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PubMed2005

The human organic anion transporter 3 (OAT3; SLC22A8): genetic variation and functional genomics.

The human organic anion transporter, OAT3 (SLC22A8), plays a critical role in renal drug elimination, by mediating the entry of a wide variety of organic anions, including a number of commonly used pharmaceuticals, into the renal proximal tubular cells. To understand the nature and extent of genetic variation in OAT3, and to determine whether such variation affects its function, we identified OAT3 variants in a large, ethnically diverse sample population and studied their transport activities in cellular assays. We identified a total of 10 distinct coding-region variants, which altered the encoded amino acid sequence, in DNA samples from 270 individuals (80 African-Americans, 80 European-Americans, 60 Asian-Americans, and 50 Mexican-Americans). The overall prevalence of these OAT3 variants was relatively low among the screened population, with only three variants having allele frequencies of >1% in a particular ethnic group. Clones of each variant were created by site-directed mutagenesis, expressed in HEK-293 cells, and tested for function using the model substrates, estrone sulfate (ES) and cimetidine (CIM). The results revealed a high degree of functional heterogeneity among OAT3 variants, with three variants (p. Arg149Ser, p. Gln239Stop, and p. Ile260Arg) that resulted in complete loss of function, and several others with significantly reduced function. One of the more common variants (p. Ile305Phe), found in 3.5% of Asian-Americans, appeared to have altered substrate specificity. This variant exhibited a reduced ability to transport ES, but a preserved ability to transport CIM. These data suggest that genetic variation in OAT3 may contribute to variation in the disposition of drugs.

Alleles↗

PubMed1988

Genetic variation among geographic isolates of Rift Valley fever virus.

The genetic variation of Rift Valley fever virus (RVFV) was estimated by sequencing a portion of the M segment RNA of 22 isolates from a variety of host species collected over 34 years in 6 African countries. The M segment RNA of the Egyptian isolate, ZH501, which has been molecularly cloned and sequenced, was used as a reference for these comparisons. Specific gene regions, responsible for antigenic determinants presumed to play a role in protection against disease, were emphasized in these investigations. Comparative sequence data revealed that most isolates were very similar to ZH501 at both the nucleic acid and deduced amino acid sequence levels. Nucleic acid sequence variation range was 0-4.5%. Amino acid sequence variation range was 0-2.4%. We identified specific amino acid coding changes which may be involved in virus neutralization and may contribute to the virulence characteristics of RVFV.

Amino Acid Sequence↗

PubMedDate not supplied

[Genetic variations of the tumor suppressor TP53: outstanding and strategies of analysis].

In the modern society, cancer remains an important cause of death. Cancer development is a very complex process that involves alterations in genes regulating cellular growth. Among these alterations or variations, are included point mutations, genetic susceptibility by single nucleotide polymorphisms or "SNP" and alteration or loss in tumor suppressor genes functions. The tumor suppressor TP53 is one of the most important and studied genes on cancer genetics. Therefore, it has been demonstrated that TP53 present mutations in more than 50% of all types of human cancer and encodes a multifunctional protein whose absence contributes to genomic instability, the accumulation of mutations and increased tumor development. The identification of such alterations in cancerous cells at level of single nucleotide is very important, because its implication in the loss or alteration in the function of this gene, its clinical relevance and finally, its association with response to therapy and prognosis. Due to the large interesting issue, in this work we are focused only in two of the most common genetic variations present in this gene: the point mutations and SNP remarking some outstanding molecular characteristics needed for design its analysis.

