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PubMed2005

Single-nucleotide polymorphism-based population genetic analysis of Mycobacterium tuberculosis strains from 4 geographic sites.

We studied genetic relationships among 5069 Mycobacterium tuberculosis strains recovered from patients enrolled in 4 population-based studies in the United States and Europe, by analysis of 36 synonymous single-nucleotide polymorphisms (SNPs). All strains were assigned to 1 of 9 major genetic clusters based on sSNP profile. The same 9 genetic clusters were revealed by analysis of 227 nonsynonymous SNPs, 121 intergenic SNPs, and concatenated profiles of 578 SNPs available for a subset of 48 representative strains. IS6110 profiles, spoligotypes, and mycobacterial interspersed repetitive unit patterns were nonrandomly associated with SNP-based phylogenetic lineages, together indicating a strongly clonal population structure. Isolates of the 9 genetic clusters were not distributed with equal frequency in all localities, reflecting geographic subdivision. The SNP-based phylogenetic framework provides new insight into the worldwide evolution of M. tuberculosis and a gateway for investigating genotype-disease phenotype relationships in large samples of strains.

Bacterial Typing Techniques↗
PubMed1998

Infertile couples with Robertsonian translocations: preimplantation genetic analysis of embryos reveals chaotic cleavage divisions.

Preimplantation genetic diagnosis (PGD) may provide a feasible option for some Robertsonian translocation carriers who experience severe difficulty in achieving a normal pregnancy. We report on five PGD cycles for two such couples, 45,XY,der(13;14)(q10:q10) and 45,XX,der(13;21)(q10;q10), carried out by biopsy of two cells from day 3 post-insemination embryos generated by in vitro fertilisation. Locus-specific YAC probes for chromosomes 13, 14 and 21 were used to detect the chromosomes involved in the translocation using multicolour FISH. Three embryos transfers were carried out (two single embryo transfers and one double transfer) but no clinical pregnancies were established. In two cycles no embryos were transferred as all those biopsied were chromosomally abnormal. Combined results from both couples show 13% (6/45) of embryos analysed were normal for the translocation chromosomes and 87% (39/45) were chromosomally abnormal; these were categorised as 36% aneuploid or aneuploid mosaic and 51% chaotic where the chromosome constitution varied randomly from cell to cell. This suggests two factors may be acting to reduce fertility in these couples; the aneuploid segregation of the parental Robertsonian translocation and also a post-zygotic factor leading to uncontrolled chromosome distribution in early cleavage stages in an exceptionally high proportion of embryos.

Blastomeres↗
PubMed1987

Genetic analysis of tumorigenesis: a conserved region in the human and Chinese hamster genomes contains genetically identified tumor-suppressor genes.

Regional chromosome homologies were found in a comparison of human 11p with Chinese hamster 3p. By use of probes that recognize six genes of human 11p (INS, CAT, HBBC, CALC, PTH, and HRAS), the corresponding genes were localized by in situ hybridization on Chinese hamster chromosome 3. INS and CAT were located close to the centromere on 3p, whereas HBBC, CALC, and PTH were at 3q3-4 and HRAS at 3q4. Extensive prior data from chromosome studies of tumorigenic and tumor-derived Chinese hamster cells have suggested the presence of a tumor-suppressor gene on 3p. Two tumor-suppressor genes have been described on human 11p, one linked to CAT and one to INS. The present study raises the possibility that the Chinese hamster suppressor may be closely linked to INS or CAT.

Animals↗
PubMed1983

Genetic analysis of clindamycin resistance in Bacteroides species.

