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PubMed2004

Quantile smoothing of array CGH data.

MOTIVATION: Plots of array Comparative Genomic Hybridization (CGH) data often show special patterns: stretches of constant level (copy number) with sharp jumps between them. There can also be much noise. Classic smoothing algorithms do not work well, because they introduce too much rounding. To remedy this, we introduce a fast and effective smoothing algorithm based on penalized quantile regression. It can compute arbitrary quantile curves, but we concentrate on the median to show the trend and the lower and upper quartile curves showing the spread of the data. Two-fold cross-validation is used for optimizing the weight of the penalties. RESULTS: Simulated data and a published dataset are used to show the capabilities of the method to detect the segments of changed copy numbers in array CGH data.

Algorithms↗
PubMed2004

Bayesian models for the analysis of genetic structure when populations are correlated.

MOTIVATION: Population allele frequencies are correlated when populations have a shared history or when they exchange genes. Unfortunately, most models for allele frequency and inference about population structure ignore this correlation. Recent analytical results show that among populations, correlations can be very high, which could affect estimates of population genetic structure. In this study, we propose a mixture beta model to characterize the allele frequency distribution among populations. This formulation incorporates the correlation among populations as well as extending the model to data with different clusters of populations. RESULTS: Using simulated data, we show that in general, the mixture model provides a good approximation of the among-population allele frequency distribution and a good estimate of correlation among populations. Results from fitting the mixture model to a dataset of genotypes at 377 autosomal microsatellite loci from human populations indicate high correlation among populations, which may not be appropriate to neglect. Traditional measures of population structure tend to overestimate the amount of genetic differentiation when correlation is neglected. Inference is performed in a Bayesian framework. CONTACT: fur@ohsu.edu.

Bayes Theorem↗
PubMed2005

A genotype calling algorithm for affymetrix SNP arrays.

MOTIVATION: A classification algorithm, based on a multi-chip, multi-SNP approach is proposed for Affymetrix SNP arrays. Current procedures for calling genotypes on SNP arrays process all the features associated with one chip and one SNP at a time. Using a large training sample where the genotype labels are known, we develop a supervised learning algorithm to obtain more accurate classification results on new data. The method we propose, RLMM, is based on a robustly fitted, linear model and uses the Mahalanobis distance for classification. The chip-to-chip non-biological variance is reduced through normalization. This model-based algorithm captures the similarities across genotype groups and probes, as well as across thousands of SNPs for accurate classification. In this paper, we apply RLMM to Affymetrix 100 K SNP array data, present classification results and compare them with genotype calls obtained from the Affymetrix procedure DM, as well as to the publicly available genotype calls from the HapMap project.

Algorithms↗
PubMed2006

GGtools: analysis of genetics of gene expression in bioconductor.

UNLABELLED: This paper reviews the central concepts and implementation of data structures and methods for studying genetics of gene expression with the GGtools package of Bioconductor. Illustration with a HapMap+expression dataset is provided. AVAILABILITY: Package GGtools is part of Bioconductor 1.9 (http://bioconductor.org). Open source with Artistic License.

Chromosome Mapping↗
PubMed2004

Evolutionary mapping of the SHV beta-lactamase and evidence for two separate IS26-dependent blaSHV mobilization events from the Klebsiella pneumoniae chromosome.

OBJECTIVES: To determine the most likely evolutionary pathway that has led to the development of extended-spectrum SHV derivatives, and to the mobilization of blaSHV. MATERIALS AND METHODS: Evolutionary mapping used a shortest-path analysis of aligned blaSHV variants, and other basic bioinformatic approaches, such as CLUSTAL W and Blast were employed. RESULTS: Two main branches of the blaSHV evolutionary tree were located; both are derived from variant blaSHV-1 alleles. Identical mutations, responsible for extended-spectrum SHV substrate profiles, have been selected independently in each branch. There is evidence for a pool of non-mobile blaSHV framework sequences. Analysis of the genome sequence of Klebsiella pneumoniae confirms the chromosomal origin of blaSHV, whose mobilization has occurred at least twice, once for each of the main evolutionary branches. Both these mobilization events have been catalysed by IS26. Evolution of blaSHV to give common extended-spectrum variants is most likely to have occurred following mobilization. CONCLUSIONS: These data shed new light on the evolution and mobilization of blaSHV, and these observations may be useful in predicting what might happen in future, both for blaSHV, and for other beta-lactamase genes.

