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PubMed1998

Identification of three major clones of multiply antibiotic-resistant Streptococcus pneumoniae in Taiwanese hospitals by multilocus sequence typing.

In this paper we demonstrate the advantages of a new molecular typing procedure, multilocus sequence typing, for the unambiguous characterization of penicillin-resistant pneumococci. The sequences of approximately 450-bp fragments of seven housekeeping genes were determined for 74 penicillin-resistant Taiwanese isolates of Streptococcus pneumoniae (MIC of penicillin > 0.5 microgram/ml). The combination of alleles at the seven loci defined an allelic profile for each strain, and a dendrogram, based on the pairwise mismatches in allelic profiles, grouped 86% of the isolates into one of three penicillin-resistant clones for which the MICs of penicillin were 1 to 2 microgram/ml. Isolates within each clone had identical alleles at all seven loci or differed at only a single locus, and the fingerprints of their pbp1A, pbp2B, and pbp2X genes were uniform. Isolates of the Taiwan-19F clone and the Taiwan-23F clone were resistant to penicillin, tetracycline, and erythromycin but were susceptible to chloramphenicol. A second serotype 23F clone and serotype 19F variants of this clone were resistant to penicillin, tetracycline, chloramphenicol, and, in some cases, erythromycin. Comparisons of the allelic profiles of the three major clones with those of reference isolates of the known penicillin-resistant clones showed that the Taiwan-19F and Taiwan-23F clones were previously undescribed, whereas the second serotype 23F clone was indistinguishable from the Spanish multidrug-resistant serotype 23F clone. Single isolates of the Spanish penicillin-resistant serotype 9V clone and the Spanish multidrug-resistant serotype 6B clone were also identified in the collection.

Bacterial Typing Techniques↗

PubMed2005

Genetic basis for the psychostimulant effects of nicotine: a quantitative trait locus analysis in AcB/BcA recombinant congenic mice.

Genetic differences in sensitivity to nicotine have been reported in both animals and humans. The present study utilized a novel methodology to map genes involved in regulating both the psychostimulant and depressant effects of nicotine in the AcB/BcA recombinant congenic strains (RCS) of mice. Locomotor activity was measured in a computerized open-field apparatus following subcutaneous administration of saline (days 1 and 2) or nicotine on day 3. The phenotypic measures obtained from this experimental design included total basal locomotor activity, as well as total nicotine activity, nicotine difference scores, nicotine percent change and nicotine regression residual scores. The results indicated that the C57BL/6J (B6) were insensitive to nicotine over the entire dose-response curve (0.1, 0.2, 0.4 and 0.8 mg/kg). However, the 0.8-mg/kg dose of nicotine produced a significant decrease in the locomotor activity in the A/J strain and a wide and continuous range of both locomotor excitation and depression among the AcB/BcA RCS. Single-locus association analysis in the AcB RCS identified quantitative trait loci (QTL) for the psychostimulant effects of nicotine on chromosomes 11, 12, 13, 14 and 17 and one QTL for nicotine-induced depression on chromosome 11. In the BcA RCS, nicotine-induced locomotor activation was associated with seven putative regions on chromosomes 2, 7, 8, 13, 14, 16 and 17. There were no overlapping QTL and no genetic correlations between saline- and nicotine-related phenotypes in the AcB/BcA RCS. A number of putative candidate genes were in proximity to regions identified with nicotine sensitivity, including the alpha2 subunit of the nicotinic acetylcholine receptor and the dopamine D3 receptor.

Analysis of Variance↗

PubMed2001

Trade-offs between male and female reproduction associated with allozyme variation in phosphoglucoisomerase in an annual plant (Clarkia unguiculata: Onagraceae).