The genetic basis of clindamycin and tetracycline resistance in species of Bacteroides was studied in 13 resistant clinical isolates; 10 isolates were resistant to high levels of clindamycin (greater than 160 micrograms/ml) and three were resistant to low levels of clindamycin (5-20 micrograms/ml). All of the isolates were resistant to tetracycline. None of the strains with low-level clindamycin resistance could transfer resistance to either antibiotic. Three isolates resistant to high levels of clindamycin transferred tetracycline resistance to a sensitive Bacteroides fragilis recipient, and one of these (strain 1126) also transferred high-level clindamycin resistance. None of the transfer-proficient strains of Bacteroides contained plasmid DNA. However, DNA homology was detected by hybridization between the clindamycin resistance plasmid pBF4 isolated in France and sequences in our high-level clindamycin-resistant strains from California. A common homologous 4.8 megadalton EcoR1 fragment was identified in the whole cell DNA of the transfer-proficient strain 1126 of B. fragilis and two other species of the B. fragilis group.

Bacteroides↗
PubMed2002

Genetic analysis of vascular factors in Alzheimer's disease.

Genetic risk factors for Alzheimer's disease (AD) have been extensively examined. Several risk factors for AD are shared with vascular dementia (VaD). We performed genetic case-control studies on polymorphisms of the apolipoprotein E (ApoE) gene, the methylene tetrahydrofolate reductase (MTHFR) gene, and the angiotensin-converting enzyme (ACE) gene. The most acceptable genetic risk factor for the development of AD is the ApoE epsilon-4 (ApoE epsilon4) allele. ApoE promoter polymorphisms have also been reported to be associated with AD. As expected, the ApoE epsilon4 allele had strong association with AD in our samples. The ApoE epsilon4 allele was also estimated as a risk factor for VaD. An ApoE promoter polymorphism (-291T/G) did not show positive association with AD or any other diseases. Common MTHFR phenotypes are thought to genetically regulate blood homocysteine level, which has been associated with AD. We failed to show independent associations between AD and the common MTHFR polymorphisms (C677T and A1298C). A deletion polymorphism at intron 16 of the ACE gene has also been associated with AD. In our study, we found a significant ethnic difference of the genotype distribution, but failed to replicate the positive association between the I allele and AD.

Alleles↗
PubMed1976

Genetic analysis of lymphocyte activation by lipopolysaccharide Endotoxin.

A genetic study of in vitro lymphocyte blastogenesis by the B-cell mitogen lipopolysaccharide endotoxin has been performed, using both low-responder C3H/HeJ mice and high-responder CBA/J mice. The crossbreeding of these strains produced F1 progeny that were intermediate in responsiveness. Responder types from the backcross of the F1 to the C3H/HeJ strain segregated into intermediate- and low-responder phenotypes, whereas intermediate- and high-responder phenotypes were produced from the backcross of the F1 to the CBA/J strain. The F2 generation consisted of all three responder phenotypes in frequencies that fit the classical Mendelian ratio of 1:2:1, indicating that the mitogenic response to lipopolysaccharide endotoxin in mice is most likely governed by a pair of autosomal co-dominant genes.

Animals↗
PubMed1978

Genetic analysis of antibiotic resistance in Streptococcus pyogenes.

The genetics of antibiotic resistance in mutant strains of Streptococcus pyrogenes was studied. Utilizing a type 6 strain (9440) primarily resistant to strepttomycin (Strr), classes of mutant strains were isolated that were resistant to one of the following antibiotics: rifampin (Rifr), erythromycin (Eryr), thiostrepton (Tstr), spiramycin (Sprr), fusidic acid (Fusr), gramicidin (Grcr), ethidium bromide (Ebrr), kanamycin (Kanr), neomycin (Neor), oleandomycin (Oler), gentamicin (Genr), and novobiocin (Novr). Transduction experiments separated antibiotic resistance markers into two distinct groups: transducible markers, including Fusr, Bacr, Ksg+, Spcr, Eryr, Sprr, Rifr, Stlr, and Tstr (Bacr, Ksgr, Spcr, and Stlr refer to resistance to bacitracin, kasugamycin, spectinomycin, and streptolydigan, respectively), and nontransducible markers, including Grcr, Ebrr, Kanr, Neor, Oler, Genr, and Novr. By means of two- and three-point crosses, transducible markers (excluding tst) were located in three separate linkage groups. spr was found to be linked with ery and spc in the order spc-ery-spr, whereas in a separate linkage group the order was determined to be str-fus-bac-ksg. The third linkage group contained the rif and stl markers.

