coast are well correlated in Cakile and Eryngium. This implies that dispersal in both species is largely along the coast. The NJ analyses resulted in the recognition of Atlantic and Mediterranean clusters in both Cakile and Eryngium. The genetic distance between these two clusters is much larger in Eryngium (0. 285) than in Cakile (0.037). Mean genetic distances are substantially higher in the Mediterranean than in the Atlantic clusters in both species, and higher in Cakile than in Eryngium particularly in the Atlantic cluster. It is argued that all similarities and differences between the two species can be explained with the presumed distribution of the two species in the Würm glacial as reconstructed from their extant temperature requirements, the distribution of ice cover, permafrost, and sea surface temperatures in that period, and indirect fossil evidence.

Apiaceae↗

PubMed2006

Genetic variation and species identification of Thai Boesenbergia (Zingiberaceae) analyzed by chloroplast DNA polymorphism.

Genetic variation and molecular phylogeny of 22 taxa representing 14 extant species and 3 unidentified taxa of Boesenbergia in Thailand and four outgroup species (Cornukaempferia aurantiflora, Hedychium biflorum, Kaempferia parviflora, and Scaphochlamys rubescens) were examined by sequencing of 3 chloroplast (cp) DNA regions (matK, psbA-trnH and petA-psbJ). Low interspecific genetic divergence (0.25-1.74%) were observed in these investigated taxa. The 50% majority-rule consensus tree constructed from combined chloroplast DNA sequences allocated Boesenbergia in this study into 3 different groups. Using psbA-1F/psbA-3R primers, an insertion of 491 bp was observed in B. petiolata. Restriction analysis of the amplicon (380-410 bp) from the remaining species with Rsa I further differentiated Boesenbergia to 2 groupings; I (B. basispicata, B. longiflora, B. longipes, B. plicata, B.pulcherrima, B. tenuispicata, B. thorelii, B. xiphostachya, Boesenbergia sp.1 and Boesenbergia sp.3; phylogenetic clade A) that possesses a Rsa I restriction site and II (B.curtisii, B. regalis, B. rotunda and Boesenbergia sp.2; phylogenetic clade B and B. siamensis; phylogenetic clade C) that lacks a restriction site of Rsa I. Single nucleotide polymorphism (SNP) and indels found can be unambiguously applied to authenticate specie-origin of all investigated samples and revealed that Boesenbergia sp.1, Boesenbergia sp.2 and B. pulcherrima (Mahidol University, Kanchanaburi), B. cf. pulcherrima1 (Prachuap Khiri Khan) and B. cf. pulcherrima2 (Thong Pha Phum, Kanchanaburi) are B. plicata, B. rotunda and B. pulcherrima, respectively. In addition, molecular data also suggested that Boesenbergia sp.3 should be further differentiated from B. longiflora and regarded as a newly unidentified Boesenbergia species.

DNA, Chloroplast↗

PubMed2006

Genetic variation and relationships between isolates and species of the entomopathogenic nematode genus Heterorhabditis deciphered through isozyme profiles.

We studied variation in isozyme patterns of 8 metabolic enzymes in 5 species of Heterorhabditis (H. bacteriophora, H. indica, H. marelata, H. megidis, and H. zealandica) comprising 18 isolates. Isozyme banding patterns of all the 8 enzymes were species specific; however, 3 enzymes, i.e., arginine kinase, fumarate hydratase, and malate dehydrogenase, displayed distinct patterns among all the 18 isolates. Phylogenetic analysis of the isozyme patterns produced dendrograms depicting a high degree of genetic variation among Heterorhabditis species, with the average pairwise distance of 0.2000. Trees constructed using different phylogenetic methods showed a relatively close genetic relationship between H. megidis and H. zealandica and between H. bacteriophora and H. indica. Also, H. bacteriophora HP88 was the most distant species from H. megidis (UK isolate), H. marelatus (Oregon isolate), and H. zealandica (X1 isolate) with pairwise distance of 0.1957, 0.2228, and 0.2120, respectively. Phylogenetic analysis also revealed genetic variation among H. bacteriophora isolates with the average pairwise distance of 0.1507. GPS2 and GPS3 were the most closely related isolates with the average distance of only 0.0870, followed by GPS1 and GPS2 with average distance of 0.1087. In contrast, KMD19 and HP88, OH25, and HP88, and OH25 and Acows isolates were the most divergent populations with a pairwise distance of 0.2011 and 37 character differences. Pairwise distance analysis also revealed that genetic divergence among populations of H. bacteriophora is relatively independent of geographic distance. Overall, these results demonstrate strong subspecies structuring in H. bacteriophora.