The genotype of an individual for allozymes such as phosphoglucoisomerase (Pgi) is often not neutral with regard to fitness. Studies of several taxa have found consistent fitness differences among Pgi genotypes expressing different allozymes. We conducted a greenhouse experiment with Clarkia unguiculata to determine whether allelic variation at the Pgi-C1 locus may affect components of male and female function. We found significant differences in siring success between pollen donors homozygous for different Pgi alleles. When a mixture of pollen was applied to stigmas under conditions of gametophytic competition (more pollen deposited on stigmas than there are ovules available to fertilize), donors homozygous for the C allele of Pgi sired more seeds per fruit than B-allele donors. Differences between genotypes with respect to female fertility per fruit contrasted with the male advantage associated with the C allele. Recipients homozygous for the C allele produced fruits with more aborted seeds and fewer viable seeds than recipients homozygous for the B allele. These results suggest that allelic variation at a single locus may have opposing effects on male and female reproductive success in C. unguiculata, and that trade-offs between the two types of reproductive success could contribute to the maintenance of variation at the Pgi-C1 locus.

Animals↗

PubMed1985

Type 1 (insulin-dependent) diabetes and a highly variable locus close to the insulin gene on chromosome 11.

A polymorphic DNA sequence in the 5'-flanking region of the human insulin gene was studied in relation to Type 1 (insulin-dependent) diabetes. In 141 Caucasoid subjects analysed by Southern blot hybridisation techniques, two major DNA insertions were observed: a Class 1 allele or a Class 3 allele. The Class 2 allele was not observed in this group of subjects. Genotype frequencies in a control population (n = 88) were: homozygous 1/1, 42%; heterozygous 1/3, 50%; and homozygous 3/3, 8%. Corresponding genotype frequencies in 53 Type 1 diabetic patients were 79%, 21% and 0%, respectively (p less than 0.0005 from chi 2 test). This confirms prevalence data reported by Bell et al. [16]. There appeared to be no coinheritance with HLA-DR3/DR4 related antigens, nor with autoimmune features. Analysis of 17 Type 1 diabetic pedigrees including 34 diabetic and 69 non-diabetic subjects did not demonstrate genetic linkage of these DNA inserts with diabetes, using an autosomal recessive, single locus model of inheritance.

Alleles↗

PubMed1996

S-allele diversity in a natural population of Physalis crassifolia (Solanaceae) (ground cherry) assessed by RT-PCR.

Allelic diversity at the self-incompatibility (S-) locus in the ground cherry, Physalis crassifolia (Solanaceae), was surveyed in a natural population occurring in Deep Canyon, CA, using a molecular assay to determine the genotype of individual plants. A total of 28 different S-alleles were identified and sequenced from a sample of 22 plants. All plants examined were heterozygous, as expected under gametophytic self-incompatibility (GSI). The estimated number of alleles in this population is 43-44, comparable to allelic diversity reported for other species, as determined by the standard diallel crossing method. Allele frequencies in the sample deviated from the expectation of equal frequency under GSI; it is suggested that this deviation may result from sampling of related individuals. Molecular analysis of genotypes within single pollen donor families indicates that, for all alleles examined, segregation is consistent with predictions for single-locus GSI. The implications of a reliable and efficient molecular assay for determining the S-genotype of plants are discussed.

Alleles↗

PubMed2002

[Heterozygosity in patients with pulmonary tuberculosis showing varying responses to therapy].

The distribution of the levels of heterozygosity was analyzed by 9 loci of genetic markers: PI, TF, PGM1, ACPI, HP, GC, GLO1 C3, and ESD in two groups of patients with pulmonary tuberculosis who had improvements (Group 1, n = 71) and failures (Group 2, n = 35). The heterozygosity observed in the groups was compared with that calculated by the Hardy-Weinberg law by using data on healthy controls (n = 328; the locus ESD was investigated in 78 healthy individuals). The analysis indicated that there were statistically significant deviations of the observed heterozygosities, g1, at 4 loci (GC, PI, C3, and ACPI) from the expected ones; h1 calculated from the data in the control group. The observed heterozygisities were higher than the expected ones at 3 loci (PI, C3, and ACPI), and at the GC locus. the observed heterozygosity being lower than the expected one. Comparing the observed heterozygosities. g1, within the loci, by using Fisher's exact test revealed significant differences between the groups of patients and healthy controls at the same loci, which showed significant differences between the observed and expected heterozygosities. There were no differences between the groups of patients by the observed heterozygosities. The mean expected heterozygosity were h = 0.386 +/- 0.056. The mean observed heterozygosity, were g = 0.415 +/- 0.037, 0.402 +/- 0.061, 0.371 +/- 0.055 in Groups 1 and 2 and in the controls, respectively. There were no differences between the mean expected and obsorved heterozygosities or between the mean observed heterozygosities in the three groups under study. It is proposed that a single locus rather than the mean heterozygosities should be used as a generalized nonspecific measure of genetic control over diseases while the former can show the involvement of a specific marker locus to develop a disease, the latter can simply veil the effects of each of the loci alone. Thus, the findings produce strong evidence for that there is a genetic control in the development of pulmonary tuberculosis.