Anti-Bacterial Agents↗
PubMed2000

Substrate range and genetic analysis of Acinetobacter vanillate demethylase.

An Acinetobacter sp. genetic screen was used to probe structure-function relationships in vanillate demethylase, a two-component monooxygenase. Mutants with null, leaky, and heat-sensitive phenotypes were isolated. Missense mutations tended to be clustered in specific regions, most of which make known contributions to catalytic activity. The vanillate analogs m-anisate, m-toluate, and 4-hydroxy-3,5-dimethylbenzoate are substrates of the enzyme and weakly inhibit the metabolism of vanillate by wild-type Acinetobacter bacteria. PCR mutagenesis of vanAB, followed by selection for strains unable to metabolize vanillate, yielded mutant organisms in which vanillate metabolism is more strongly inhibited by the vanillate analogs. Thus, the procedure opens for investigation amino acid residues that may contribute to the binding of either vanillate or its chemical analogs to wild-type and mutant vanillate demethylases. Selection of phenotypic revertants following PCR mutagenesis gave an indication of the extent to which amino acid substitutions can be tolerated at specified positions. In some cases, only true reversion to the original amino acid was observed. In other examples, a range of amino acid substitutions was tolerated. In one instance, phenotypic reversion failed to produce a protein with the original wild-type sequence. In this example, constraints favoring certain nucleotide substitutions appear to be imposed at the DNA level.

Acinetobacter↗
PubMed1999

Genetic analysis of Borrelia garinii OspA serotype 4 strains associated with neuroborreliosis: evidence for extensive genetic homogeneity.

Infection with Borrelia garinii outer surface protein (Osp) A serotype 4 strains has been correlated with the development of neuroborreliosis in Lyme borreliosis patients in Europe. OspA serotype 4 isolates have been recovered primarily from human cerebrospinal fluid, suggesting a tropism for this environment. Previous studies with monoclonal antibodies directed against OspA and OspC demonstrated that OspA serotype 4 strains are antigenically closely related. In view of the pronounced antigenic and genetic variability that has been noted in the Osps of other Borrelia isolates, we sought to determine if OspA serotype 4 strains represent a recently emerged clonal lineage of B. garinii. Toward this goal, a representative group of OspA serotype 4 strains was analyzed for traits that typically exhibit hypervariability among isolates that cause Lyme borreliosis. The following criteria were assessed: (i) ospC sequences, (ii) plasmid composition, (iii) genomic restriction fragment length polymorphism (RFLP) patterns, and (iv) the RFLP patterns of the upstream homology box (UHB) element which flanks members of the UHB gene family at their 5' end. Collectively, these analyses demonstrate genetic homogeneity, suggesting that OspA serotype 4 strains are a recently emerged clonal lineage with an apparent tropism for the central nervous system.

Antigens, Bacterial↗
PubMed2003

Genetic analysis and genome mapping in Raphanus.

The first genetic map of the Raphanus genome was developed based on meiosis in a hybrid between Raphanus sativus (cultivated radish) and Raphanus raphanistrum (wild radish). This hybrid was used to produce a BC1 population of 54 individuals and an F2 population of 85 individuals. A total of 236 marker loci were assayed in these populations using a set of 144 informative Brassica RFLP probes previously used for genetic mapping in other crucifer species. The genetic maps derived from the BC1 and F2 populations were perfectly collinear and were integrated to produce a robust Raphanus map. Cytological observations demonstrated strict bivalent pairing in the R. sativus x R. raphanistrum hybrids. Productive pairing along the length of each chromosome was confirmed by the identification of nine extensive linkage groups and the lack of clustering of marker loci. Indeed, the distributions of both marker loci and crossovers was more random than those reported for other crop species. The genetic markers and the reference map of Raphanus will be of considerable value for future trait mapping and marker-assisted breeding in this crop, as well as in the intergenomic transfer of Raphanus genes into Brassica crops. The future benefits of comparative mapping with Arabidopsis and Brassica species are also discussed.