Animals↗

PubMed2006

Linkage and association of schizophrenia with genetic variations in the locus of neuregulin 1 in Korean population.

Chromosome 8p21-12 has been reported to be a susceptibility locus for schizophrenia based on genome-wide linkage scans. After neuregulin 1 (NRG1) was identified as a positional candidate gene for schizophrenia in this locus, several independent association studies have reported controversial results. To determine whether genetic variations in this locus are associated with schizophrenia in the Korean population, we investigated multiplex families and unrelated patients using linkage and association analyses. Seven microsatellite markers in 8p21-12 were genotyped for 40 families with schizophrenia, and a non-parametric linkage analysis was applied. The association study was performed with 242 unrelated schizophrenia patients and the same number of normal controls for three single nucleotide polymorphisms (SNPs), two microsatellite markers and their haplotypes. A significant linkage signal was observed on D8S1769, which is located 352 kb upstream of the 5' end of the first exon of NRG1 for two ("narrow" and "narrow with auditory hallucination (AH)") of the three adopted phenotype classes. In the association study, the G allele of SNP8NRG241930 was significantly in excess in the subgroup of patients with AHs. We also found haplotypes which were associated with schizophrenia with a protective effect. This study provides additional suggestive evidence for both the linkage and association of genetic variations on 8p12, a locus of NRG1, with schizophrenia. NRG1 might either play a role in the predisposition to schizophrenia or be in linkage disequilibrium (LD) with a causal locus of this illness.

Alleles↗

PubMed1998

Thymic lineage commitment rather than selection causes genetic variations in size of CD4 and CD8 compartments.

During their development, immature CD4+ CD8+ thymocytes become committed to either the CD4 or CD8 lineage. Subsequent complete maturation of CD4+ and CD8+ cells requires a molecular match of the expressed coreceptor and the MHC specificity of the TCR. The final size of the mature CD4+ and CD8+ thymic compartments is therefore determined by a combination of lineage commitment and TCR-mediated selection. In humans and mice, the relative size of CD4+ and CD8+ peripheral T cell compartments shows marked genetic variability. We show here that genetic variations in thymic lineage commitment, rather than TCR-mediated selection processes, are responsible for the distinct CD4/CD8 ratios observed in common inbred mouse strains. Genetic variations in the regulation of lineage commitment open new ways to analyze this process and to identify the molecules involved.

Animals↗

PubMed2003

Genetic variation and activity of mouse Nod2, a susceptibility gene for Crohn's disease.

Genetic variation in human Nod2 has been associated with susceptibility to Crohn's disease. The mouse Nod2 locus is located at chromosome 8 and composed of 12 exons, 11 of which encode the Nod2 protein. Sequence analysis of Nod2 from 45 different strains of Mus musculus and Mus spretus revealed extensive polymorphism involving all exons of Nod2. Of the 140 polymorphic sites identified, 68 were located in the coding region, of which 28 created amino acid substitutions in Nod2. Expression of mouse Nod2 activated NF-kappaB and conferred responsiveness to bacterial components, an activity that was deficient in mutants corresponding to those associated with susceptibility to Crohn's disease. These studies demonstrate a conserved role for Nod2 in the response to bacterial components and suggest that selective evolutionary pressure exerted by pathogens may have contributed to the high level of variability of Nod2 sequences in both humans and mice.

Amino Acid Sequence↗

PubMed2005

Genetic variation within and among domesticated Atlantic salmon broodstocks in British Columbia, Canada.

Atlantic salmon have been reared in the British Columbia, Canada aquaculture industry since the early 1980s. No breeding programmes spanned the entire production period and pedigree records were not kept for broodstocks prior to or since importation. Of the three recognized industry strains, two are of European ancestry ('Mowi' from Norway and 'McConnell' from Scotland) and one is of North American heritage ('Cascade' from Gaspe, Quebec). We evaluated the amount and distribution of genetic variation within industry broodstocks by surveying microsatellite variation at 11 loci in 20 broodstock groups sampled from major production facilities. Allelic richness averaged 10.9 (range 5.8-13.8), compared with a value of 20.3 obtained for a North American wild population. Pairwise genetic distances (D(S)) between samples within strains were generally less than those between strains, with samples attributed to the same strain clustering together in a neighbour-joining dendrogram. Nevertheless, average distances between samples within the European strains were high (0.41 for Mowi; 0.71 for McConnell) but lower (0.06) for the Cascade strain. The reduced intra-sample and increased intra-strain genetic variation observed for the BC domesticated samples compared with wild populations was similar to observations for European domesticated Atlantic salmon. Evidence of introgression of the Cascade strain into European broodstocks was provided by the presence of large Ssa202 alleles (confined to North America in wild populations) in some Mowi and McConnell samples. Introgression likely also contributed to the decreased intercontinental genetic distance for the domesticated samples of this study compared with that observed for wild populations.