Genetic Carrier Screening↗

PubMed1999

Summary of analyses of problem 2 simulated data for GAW11.

The simulated data for Problem 2 of the 11th Genetic Analysis Workshop (GAW11) consisted of family linkage data and disease data from three populations, each population with different genetic parameters. The disease was simulated such that there were two genetically distinct diseases, one caused by a single locus with three alleles and the other by two epistatically interacting loci. The two diseases were clinically identical. Each of the diseases had a severe and mild form. One of the diseases was influenced by an environmental factor and one by an allele at one of the marker loci (association). Linkage data consisted of 300 polymorphic markers. Investigators analyzed these data in a myriad of ways, using most currently available linkage techniques and association analysis methods. In addition, investigators also tested newly developed methods, some of which took advantage of the existence of the environmental component. Other types of analyses included meta-analyses, methods of combining data from different studies, questions of replication, how much information is available in a single data set, and analyses for gene x gene and gene x environment interaction.

Computer Simulation↗

PubMed2006

Sex-specific expression of alternative transcripts in Drosophila.

BACKGROUND: Many genes produce multiple transcripts due to alternative splicing or utilization of alternative transcription initiation/termination sites. This 'transcriptome expansion' is thought to increase phenotypic complexity by allowing a single locus to produce several functionally distinct proteins. However, sex, genetic and developmental variation in the representation of alternative transcripts has never been examined systematically. Here, we describe a genome-wide analysis of sex-specific expression of alternative transcripts in Drosophila melanogaster. RESULTS: We compared transcript profiles in males and females from eight Drosophila lines (OregonR and 2b, and 6 RIL) using a newly designed 60-mer oligonucleotide microarray that allows us to distinguish a large proportion of alternative transcripts. The new microarray incorporates 7,207 oligonucleotides, satisfying stringent binding and specificity criteria that target both the common and the unique regions of 2,768 multi-transcript genes, as well as 12,912 oligonucleotides that target genes with a single known transcript. We estimate that up to 22% of genes that produce multiple transcripts show a sex-specific bias in the representation of alternative transcripts. Sexual dimorphism in overall transcript abundance was evident for 53% of genes. The X chromosome contains a significantly higher proportion of genes with female-biased transcription than the autosomes. However, genes on the X chromosome are no more likely to have a sexual bias in alternative transcript representation than autosomal genes. CONCLUSION: Widespread sex-specific expression of alternative transcripts in Drosophila suggests that a new level of sexual dimorphism at the molecular level exists.

Alternative Splicing↗

PubMed2000

The origin of the Jingwei gene and the complex modular structure of its parental gene, yellow emperor, in Drosophila melanogaster.

Jingwei (jgw) is the first gene found to be of sufficiently recent origin in Drosophila to offer insights into the origin of a gene. While its chimerical gene structure was partially resolved as including a retrosequence of alcohol dehydrogenase (ADH:), the structure of its non-ADH: parental gene, the donor of the N-terminal domain of jgw, is unclear. We characterized this non-ADH: parental locus, yellow emperor (ymp), by cloning it, mapping it onto the polytene chromosomes, sequencing the entire locus, and examining its expression patterns in Drosophila melanogaster. We show that ymp is located in the 96-E region; the N-terminal domain of ymp has donated the non-ADH: portion of jgw via a duplication. The similar 5' portions of the gene and its regulatory sequences give rise to similar testis-specific expression patterns in ymp and jgw in Drosophila teissieri. Furthermore, between-species comparison of ymp revealed purifying selection in the protein sequence, suggesting a functional constraint in ymp. While the structure of ymp provides clear information for the molecular origin of the new gene jgw, it unexpectedly casts a new light on the concept of genes. We found, for the first time, that the single locus of the ymp gene encompasses three major molecular mechanisms determining structure of eukaryotic genes: (1) the 5' exons of ymp are involved in an exon-shuffling event that has created the portion recruited by jgw; (2) using alternative cleavage sites and alternative splicing sites, the 3' exon groups of ymp produce two proteins with nonhomologous C-terminal domains, both exclusively in the testis; and (3) in the opposite strand of the third intron of ymp is an essential gene, musashi (msi), which encodes an RNA-binding protein. The composite gene structure of ymp manifests the complexity of the gene concept, which should be considered in genomic research, e.g., gene finding.

