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PubMed2004

Genetic variation in DLG5 is associated with inflammatory bowel disease.

Crohn disease and ulcerative colitis are two subphenotypes of inflammatory bowel disease (IBD), a complex disorder resulting from gene-environment interaction. We refined our previously defined linkage region for IBD on chromosome 10q23 and used positional cloning to identify genetic variants in DLG5 associated with IBD. DLG5 encodes a scaffolding protein involved in the maintenance of epithelial integrity. We identified two distinct haplotypes with a replicable distortion in transmission (P = 0.000023 and P = 0.004 for association with IBD, P = 0.00012 and P = 0.04 for association with Crohn disease). One of the risk-associated DLG5 haplotypes is distinguished from the common haplotype by a nonsynonymous single-nucleotide polymorphism 113G-->A, resulting in the amino acid substitution R30Q in the DUF622 domain of DLG5. This mutation probably impedes scaffolding of DLG5. We stratified the study sample according to the presence of risk-associated CARD15 variants to study potential gene-gene interaction. We found a significant difference in association of the 113A DLG5 variant with Crohn disease in affected individuals carrying the risk-associated CARD15 alleles versus those carrying non-risk-associated CARD15 alleles. This is suggestive of a complex pattern of gene-gene interaction between DLG5 and CARD15, reflecting the complex nature of polygenic diseases. Further functional studies will evaluate the biological significance of DLG5 variants.

Alleles↗
PubMed1980

Unequal crossing over at the rRNA tandon as a source of quantitative genetic variation in Drosophila.

Abdominal bristle selection lines (three high and three low) and controls were founded from a marked homozygous line to measure the contribution of sex-linked "mutations" to selection response. Two of the low lines exhibited a period of rapid response to selection in females, but not in males. There were corresponding changes in female variance, in heritabilities in females, in the sex ratio (a deficiency of females) and in fitness, as well as the appearance of a mutant phenotype in females of one line. All of these changes were due to bb alleles (partial deficiencies for the rRNA tandon) in the X chromosomes of these lines, while the Y chromosomes remained wild-type bb+. We argue that the bb alleles arose by unequal crossing over in the rRNA tandon.--A prediction of this hypothesis is that further changes can occur in the rRNA randon as selection is continued. This has now been shown to occur.--Our minimum estimate of the rate of occurrence of changes at the rRNA tandom is 3 X 10(-4). As this is substantially higher than conventional mutation rates, the questions of the mechanisms and rates of origin of new quantitative gaenetic variation require careful re-examination.

Animals↗
PubMed1992

Genetic variation and quasi-species.

During the past year the relative fitness, that is, overall replication ability, and the fitness gain of animal virus variants have been quantified, providing new insight into the dynamics for the generation of RNA virus quasi-species. Measurements of mutant frequencies and rates of genetic diversification have confirmed the extreme complexity of RNA virus and retrovirus populations.

Genetic Variation↗
PubMed2000

The effect of genetic variation in chemokines and their receptors on HIV transmission and progression to AIDS.

The pivotal discovery that two chemokine receptors, CCR5 and CXCR4, serve along with the T-cell receptor-interacting CD4 molecule as the principal co-receptors for HIV-1 entry stimulated a search for common genetic polymorphism in their genes which might affect the course of AIDS. Four mutational variants, CCR5-delta32, CCR5-P1, CCR2-641 and SDF1-3'A were discovered to play a regulatory role in HIV-1 infection, in the rate of progression to AIDS or both. Plausible physiological mechanisms to explain the population genetic association by these alleles have been advanced and are discussed critically here. Genetic ablation of AIDS progression by chemokine receptor and ligand gene variants has catalyzed development of novel therapies targeting the virus-co-receptor interaction. The functional and therapeutic implications of these AIDS restriction genes for disease progression and intervention are explored in this review.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Molecular epidemiology of breast cancer: genetic variation in steroid hormone metabolism.