Alleles↗

PubMed1980

Genetic variation and host markers in the src gene of recovered avian sarcoma viruses.

The src genes of three recovered avian sarcoma viruses were compared by RNase T1 oligonucleotide fingerprinting and tryptic peptide analysis. In all three recovered avian sarcoma viruses the oligonucleotide composition of src was different and also distinct from that of the parental Schmidt-Ruppin strain of Rous sarcoma virus. This evidence for genetic variation src was strengthened by two dimensional peptide maps of the src gene products pp60src, translated in a reticulocyte lysate system in vitro. Numerous differences between the peptide patterns of the pp60src proteins produced by the parental and the recovered viruses were detected. No two src proteins were identical, while the tryptic peptide maps of the internal gag proteins synthesized by these viruses were indistinguishable. The src proteins of recovered avian sarcoma viruses also contained peptides that were absent from the src protein of parental Schmidt-Ruppin D virus but were found in the endogenous src protein of normal cells. We conclude that there is considerable genetic variation in the src gene of recovered avian sarcoma viruses and that these recovered src genes contain host cell-derived markers.

Animals↗

PubMed2004

Neutral genetic variation among wild North American populations of the weedy plant Arabidopsis thaliana is not geographically structured.

We investigated neutral genetic variation within and among 53 wild-collected populations of the weedy annual plant, Arabidopsis thaliana, in North America, using amplified fragment length polymorphism (AFLP) markers. A. thaliana is thought to have been introduced to North America from Eurasia by humans; such an introduction might be expected to leave a clear geographical signal in the genetic data. To detect such patterns, we sampled populations at several hierarchical geographical levels. We collected individuals from populations in two areas of the Southeast and one in the Midwest, as well as individuals from populations in the Pacific Northwest and Northeast. To estimate within-population variation, we sampled eight individuals from each of six populations in the Southeast and Midwest. Among all 95 individuals analysed, we detected 131 polymorphic AFLP fragments. We found no evidence for continental or regional diversification. Individuals sampled from Midwestern and Southeastern populations intermingled in a neighbour-joining tree, and Mantel tests conducted within the Midwestern and Southeastern regions as well as the full data set failed to detect any significant relationship between geographical and genetic distance. These results mirror those found for most global surveys of neutral genetic variability in A. thaliana. Surprisingly, we detected substantial amounts of neutral genetic variability within populations. The levels of genetic variation within populations, coupled with the nongeographical nature of divergence among populations, are consistent with contemporary gene flow and point to a complex and dynamic population history of A. thaliana in North America.

Arabidopsis↗

PubMed1980

Phenotypic and genetic variation in the susceptibility of Haemophilus influenzae type b to antibodies to somatic antigens.

Haemophilus influenzae type b (H.i.b) has been investigated with respect to phenotypic and genetic variations resulting in differential susceptibility to bactericidal antibody. Previous studies had shown that after growth in infected rats or in dialysate of rat serum, H.i.b strain Eag became more resistant to the bactericidal activity of antisomatic antibody. We now report that a similar phenotypic shift occurs when strain Eag is incubated with dialysate of human serum, that the increased resistance is to antibodies against determinants in the lipopolysaccharide not for the somatic antigens generally, and that most strains of H.i.b undergo the shift. To assess genetic differences in exposed antigens, a panel of 13 H.i.b isolates from cerebrospinal fluid were analyzed with cross-adsorbed antisera. Seven different patterns were found that could be accounted for through the variable expression of six antigens. These ranged from infrequent (found on 1:13 strains) to common (10:13 strains). At least four were somatic rather than capsular determinants; the most common (antigen 1) was contained in lipopolysaccharide. The epidemiologic relevance of the genetic variations was explored using pairs of isolates from two children who had had two documented infections with H.i.b. In both cases the isolates varied in somatic antigen expression. The strains from one patient differed in the expression of antigen 1. The isolates from the other were indistinguishable in sub-typing for the six classified antigens, but differed in the expression of an additional antigen identified by use of the patient's serum.

Antibodies, Bacterial↗

PubMed1982

Genetic variation in Bougainville and Solomon Islands populations.

This paper reports the findings of genetic variation in eight populations of the Solomon Islands. Blood specimens collected from 345 Aita, 191 Nasioi and 416 Nagovisi of Bougainville, 379 Lau, 453 Baegu and 385 Kwaio of Malaita, and 504 Ontong Java, and 328 Ulawa subjects were tested for A-B-O, M-N-S-s, Rh, Hp, Tf, secretor, and red-cell acid phosphatase systems. Considerable differences were found among the eight populations with respect to all polymorphic systems studied. It was not possible to distinguish Austronesian groups from non-Austronesian groups on the basis of gene frequencies.