Alternative Splicing↗

PubMed2006

Family-based association study of Epsin 4 and Schizophrenia.

Recently, Pimm et al. identified Epsin 4 on chromosome 5q33 as a susceptibility gene for schizophrenia in the British population, based on linkage and association evidence. In Pimm's case-control study, both the single polymorphisms and the individual haplotypes at the 5' end of the gene showed genetic association with schizophrenia. Here, we report the first study evaluating the relevance of Epsin 4 and schizophrenia outside the British population. Markers showing positive results in the original work as well as two additional polymorphisms were genotyped in 308 Han Chinese family trios. Transmission disequilibrium analysis was used to test for association of single-locus markers and multi-locus haplotypes with schizophrenia. Although no individual marker was significant at the P=0.05 level, the haplotypes detected in our samples, different from those previously reported, showed strong evidence of association (most significant global P=0.0021). Our results indicate the presence of a locus near the 5' end of Epsin 4 conferring susceptibility to the disease and provide further support for Epsin 4 as an important potential contributor to genetic risk in schizophrenia.

Adaptor Proteins, Vesicular Transport↗

PubMed2000

DNA technology for the detection of common genetic variants that predispose to thrombophilia.

With the identification of common single locus point mutations as risk factors for thrombophilia, many DNA testing methodologies have been described for detecting these variations. Traditionally, functional or immunological testing methods have been used to investigate quantitative anticoagulant deficiencies. However, with the emergence of the genetic variations, factor V Leiden, prothrombin 20210 and, to a lesser extent, the methylene tetrahydrofolate reductase (MTHFR677) and factor V HR2 haplotype, traditional testing methodologies have proved to be less useful and instead DNA technology is more commonly employed in diagnostics. This review considers many of the DNA techniques that have proved to be useful in the detection of common genetic variants that predispose to thrombophilia. Techniques involving gel analysis are used to detect the presence or absence of restriction sites, electrophoretic mobility shifts, as in single strand conformation polymorphism or denaturing gradient gel electrophoresis, and product formation in allele-specific amplification. Such techniques may be sensitive, but are unwielding and often need to be validated objectively. In order to overcome some of the limitations of gel analysis, especially when dealing with larger sample numbers, many alternative detection formats, such as closed tube systems, microplates and microarrays (minisequencing, real-time polymerase chain reaction, and oligonucleotide ligation assays) have been developed. In addition, many of the emerging technologies take advantage of colourimetric or fluorescence detection (including energy transfer) that allows qualitative and quantitative interpretation of results. With the large variety of DNA technologies available, the choice of methodology will depend on several factors including cost and the need for speed, simplicity and robustness.

DNA↗

PubMed2001

One INK4 gene and no ARF at the Fugu equivalent of the human INK4A/ARF/INK4B tumour suppressor locus.

The INK4A/ARF/INK4B locus, conserved in mammals, encodes three polypeptides that regulate cell proliferation via the pRb and p53 tumour suppressor pathways. The locus is mutated in many cancers. The related, tandemly-linked INK4A and INK4B genes encode the p16(INK4A) and p15(INK4B) members of the INK4 family of cyclin-dependent kinase inhibitors which block phosphorylation of pRb, whereas the third product, ARF, derived from an alternative reading frame of INK4A, regulates p53 activity. We assessed the status of this unusual locus in the puffer fish, Fugu rubripes, and identified two INK4 genes using degenerate PCR and hybridization analyses. Sequence conservation and conservation of synteny between human and Fugu predict one gene to be an INK4A or INK4B homologue and the other an INK4D homologue. Analysis of the Fugu INK4A/B gene and the surrounding 40-kb of genomic DNA did not reveal the presence of any ARF-encoding potential or another related INK4 gene. We conclude that the gene duplication event that generated adjacent INK4A and INK4B genes and the association of ARF with the ancestral INK4A gene occurred after the divergence of the lineage leading to mammals from fish. Thus, unlike mammals, the fish p53 and pRb tumour suppressor pathways are not regulated by a single locus.