Alleles↗
PubMed2004

Genetic relatedness of ciprofloxacin-resistant Shigella dysenteriae type 1 strains isolated in south Asia.

OBJECTIVES: The aim of the present study was to determine the clonal relationships of ciprofloxacin-resistant Shigella dysenteriae type 1 strains isolated from south Asia, and S. dysenteriae 1 strains associated with epidemics in 1978, 1984 and 1994. METHODS: The antimicrobial susceptibilities were examined by NCCLS methods. Molecular epidemiological characterization was performed by plasmid profiling, pulsed-field gel electrophoresis (PFGE) and mutation analysis of the quinolone resistance-determining region (QRDR) of gyrA by sequencing. RESULTS: Plasmid patterns of the current ciprofloxacin-resistant strains from India, Nepal and Bangladesh were very similar to those of the 1978, 1984 and 1994 epidemic isolates of S. dysenteriae 1, except for the presence of a new plasmid of approximately 2.6 MDa, which was found in one recent ciprofloxacin-resistant strain isolated in Bangladesh. PFGE analysis showed that the ciprofloxacin-resistant strains isolated in Bangladesh, India and Nepal belonged to a PFGE type (type A), which was possibly related to that of the 1984 and 1994 clone of S. dysenteriae 1, but different from 1978 epidemic strains. The current ciprofloxacin-resistant strains belong to five subtypes (A3-A7), all of which were found in India, but in Bangladesh and Nepal, only A3 existed. Mutation analysis of the QRDR of gyrA revealed that amino acid substitutions at positions 83 and 87 of ciprofloxacin-resistant strains isolated in Bangladesh were similar to those of the strains isolated in Nepal, but different (at position 87) from ciprofloxacin-resistant strains isolated in India. CONCLUSIONS: PFGE and mutation analysis of gyrA showed differences between the current ciprofloxacin-resistant S. dysenteriae 1 strains isolated in south Asia and those associated with epidemics in 1978, 1984 and 1994.

Amino Acid Substitution↗
PubMed2005

The role of monovalent cation transporters in plant responses to salinity.

Exposure to high ambient levels of NaCl affects plant water relations and creates ionic stress in the form of the cellular accumulation of Cl- and, in particular, Na+ ions. However, salt stress also impacts heavily on the homeostasis of other ions such as Ca2+, K+, and NO(3)(-) and therefore requires insights into how transport and compartmentation of these nutrients is altered during salinity stress. A genomics approach can greatly help with the identification of genes, and therefore potentially gene products, that are involved in plant salinity. Both the literature and public databases contain the results of many genomics studies and, in this report, those data are collated in the context of cation membrane transport and salinity. The efficacy of genomics approaches in isolation is low due to large inherent variability and the exclusion of gene products that are predominantly regulated post-transcriptionally. In conjunction with complementary approaches, however, transcriptomics can help identify important transcripts and relevant associations between physiological processes. This analysis identified (i) vascular K+ circulation, (ii) root shoot translocation of Ca2+, and (iii) transition metal homeostasis as potentially important aspects of the plant response to salt stress.

Arabidopsis↗
PubMed2003

ASAP, a systematic annotation package for community analysis of genomes.

ASAP (a systematic annotation package for community analysis of genomes) is a relational database and web interface developed to store, update and distribute genome sequence data and functional characterization (https://asap.ahabs.wisc.edu/annotation/php/ASAP1.htm). ASAP facilitates ongoing community annotation of genomes and tracking of information as genome projects move from preliminary data collection through post-sequencing functional analysis. The ASAP database includes multiple genome sequences at various stages of analysis, corresponding experimental data and access to collections of related genome resources. ASAP supports three levels of users: public viewers, annotators and curators. Public viewers can currently browse updated annotation information for Escherichia coli K-12 strain MG1655, genome-wide transcript profiles from more than 50 microarray experiments and an extensive collection of mutant strains and associated phenotypic data. Annotators worldwide are currently using ASAP to participate in a community annotation project for the Erwinia chrysanthemi strain 3937 genome. Curation of the E. chrysanthemi genome annotation as well as those of additional published enterobacterial genomes is underway and will be publicly accessible in the near future.