Chromosome Mapping↗
PubMed1996

Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease.

Mild hyperhomocysteinemia is an established risk factor for cardiovascular disease. Genetic aberrations in the cystathionine beta-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) genes may account for reduced enzyme activities and elevated plasma homocysteine levels. In 15 unrelated Dutch patients with homozygous CBS deficiency, we observed the 833T-->C (I278T) mutation in 50% of the alleles. Very recently, we identified a common mutation (677C-->T; A-->V) in the MTHFR gene, which, in homozygous state, is responsible for the thermolabile phenotype and which is associated with decreased specific MTHRF activity and elevated homocysteine levels. We screened 60 cardiovascular patients and 111 controls for these two mutations, to determine whether these mutations are risk factors for premature cardiovascular disease. Heterozygosity for the 833T-->C mutation in the CBS gene was observed in one individual of the control group but was absent in patients with premature cardiovascular disease. Homozygosity for the 677C-->T mutation in the MTHFR gene was found in (15%) of 60 cardiovascular patients and in only 6 (approximately 5%) of 111 control individuals (odds ratio 3.1 [95% confidence interval 1.0-9.2]). Because of both the high prevalence of the 833T-->C mutation among homozygotes for CBS deficiency and its absence in 60 cardiovascular patients, we may conclude that heterozygosity for CBS deficiency does not appear to be involved in premature cardiovascular disease. However, a frequent homozygous mutation in the MTHFR gene is associated with a threefold increase in risk for premature cardiovascular disease.

Alleles↗
PubMed1998

Genetic analysis of chromosomal rearrangements in the cyclops region of the zebrafish genome.

Genetic screens in zebrafish have provided mutations in hundreds of genes with essential functions in the developing embryo. To investigate the possible uses of chromosomal rearrangements in the analysis of these mutations, we genetically characterized three gamma-ray induced alleles of cyclops (cyc), a gene required for development of midline structures. We show that cyc maps near one end of Linkage Group 12 (LG 12) and that this region is involved in a reciprocal translocation with LG 2 in one gamma-ray induced mutation, cyc(b213). The translocated segments together cover approximately 5% of the genetic map, and we show that this rearrangement is useful for mapping cloned genes that reside in the affected chromosomal regions. The other two alleles, cyc(b16) and cyc(b229), have deletions in the distal region of LG 12. Interestingly, both of these mutations suppress recombination between genetic markers in LG 12, including markers at a distance from the deletion. This observation raises the possibility that these deletions affect a site required for meiotic recombination on the LG 12 chromosome. The cyc(b16) and cyc(b229) mutations may be useful for balancing other lethal mutations located in the distal region of LG 12. These results show that chromosomal rearrangements can provide useful resources for mapping and genetic analyses in zebrafish.

Alleles↗
PubMed1986

Genetic analysis of Aspergillus nidulans AmdS+ transformants.

To correlate the genetic background of the Aspergillus nidulans amdS deletion strain MH1277 with the integrational behaviour of transforming vectors, classical genetic methods were used to construct AmdS- strains in which whole chromosomes had been exchanged with those of a master strain. Progeny strains were transformed to the AmdS+ phenotype with vector p3SR2. From Southern analysis it was concluded that transformants from all constructions contained tandemly repeated, multiple copy inserts of vector DNA as found for MH1277-derived AmdS+ transformants. AmdS+ transformants of MH1277 were analysed genetically to prove that the transformant phenotype is genome linked and that transformation by integration can take place on various chromosomes. In one case the AmdS+ property showed linkage to both chromosomes II and IV, due to a chromosomal translocation. Sexual analysis of two transformants with AmdS+ insertions on the same chromosome revealed a considerable instability of the AmdS+ phenotype in one of the strains upon selfing. Due to this instability no decisive answer could be given for the degree of linkage between the AmdS+ insertions in these transformants.

Aspergillus nidulans↗
PubMed2006

Developmental genetic analysis of seed size in soybean (Glycine max).