Amino Acid Sequence↗

PubMed2005

Investigation of second genetic hits at the BMPR2 locus as a modulator of disease progression in familial pulmonary arterial hypertension.

BACKGROUND: Primary pulmonary arterial hypertension (PAH) is a potentially devastating condition resulting from occlusion of the pulmonary arterioles by the formation of vascular lesions. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) have been identified in both familial (FPAH) and idiopathic PAH. Mutant alleles are typically of low penetrance, indicating that other factors are required for the onset of PAH. Previous reports have suggested that the characteristic plexiform lesions in affected lungs are akin to neoplasia, showing monoclonal expansion and microsatellite instability. We hypothesized that in patients with germline mutations, BMPR2 might behave as a classic tumor suppressor gene, with somatic loss of the wild-type allele contributing to disease progression. METHODS AND RESULTS: To test this hypothesis, plexiform and concentric vascular lesions were serially microdissected from lung explant tissue derived from 7 FPAH cases. DNA was analyzed for loss of heterozygosity at BMPR2 and for microsatellite instability (MSI) at 5 loci. MSI was detected in 1 of 37 lesions at a single locus, BAT-26, whereas heterozygosity at BMPR2 was retained at all informative loci. We also describe a FPAH patient carrying biallelic constitutional missense mutations of BMPR2 who manifested disease at a stage and manner similar to heterozygous patients. CONCLUSIONS: Taken together, these data demonstrate that MSI is uncommon in FPAH and suggest that somatic loss of the remaining wild-type BMPR2 allele in heterozygous mutation carriers likely does not play a significant role in modulating the onset or progression of FPAH.

Adult↗

PubMed2006

Mammalian monogamy is not controlled by a single gene.

Complex social behavior in Microtus voles and other mammals has been postulated to be under the direct genetic control of a single locus: the arginine vasopressin 1a receptor (avpr1a) gene. Using a phylogenetic approach, we show that a repetitive element in the promoter region of avpr1a, which reportedly causes social monogamy, is actually widespread in nonmonogamous Microtus and other rodents. There was no evidence for intraspecific polymorphism in regard to the presence or absence of the repetitive element. Among 25 rodent species studied, the element was absent in only two closely related nonmonogamous species, indicating that this absence is certainly the result of an evolutionarily recent loss. Our analyses further demonstrate that the repetitive structures upstream of the avpr1a gene in humans and primates, which have been associated with social bonding, are evolutionarily distinct from those in rodents. Our evolutionary approach reveals that monogamy in rodents is not controlled by a single polymorphism in the promoter region of the avpr1a gene. We thus resolve the contradiction between the claims for an evolutionarily conserved genetic programming of social behavior in mammals and the vast evidence for highly complex and flexible mating systems.

Animals↗

PubMed1992

The locus Om, responsible for the DDK syndrome, maps close to Sigje on mouse chromosome 11.

The DDK inbred strain of mouse has a striking particularity: when DDK females are crossed to males of other strains they exhibit a reduced fertility, whereas the reciprocal crosses (non-DDK females x DDK males) are fertile (Wakasugi et al. 1967; Wakasugi 1973). The low fertility results from an early embryonic lethality, the F1 embryos dying near the late morula-early blastocyst stage. Genetic analyses (Wakasugi 1974) and nuclear and cytoplasmic transfers (Renard and Babinet 1986; Babinet et al. 1990; Mann 1986), have shown that the failure of the embroys to develop is due to an incompatibility between a DDK maternally encoded cytoplasmic product and the non-DDK paternal genome. In order to elucidate the genetic determinism of this embryonic lethality, we have analyzed the fertility of male progeny from a backcross BALB/c females x (BALB/c x DDK)F1 males and that of males from a set of recombinant inbred (RI) strains, established from DDK and BALB/c progenitors, when mated with DDK females. Our results indicate that a single locus, Om, is responsible for the DDK syndrome and is located on Chromosome (Chr) 11, very close to the Sigje locus.