The age-specific incidence rate of breast cancer in women rises until menopause, levels off and then rises again at a much lower rate indicating a possible hormonal influence on the disease risk. A large amount of evidence has implicated hormones and other compounds with oestrogen activity in the pathogenesis of certain endocrine cancers, particularly breast cancer. Widely dispersed hormone-like chemicals, capable of disrupting the endocrine system and interfering with proliferation, have been described. Compounds such as dioxins, some polychlorinated biphenyls and the plastic ingredient bisphenol-A have been shown to interfere with human reproduction and hormonal regulation. The levels of these foreign compounds as well as the levels of endogenous oestradiol may influence the risk of breast cancer. Endogenous oestradiol is synthesised in the ovarian theca cells of premenopausal women or in the stromal adipose cells of the breast of postmenopausal women and minor quantities in peripheral tissue. These cells, as well as breast cancer tissue, express all the necessary enzymes for this synthesis: CYP17, CYP11a, CYP19, hydroxysteroid hydrogenase, steroid sulphatase as well as enzymes further hydroxylating oestradiol such as CYP1A1, CYP3A4, CYP1B1. Polymorphisms in these enzymes may have a possible role in the link between environmental estrogens and hormone-like substances and the interindividual risk of breast cancer.

17-Hydroxysteroid Dehydrogenases↗
PubMed2001

Genetic variation among chicken lines and mammalian species in specific genes.

Thirteen gene-specific primer sets provided by the U.S. Poultry Genome Coordinators were used to investigate DNA polymorphisms between two highly inbred chicken lines of Leghorn and Fayoumi origin. Nucleotide and predicted amino acid sequences were then compared among these chicken lines and the Genbank sequences of chicken, mouse, and human. The following genes were selected as candidates for immune response or transcription activation: B2M, DAD1, IAP1, IL2, IREB1, LAP18, MAFL, POU1F1, RREB1, TAD, TBP1, TCRG, and ZOV3. Total cDNA was obtained from the spleens of Leghorn and Fayoumi lines by reverse transcriptase-polymerase chain reaction (PCR) and was used as a template to PCR-amplify gene-specific products. All primers except POU1F1 and TCRG generated single PCR products of the predicted 325- to 667-bp size, confirming the efficacy of these gene-specific primers in the chicken. Three and seven of the 11 amplified gene fragments yielded line-specific nucleotide polymorphisms between the Leghorn and Fayoumi sequences and between the Leghorn and Genbank chicken sequences respectively. Similarities between inbred Leghorn and mammalian species were 36 to 86% for nucleotides and 25 to 96% for predicted amino acid sequence. The polymorphisms of some gene fragments between the Leghorn and Fayoumi lines will allow for investigation of associations of these genes with immune response and other biological traits.

Amino Acid Sequence↗
PubMed1998

Linkage disequilibrium at the cystathionine beta synthase (CBS) locus and the association between genetic variation at the CBS locus and plasma levels of homocysteine. The Ears II Group. European Atherosclerosis Research Study.