Cocarcinogenesis↗

PubMed2004

Genetic variation in COL17A1 and the development of bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering disease of the skin characterized by autoantibody attack on collagen XVII. OBJECTIVES: To characterize the genetic complexity of COL17A1, the gene which encodes for the autoantigen collagen XVII. The data will be used to determine whether there is an association between polymorphisms and haplotypes of COL17A1 and genetic susceptibility to development of BP. METHODS: The genetic complexity in COL17A1 was deduced by screening and then sequencing the gene. Haplotypes were constructed from the resulting polymorphisms using the statistical programme PHASE. The linkage disequilibrium (D') between the polymorphisms was deduced from haplotypic data using the statistical programme GOLD. Association of the polymorphisms and haplotypes was tested for, in a cohort of BP patients and controls. RESULTS: Screening of COL17A1 for genetic variation was carried out in 29 individuals of North European caucasoid origin, and it revealed 19 single-nucleotide polymorphisms in approximately 14.7 kb of sequence. These variants resulted in 60 different haplotypes in 191 individuals, of which 13 occurred above 1% in the population. D' between the variants was found to be extensive, have a low correlation with physical distance and to extend over 33.8 kb. No association was found with any of the polymorphisms or haplotypes and development of BP, when tested for, in a cohort of patients and controls. CONCLUSION: This study provides an extensive description of the genetic variation in COL17A1 and shows no association of the genetic variants with susceptibility to BP.

Autoantigens↗

PubMed2002

The nature of quantitative genetic variation for Drosophila longevity.

Longevity is a typical quantitative trait: the continuous variation in life span observed in natural populations is attributable to genetic variation at multiple quantitative trait loci (QTL), environmental sensitivity of QTL alleles, and truly continuous environmental variation. To begin to understand the genetic architecture of longevity at the level of individual QTL, we have mapped QTL for Drosophila life span that segregate between two inbred strains that were not selected for longevity. A mapping population of 98 recombinant inbred lines (RIL) was derived from these strains, and life span of virgin male and female flies measured under control culture conditions, chronic heat and cold stress, heat shock and starvation stress, and high and low density larval environments. The genotypes of the RIL were determined for polymorphic roo transposable element insertion sites, and life span QTL were mapped using composite interval mapping methods. A minimum of 19 life span QTL were detected by recombination mapping. The life span QTL exhibited strong genotype by sex, genotype by environment, and genotype by genotype (epistatic) interactions. These interactions complicate mapping efforts, but evolutionary theory predicts such properties of segregating QTL alleles. Quantitative deficiency mapping of four longevity QTL detected in the control environment by recombination mapping revealed a minimum of 11 QTL in these regions. Clearly, longevity is a complex quantitative trait. In the future, linkage disequilibrium mapping can be used to determine which candidate genes in a QTL region correspond to the genetic loci affecting variation in life span, and define the QTL alleles at the molecular level.

Animals↗

PubMed2001

Genetic variation at microsatellite loci in Spanish sheep.

Genetic variation at 18 microsatellite loci was analysed in six indigenous Spanish sheep: Churra; Latxa; Manchega; Rasa-Aragonesa; Castellana and Merino. Merinos had frequently the highest number of alleles per locus, whereas Latxas showed the lowest one at many loci. Markers ordered decreasingly according to the number of variants differentiated in the whole population were: MAF70; TGLA13; CSSM66; BM143, BM6444; MAF36; MAF64; CSSM6; TGLA53; OarFCB11; MAF33; BM4621; MAF48; MAF65; BM1258; ILSTS002; ADCYC and OarCP34. Parameters of variability such as effective number of alleles and gene diversities corroborated the high level of variation frequently displayed by microsatellite markers. Comparison of allele distributions among populations and loci did not reveal consistent shapes. Distributions were centralised in some cases, whereas in others some kind of skewness was evident. Breed-specific alleles were detected at most loci, being frequent in Merinos and rare in Churras.

Journal Article↗

PubMed2001

Random amplified polymorphic DNA and amplified fragment length polymorphism assessment of genetic variation in Nicaraguan populations of Pinus oocarpa.

Pinus oocarpa is the most widely distributed pine species of Mexico and Central America. The natural populations of Nicaragua have been affected by extensive human activities. As a consequence, their size has been reduced, and there is a serious threat to the development of mature woodland. Knowledge of population structures and the genetic diversity of the species is required for the design of sustainable use and conservation strategies. Random amplified polymorphic DNA (RAPD) and amplified fragment length polymorphism (AFLP) markers were used to assess the genetic variation among 10 populations from three geographical regions of Nicaragua. Both markers revealed high levels of diversity in these populations. G(ST) values and analyses of molecular variance (AMOVA) found that most variation was within populations but there is still a significant differentiation between populations indicating that the populations sampled cannot be considered a single panmictic unit. The partitions created by AMOVA also showed that there was little differentiation between populations of different regions, although cluster analyses based on RAPDs and AFLPs indicated a closer relationship among most of the populations from a same geographical region. Management of P. oocarpa in Nicaragua should be aimed to maintain the high degree of genetic variation within individual populations that is still observed even in some of these highly degraded populations.