Animals↗

PubMed2005

Powdery mildew resistance and Lr34/Yr18 genes for durable resistance to leaf and stripe rust cosegregate at a locus on the short arm of chromosome 7D of wheat.

The incorporation of effective and durable disease resistance is an important breeding objective for wheat improvement. The leaf rust resistance gene Lr34 and stripe rust resistance gene Yr18 are effective at the adult plant stage and have provided moderate levels of durable resistance to leaf rust caused by Puccinia triticina Eriks. and to stripe rust caused by Puccinia striiformis Westend. f. sp. tritici. These genes have not been separated by recombination and map to chromosome 7DS in wheat. In a population of 110 F(7) lines derived from a Thatcher x Thatcher isogenic line with Lr34/Yr18, field resistance to leaf rust conferred by Lr34 and to stripe rust resistance conferred by Yr18 cosegregated with adult plant resistance to powdery mildew caused by Blumeria graminis (DC) EO Speer f. sp. tritici. Lr34 and Yr18 were previously shown to be associated with enhanced stem rust resistance and tolerance to barley yellow dwarf virus infection. This chromosomal region in wheat has now been linked with resistance to five different pathogens. The Lr34/Yr18 phenotypes and associated powdery mildew resistance were mapped to a single locus flanked by microsatellite loci Xgwm1220 and Xgwm295 on chromosome 7DS.

Chromosome Mapping↗

PubMed2005

Fine mapping by linkage and association in nuclear family and case-control designs.

This report summarizes the Genetic Analysis Workshop 14 contributions related to fine-mapping strategies, in which examining smaller regions by association with single-nucleotide polymorphisms (SNPs) can yield savings in genotyping and multiple-testing penalties. The aim of the analyses conducted in Group 7 contributions was to localize disease susceptibility loci from either the simulated or the Collaborative Study on the Genetics of Alcoholism (COGA) data within identified regions of linkage. Among the 10 contributions, most groups analyzed the simulated data, one group analyzed the COGA data only, and one group analyzed both data sets. The research questions included evaluation of new methods of analysis, as well as comparisons among alternative methods, analytic strategies, and study designs. Methods of interest included an algorithm for SNP marker ordering, a locally weighted transmission disequilibrium test statistic, a likelihood-ratio test statistic for family-based association in nuclear families, a robust test statistic for case-control association studies, and Bayesian spatial modeling methods for haplotype clustering and association. Evaluations included comparisons among confidence intervals for loci detected via linkage, effects of multiple testing adjustments and trade-offs between type I error and power, comparisons among haplotype-based (multilocus) and genotype-based (multilocus and single-locus) association analyses, and design of fine-mapping and replication studies. While several promising new approaches were identified, further development and evaluation of methods for multiple testing, regression modeling of association with multiple markers and haplotypes, and combined treatment of linkage and association data are necessary if we are to identify many of the genes that contribute to complex traits.

Alcoholism↗

PubMed2004

Genomewide linkage searches for Mendelian disease loci can be efficiently conducted using high-density SNP genotyping arrays.

Genomewide linkage searches aimed at identifying disease susceptibility loci are generally conducted using 300-400 microsatellite markers. Genotyping bi-allelic single nucleotide polymorphisms (SNPs) provides an alternative strategy. The availability of dense SNP maps coupled with recent technological developments in highly paralleled SNP genotyping makes it practical to now consider the use of these markers for whole-genome genetic linkage analyses. Here, we report the findings from three successful genomewide linkage analyses of families segregating autosomal recessively inherited neonatal diabetes, craniosynostosis and dominantly inherited renal dysplasia using the Affymetrix 10K SNP array. A single locus was identified for each disease state, two of which are novel. The performance of the SNP array, both in terms of efficiency and precision, indicates that such platforms will become the dominant technology for performing genomewide linkage searches.

Amino Acid Sequence↗