Seed size is one of the important factors of soybean [Glycine max (L.) Merrill] yield. There have been lots of reports about genetic effects and physiology--ecological researches on seed size, but the genetic behaviors of genes during seeds development were rarely discussed. Analysis of main genetic effects for fresh seed size (FSS) and dry seed size (DSS) of soybean was conducted with diallel cross data by using a seed genetic model. Analyses of unconditional and conditional variances and correlations were used to evaluate the developmental behavior of soybean. The phenotypic means of FSS and DSS in soybean at eight stages among three generations reached the highest value at 9/6 and 9/13, respectively. The means of FSS decreased dramatically after 9/6, but the means of DSS maintained relatively stable tendency at corresponding periods. The unconditional variance analysis showed that FSS and DSS were controlled by embryo, cytoplasmic and maternal effects in the whole growth period. Genetic effects due to cytoplasmic and maternal effects were relatively important for FSS and DSS at most of the growth periods. Conditional variance analysis showed that genes from different genetic system expressed discontinuously in the whole growth period. The net genetic effects due to cytoplasmic and maternal plant on FSS and DSS were larger than those of embryo effects at most of the growth periods. Different genetic system can affect the relationship of various stages to mature solely or simultaneously. Embryo additive effects at 8/16, embryo dominance effects at 8/9 and 8/16, maternal plant dominance effects at 8/2 and 8/16 could ultimately affect the performance of FSS at maturing stage. Embryo additive effects at 8/2 and 9/13, cytoplasm effects at 8/9, maternal plant dominance effects at 8/2 could ultimately affect the performance of DSS.

Analysis of Variance↗
PubMed2000

Genetic analysis in the diagnosis of familial paragangliomas.

OBJECTIVES: In the management of two related patients with multicentric glomus jugulare tumors, given the incidence of 1:30,000 with approximately 20% familial cases, our objective was to review the genetic characteristics and inheritance patterns of these tumors and to determine what molecular genetic screening possibilities exist for the phenotypically normal family members. In addition, our aim was to review the incidence of various multicentric paraganglioma (PGL) tumor location combinations. METHODS: Molecular genetic linkage analysis testing was performed on the 2 patients and 14 other unaffected family members. We report the results of this screening and review the literature on the incidence and genetics of paragangliomas. RESULTS: The inheritance pattern in the literature demonstrates autosomal dominant transmission with maternal imprinting (inactivation). The proclivity for multicentric origin increases to 26% in familial cases, as reflected in our patients. In addition to the two patients, four unaffected family members demonstrated the presence of the disease haplotype at chromosome band 11q23, which indicates a very high likelihood of developing a paraganglioma, given the highly penetrant nature of the disease. CONCLUSIONS: It is clear that the familial PGL gene locus is situated at chromosome 11q23. The gene itself and its exact degree of penetrance, however, still await identification. Since early detection of paragangliomas reduces the incidence of morbidity and mortality, genotypic analysis as a screening tool in families of affected patients should play a front-line diagnostic role, leading to more timely and cost-effective patient management.

Chromosomes, Human, Pair 11↗
PubMed1989

Behavioral responses to novelty and structural variation of the hippocampus in mice. II. Multivariate genetic analysis.

On the basis of results from lesion studies in rodents, covariations are expected to exist between naturally-occurring heritable variations in hippocampal morphology and exploratory behavior elicited by novel surroundings. For this reason, we set up a full diallel cross between five inbred mouse strains and analyzed the behavioral and the hippocampal anatomical variation in male animals from this cross. Employing a bivariate extension of the diallel-cross analysis, estimates were obtained for the phenotypical, environmental, and genetical correlations between the phenotypes studied. A factor analysis performed on the matrix of additive-genetic correlations revealed that variations in the size of the intra- and infrapyramidal mossy fiber terminal fields (iip-MF) are negatively related to open-field exploration and novelty-induced fear. These results indicate that having larger iip-MF projections promotes the collection and processing of information about a novel environment, entailing lower levels of exploration and fear.

Animals↗