Conservation of Natural Resources↗

PubMed2002

Population structure, history and gene flow in a group of closely related land snails: genetic variation in Partula from the Society Islands of the Pacific.

Previous studies of Partula land snails from the Society Islands, French Polynesia, have shown that populations within species are highly differentiated in terms of their morphology, behaviour, ecology and molecular genetic variation. Despite this level of variability, differences between species are sometimes small, possibly reflecting the fact that reproductive isolation is not always complete and there exists the opportunity for genetic exchange between taxa through hybridization. The present study uses sequence data from a mitochondrial gene to further investigate genetic variation in Society Island Partula. Most populations are found in this study to be highly differentiated, but within individual species there seems to be no simple relationship either between genetic distance and geographical proximity, or between variation in mitochondria and that in allozymes or morphological characteristics. Among species there appears to be no simple correlation between degrees of reproductive isolation and genetic relatedness according to mitochondrial DNA. The results suggest that past events as well as ongoing drift and selection may have been important in affecting patterns of variation. Similarities among species at specific localities suggest that there must have been some genetic exchange in the past, although this may not necessarily reflect ongoing rates of hybridization. The discrepancy between results for different markers probably reflects the differential effects of drift and selection on mitochondrial and nuclear genes.

Animals↗

PubMed2000

[Genetic variation of geographical provenance of Pinus massoniana--review and analysis].

Pinus massoniana is a significant tree species constituting the subtropical forests in China. Based on morphological, physio-ecological, chromosome, and molecular levels, the genetic variation of geographical provenance of P. massoniana and its distribution were reviewed, and the methodologies on genetic diversity and the genetic variation patterns of geographical provenance of P. massoniana were synthetically analyzed. The Key problems on molecular ecology of P. massoniana were discussed.

Ecology↗

PubMed2005

Association analysis of CHMP1.5 genetic variation and bipolar disorder.

OBJECTIVES: The18p11.2 region surrounding the G-olf gene has been linked in several independent studies to bipolar disorder and schizophrenia, yet association studies between G-olf genetic variations and bipolar disorder have been negative. We hypothesized that the linkage in this region might be due to a gene in close physical proximity to G-olf, and we examined variations in the CHMP1.5 gene within intron 5 of G-olf for association with bipolar disorder. METHODS: Two single-nucleotide polymorphisms, rs1786581 and rs1249624, were analyzed for association with bipolar disorder in 402 unrelated bipolar individuals and 181 unrelated controls. Genotyping was performed via pyrosequencing and restriction fragment length polymorphism analysis; results were compared by chi2 contingency analysis. RESULTS: No evidence was found for association of either allele at rs1249624 with bipolar disorder (chi2=1.25, degrees of freedom=1, P=0.26); however, a trend towards association with the 'T' allele at rs1786581 and with the 'T/T' 1786581/1249624 haplotype was observed. The chi2 for the haplotype was 7.16, (degrees of freedom=3, P=0.067) and for rs1786581 chi2=3.56, degrees of freedom=1, P=0.060; these differences are not statistically significant. CONCLUSIONS: Variation in the CHMP1.5 gene does not appear to be associated with bipolar disorder. A systematic assessment of genetic variation in the region using association studies will be necessary.

3' Untranslated Regions↗

PubMed2002

Significance of genetic variation at the glutathione S-transferase M1 and NAD(P)H:quinone oxidoreductase 1 detoxification genes in breast cancer development.