Cystathionine beta synthase (CBS) is a key enzyme in homocysteine metabolism. We have examined four apparently non-functional polymorphisms in the CBS gene and have determined their frequency, degree of linkage disequilibrium and association with plasma homocysteine levels. The polymorphisms are a 68 bp insertion in exon 8, C699T in exon 8, C1080T in exon 11 and C1985T in the 3' untranslated region. 785 individuals participating in the European Atherosclerosis Research Study II (EARSII), from 11 countries across Europe were genotyped for these polymorphisms. The 68bp insertion had the highest frequency in the UK and in the Middle region, with a lower frequency in the Baltic and the South (p = 0.01), and the exon 11 polymorphism had the highest frequencies of the rare allele in the Baltic (p < 0.05). There was a high degree of linkage disequilibrium between the polymorphisms (p < 0.001 overall), except between C699T and the C1985T, with three common haplotypes accounting for nearly 80% of chromosomes. Examination of the association between these polymorphisms and plasma homocysteine levels revealed that the carriers of the rare alleles of the C699T, C1080T and C1985T polymorphisms had lower plasma homocysteine concentrations than those homozygous for the common alleles, although these differences were not statistically significant. The thermolabile valine variant caused by a substitution of a C for a T at nucleotide 677 in the methylenetetrahydrofolate reductase (MTHFR) has previously been shown to have profound effects on plasma levels of homocysteine in this sample, but the homocysteine-raising effect associated with this thermolabile variant was not seen in carriers of the 68 bp insertion, with this interaction being statistically significant (p < 0.001). These data demonstrate that variation in the CBS gene as detected with these four polymorphisms, had no statistically significant effect on plasma homocysteine levels in these healthy young men. However, the presence of the 68 bp insertion, which is found in approximately 7.5% of individuals in the populations of Europe sampled, abolishes the raising effect of thermolabile MTHFR Val/Val genotype, and may be of importance in the situation of high homocysteine.

Alleles↗
PubMedDate not supplied

Investigations of genetic variation between olive (Olea europaea L.) cultivars using arbitrarily primed polymerase chain reaction (AP-PCR).

Characterization and selection of olive clones for the production of olive oil is essential in Turkey because of its profitable exploitation. AP-PCR (Arbitrarily-Primed PCR) is a technique that can distinguish the genetic relationship among plant species and other organisms. In this study, AP-PCR approach was used in order to determine the genetic relationship of different six olive clones. The purity of DNA is one of the most important factors affecting the product of the AP-PCR method. In this respect, modified genomic DNA isolation procedure from Oleae europaea clones was developed so that this procedure can be used to obtain plant genomic DNA from diverse aromatic plants, which produce essential oils and secondary metabolites. By following the optimized AP-PCR amplification protocol, unique DNA fingerprint profiles for each olive clone were produced. AP-PCR-generated unique DNA fingerprint profiles can be used in the identification, distribution and diversity of various olive cultivars.

Base Sequence↗
PubMed2002

Geographic genetic variation in populations of the dengue virus vector Aedes aegypti.

Isoenzyme variation was assessed in 79 mosquito samples of Aedes aegypti, and susceptibility to a dengue 2 virus strain was evaluated in 83 samples. Analysis of FST values, differentiation indexes, and geographic distances separating populations revealed that genetic differences between populations depended on the species' history of migration and colonization. Three major clusters were identified: (1). the sylvan form, Ae. ae. formosus, from West Africa and some islands in the Indian Ocean; (2). the domestic form, Ae. ae. aegypti, from Southeast Asia and South America; and (3). Ae. ae. aegypti populations from the South Pacific islands. Two groups were identified on the basis of susceptibility to the dengue virus: (1). populations with high infection rates, mostly the Ae. ae. aegypti form, and (2). mosquitoes with lower infection rates, specifically Ae. ae. formosus. Other evolutionary and epidemiological implications of the genetic variability of Ae. aegypti are also discussed.

Aedes↗
PubMed2003

[Genetic variation of Citrus calli revealed by the ploidy analyser].

The cell DNA content of forty-eight Citrus calli of different genotype were measured by using the Ploidy Analyser. The results showed that 93.8% out of forty-eight Citrus calli had double DNA content except that Ruby. Weizhang and Kinnow had little varied cells and did not show second peak. Moreover, Pineapple, Meiwa kumquat, Changsha, Russ navel, Guoqing No. 4 and Carter had DNA varied cells including triploids and aneuploids based on the DPAC software analyse. Among the forty-eight Citrus calli, Pineapple had the highest of the DNA varied cells, which was up to 18.57%, Anliucheng had the lowest, 4.07%. There existed significant difference in the variation among genotypes by Duncan Analyse. At the same subcultured medium and at the same subcultured period, the effect of cultural duration on the variation of calli was not significant.

Aneuploidy↗