ABO Blood-Group System↗

PubMed1991

Genetic variation and evolutionary relationships amongst bluetongue viruses endemic in the United States.

The genetic variation and evolutionary relationships amongst the five serotypes of bluetongue virus (BTV) endemic to the United States were investigated by oligonucleotide fingerprint analysis. The viruses analyzed include prototype viruses of the five U.S. serotypes, and 32 viruses isolated from domestic and wild ruminants from the U.S. in the years 1979-1981. With the exception of serotype 2, most genes encoding the viral core and non-structural proteins were demonstrated to be highly conserved both within and between serotypes and some also appear to have reassorted in nature. Gene segments 2 and 6, which encode the outer capsid proteins VP2 and VP5 respectively, were more variable and were not consistently linked as serotype determination was dependent solely on gene segment 2. Gene segment 2 was the most variable gene between serotypes, but it was highly conserved within serotypes and stable over time. This suggests that the emergence of new BTV serotypes, which would require the stable incorporation of numerous mutations, must be a very slow process. Fingerprint comparisons further suggested that BTV serotypes 10, 11, 13 and 17 have evolved together in the U.S. over a considerable period of time, whereas serotype 2, which is genetically distinct, has evolved elsewhere and is most likely a recent introduction to North America.

Animals↗

PubMed2002

[Research on genetic variation of heart fatty acid-binding protein gene in ten pig breeds].

The genetic variation of heart fatty acid-binding protein (H-FABP) gene in 561 pigs including Duroc, Landrace, Large Yorkshire, Nanchang white pig, Erhualian, Meishan, Yushan black pig, Leping spotted pig, Jinhua black head-hind pig and Shanggao black head-hind pig were detected by PCR-RFLP with Hinf I, Hae III and Msp I. The results showed as follows: (1) Nanchang white pig presented only HH genotype while other breeds varied at the Hinf I-RFLP site; (2) The exotic breeds including Duroc, Landrace, Large Yorkshire and the native breed Nanchang white pig were proved to be polymorphic while the five Chinese local breeds presented no variation at the Hae III-RFLP site; (3) Among the tested breeds only Duroc presented variation at the Msp I-RFLP site. It is noted that all the Chinese local breeds present as AADD--genotypes.

Animals↗

PubMed1992

Quantitative genetic variation in body size of mice from new mutations.

To measure the amount of new genetic variation in 6-week weight of mice arising each generation from mutation, selection lines derived from an initially inbred strain were maintained for 25 generations. An analysis using an animal model with restricted maximum likelihood was applied to estimate a mutational genetic component of variance for the infinitesimal model of many genes of small effect. Assuming that the inbred base population was at a mutation-drift equilibrium, it is estimated that the heritability for body size has increased by 1.0% per generation, with lower and upper confidence limits of 0.6% and 1.6%, respectively. A model which includes a mutational genetic component of variance fits the data much better than one involving only base population genetic variance. A model with no genetic component fits the data very poorly. An environmental covariance of body size of mother and offspring was included in the model and accounts for 10% of the variance. By using information only from the observed response to selection, the estimated increase in heritability from mutation is 0.3% per generation. These values are higher than published estimates for the increase in variance from spontaneous mutations in bristle traits of Drosophila, for which there are extensive data, but similar to estimates for various skeletal traits in mice.

Animals↗

PubMed2001

Sustaining genetic variation in a small population: evidence from the Mauritius kestrel.

We obtained measures of genetic diversity in 10 kestrel species at a suite of 12 microsatellite loci. We estimated the relative effective size (Ne) of the species using a Markov chain Monte Carlo (MCMC) approach, which jointly estimated the locus specific mutation rates as nuisance parameters. There was surprisingly high genetic diversity found in museum specimens of the Mauritius kestrel. Being an endemic species on a small island, it is known to have a long history of small population size. Conversely, kestrels with a continental distribution had Ne estimates that were only one order of magnitude larger and similar to each other, despite having current population sizes that were between one and three orders of magnitude larger than the Mauritius kestrel. We show how many of the theoretical results describing the effective size of a subdivided population can be captured in terms of three rates which describe the branching pattern of the gene genealogy, and that they are useful in estimating the time to migration-drift and mutation-drift equilibrium. We use this approach to argue that population subdivision has helped retain genetic diversity in the Mauritius kestrel, and that the continental species' genetic diversity has yet to reach equilibrium after the range changes following the last ice age. We draw parallels with Hewitt's observation that genetic variation seems to survive species' range compression and is rather vulnerable to range expansion.

Animals↗