This work examined the role of constitutional genetic variation at the glutathione S-transferase M1 (GSTM1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) detoxification loci in breast cancer development. Methods included contrasting patterns of genetic variations at these loci between cases with breast cancer and healthy controls and assessing the association of genotypes with tumor characteristics. Participants were Caucasian women living in the Greater Philadelphia region, recruited from 1988 to 1994, with recently diagnosed women attending breast cancer clinics at Fox Chase Cancer Center (FCCC) and network affiliated hospitals as cases, and FCCC employees or women attending noncancer clinics as controls. The GSTM1 locus was determined for 402 cases and 238 controls, NQO1 for 346 cases and 235 controls. Results show that neither locus was associated with breast cancer occurrence, with the GSTM1 null genotype occurring at frequencies of 0.560 and 0.563 in cases and controls, respectively [odds ratio (OR) 0.98, 0.95 confidence interval (CI) 0.70-1.38] and the NQO1 wild-type allele at frequencies of 0.808 and 0.845, respectively (OR 0.77, 0.95 CI 0.55-1.06). The GSTM1 null genotype, however, was significantly overrepresented among larger (T3 and T4) primary tumors (OR 7.61, 0.95 CI 1.05-333) and with the occurrence of axillary lymph node metastases (OR 1.62, 0.95 CI 0.98-2.69). NQO1 results revealed that homozygotes for the wild type allele were more likely to have ductal carcinoma and poor histologic grade when compared with individuals carrying one or two mutated alleles (OR 3.50, 0.95 CI 1.41-9.0, and OR 2.26, 0.95 CI 1.18-4.35 for histology type and grade, respectively). We conclude that while these loci are not associated with breast cancer occurrence, the GSTM1 locus is likely associated with tumor progression. NQO1 results suggest that different quinones (possibly estrogenic quinone metabolites) might affect the histological development of breast tumors.

Adult↗

PubMed2005

The effect of genetic variation on the lipid response to dietary change: recent findings.

PURPOSE OF REVIEW: Dyslipidaemia is an important risk factor for cardiovascular disease, and can be modified by diet. However, the lipid response to dietary change may be influenced by genetic variation. This review examines recent research (published since August 2003) on the effect of genetic variation on the lipid response to dietary change. RECENT FINDINGS: In 10 reports describing intervention studies and seven reports describing observational studies, the lipid response to diet was modified by polymorphisms within the genes for apoE, apoB, apoCIII, lipoprotein lipase, hepatic lipase, endothelial lipase, the liver fatty acid-binding protein, the beta3-adrenergic receptor, adipsin and the peroxisome proliferator-activated receptor gamma. The studies varied widely in terms of the number and type of study participants, the composition and duration of the dietary interventions, the nutrients studied and dietary assessment methods used in the observational studies, and the polymorphisms analysed--some of which had not been studied before with regard to the lipid response to diet. SUMMARY: The lipid response to dietary change is highly complex. Future studies will have to be large in order to assess the effects of multiple polymorphisms, and will have to control for many factors other than diet. At present, it is premature to recommend the use of genotyping in the design of therapeutic diets. However, such studies may be useful in identifying the mechanisms by which dietary components influence lipid levels.

Animals↗

PubMed2004

Mutation-selection balance accounting for genetic variation for viability in Drosophila melanogaster as deduced from an inbreeding and artificial selection experiment.

We carried out an experiment of inbreeding and upward artificial selection for egg-to-adult viability in a recently captured population of Drosophila melanogaster, as well as computer simulations of the experimental design, in order to obtain information on the nature of genetic variation for this important fitness component. The inbreeding depression was linear with a rate of 0.70 +/- 0.11% of the initial mean per 1% increase in inbreeding coefficient, and the realized heritability was 0.06 +/- 0.07. We compared the empirical observations of inbreeding depression and selection response with computer simulations assuming a balance between the occurrence of partially recessive deleterious mutations and their elimination by selection. Our results suggest that a model assuming mutation-selection balance with realistic mutational parameters can explain the genetic variation for viability in the natural population studied. Several mutational models are incompatible with some observations and can be discarded. Mutational models assuming a low rate of mutations of large average effect and highly recessive gene action, and others assuming a high rate of mutations of small average effect and close to additive gene action, are compatible with all the observations.

Animals↗

PubMed1998

Naturally occurring genetic variation affects Drosophila photoreceptor determination.

The signal transduction pathway controlling determination of the identity of the R7 photoreceptor in the Drosophila eye is shown to harbor high levels of naturally occurring genetic variation. The number of ectopic R7 cells induced by the dosage-sensitive SevS11.1 transgene that encodes a mildly activated form of the Sevenless tyrosine kinase receptor is highly sensitive to the wild-type genetic background. Phenotypes range from complete suppression to massive overproduction of photoreceptors that exceeds reported effects of known single gene modifiers, and are to some extent sex-dependent. Signaling from the dominant gain-of-function Drosophila Epidermal Growth Factor Receptor (DER-Ellipse) mutations is also sensitive to the genetic backgrounds, but there is no correlation with the effects on SevS11.1. This implies that different genes and/or alleles modify the two activated receptor genotypes. The evolutionary significance of the existence of high levels of genetic variation in the absence of normal phenotypic variation is discussed.

Animals↗

PubMed1999

AFLP fingerprinting for analysis of yeast genetic variation.

Amplified fragment length polymorphism (AFLP) was used to investigate genetic variation in commercial strains, type strains and winery isolates from a number of yeast species. AFLP was shown to be effective in discriminating closely related strains. Furthermore, sufficient similarity in the fingerprints produced by yeasts of a given species allowed classification of unknown isolates. The applicability of the method for determining genome similarities between yeasts was investigated by performing cluster analysis on the AFLP data. Results from two species, Saccharomyces cerevisiae and Dekkera bruxellensis, illustrate that AFLP is useful for the study of intraspecific genetic relatedness. The value of the technique in strain differentiation, species identification and the analysis of genetic similarity demonstrates the potential of AFLP in yeast ecology and evolutionary studies.

Cluster Analysis↗

PubMed1987

Quantitative genetic variation in an ecological setting.

The machinery was developed to investigate the behavior of quantitative genetic variation in an ecological model of a finite number of islands of finite size, with migration rate m and extinction rate e, for a quantitative genetic model general for numbers of alleles and loci and additive, dominance, and additive by additive epistatic effects. It was necessary to reckon with seven quadratic genetic components, whose coefficients in the genotypic variance components within demes, sigma Gw2, between demes within populations, sigma s2, and between replicate populations, sigma r2, are given by descent measures. The descent measures at any time are calculated with the use of transition equations which are determined by the parameters of the ecological model. Numerical results were obtained for the coefficients of the quadratic genetic components in each of the three genotypic variance components in the early phase of differentiation. The general effect of extinction is to speed up the time course leading to fixation, to increase sigma r2, and to decrease sigma s2 (with a few exceptions) in comparison with no extinction. The general effect of migration is to slow down the time course leading to fixation, to increase sigma Gw2, at least in the later generations, and to decrease sigma s2 (with a few exceptions) in comparison with no migration. Except for these, the effects of migration and extinction on the variance components are complex, depending on the genetic model, and sometimes involve interaction of migration and extinction. Sufficient details are given for an investigator to evaluate numerically the results for variations in the quantitative genetic and ecological models.

Alleles↗

PubMed1985

Genetic variation for the sex ratio in Nasonia vitripennis.

We detected genetic variation for the sex ratio in the parasitoid wasp Nasonia vitripennis by analysis of inbred lines and with an artificial selection experiment. Sex ratios differed significantly among five independently isolated lines. Furthermore, sex ratio in broods produced by single females in single hosts shifted from 80-90% female to 50-55% female in 13 to 15 generations in each of two replicate selection lines. The final sex ratios of both selection lines were significantly lower than any of the inbred line sex ratios. Backcrosses revealed that the selection response was due to nuclear genes acting through the female parent. In light of known facultative sex ratio behavior and major genes affecting sex ratio in Nasonia, our results suggest that population and individual sex ratios in this species are molded by processes at both genetic and behavioral levels.

Animals↗

PubMed1986

The organization of genetic variation for recombination in Drosophila melanogaster.

The amount and form of natural genetic variation for recombination were studied in six lines for which second chromosomes were extracted from a natural population of Drosophila melanogaster. Multiply marked second, X and third chromosomes were used to score recombination. Recombination in the second chromosomes varied in both amount and distribution. These second chromosomes caused variation in the amount and distribution of crossing over in the X chromosome and also caused variation in the amount, but not the distribution, of crossing over in the third chromosome. The total amount of crossing over on a chromosome varied by 12-14%. One small region varied twofold; other regions varied by 16-38%. Lines with less crossing over on one chromosome generally had less crossing over on other chromosomes, the opposite of the standard interchromosomal effect. These results show that modifiers of recombination can affect more than one chromosome, and that the variation exists for fine-scale response to selection on recombination.

Analysis of Variance↗