Databases, Genetic↗
PubMed2005

RARGE: a large-scale database of RIKEN Arabidopsis resources ranging from transcriptome to phenome.

The RIKEN Arabidopsis Genome Encyclopedia (RARGE) database houses information on biological resources ranging from transcriptome to phenome, including RIKEN Arabidopsis full-length (RAFL) complementary DNAs (cDNAs), their promoter regions, Dissociation (Ds) transposon-tagged lines and expression data from microarray experiments. RARGE provides tools for searching by resource code, sequence homology or keyword, and rapid access to detailed information on the resources. We have isolated 245 946 RAFL cDNA clones and collected 11 933 transposon-tagged lines, which are available from the RIKEN Bioresource Center and are stored in RARGE. The RARGE web interface can be accessed at http://rarge.gsc.riken.jp/. Additionally, we report 90 000 new RAFL cDNA clones here.

Arabidopsis↗
PubMed2004

CENTRIN2 modulates homologous recombination and nucleotide excision repair in Arabidopsis.

A genetic screen of a population of Arabidopsis thaliana lines exhibiting enhanced somatic homologous recombination yielded a mutant affected in expression of a gene encoding a caltractin-like protein (centrin). The hyperrecombinogenic phenotype could be reproduced using RNA interference (RNAi) technology. Both the original mutant and the RNAi plants exhibited a moderate UV-C sensitivity as well as a reduced efficiency of in vitro repair of UV-damaged DNA. Transcription profiling of the mutant showed that expression of components of the nucleotide excision repair (NER) pathway and of factors involved in other DNA repair processes were significantly changed. Our data suggest an indirect involvement of centrin in recombinational DNA repair via the modulation of the NER pathway. These findings thus point to a novel interconnection between an early step of NER and homologous recombination, which may play a critical role in plant DNA repair.

Amino Acid Sequence↗
PubMed2004

The Arabidopsis Rab GTPase RabA4b localizes to the tips of growing root hair cells.

Spatial and temporal control of cell wall deposition plays a unique and critical role during growth and development in plants. To characterize membrane trafficking pathways involved in these processes, we have examined the function of a plant Rab GTPase, RabA4b, during polarized expansion in developing root hair cells. Whereas a small fraction of RabA4b cofractionated with Golgi membrane marker proteins, the majority of this protein labeled a unique membrane compartment that did not cofractionate with the previously characterized trans-Golgi network syntaxin proteins SYP41 and SYP51. An enhanced yellow fluorescent protein (EYFP)-RabA4b fusion protein specifically localizes to the tips of growing root hair cells in Arabidopsis thaliana. Tip-localized EYFP-RabA4b disappears in mature root hair cells that have stopped expanding, and polar localization of the EYFP-RabA4b is disrupted by latrunculin B treatment. Loss of tip localization of EYFP-RabA4b was correlated with inhibition of expansion; upon washout of the inhibitor, root hair expansion recovered only after tip localization of the EYFP-RabA4b compartments was reestablished. Furthermore, in mutants with defective root hair morphology, EYFP-RabA4b was improperly localized or was absent from the tips of root hair cells. We propose that RabA4b regulates membrane trafficking through a compartment involved in the polarized secretion of cell wall components in plant cells.

Actins↗
PubMed2007

PIP5K9, an Arabidopsis phosphatidylinositol monophosphate kinase, interacts with a cytosolic invertase to negatively regulate sugar-mediated root growth.

Phosphatidylinositol monophosphate 5-kinase (PIP5K) plays an essential role in coordinating plant growth, especially in response to environmental factors. To explore the physiological function of PIP5K, we characterized Arabidopsis thaliana PIP5K9, which is constitutively expressed. We found that a T-DNA insertion mutant, pip5k9-d, which showed enhanced PIP5K9 transcript levels, had shortened primary roots owing to reduced cell elongation. Transgenic plants overexpressing PIP5K9 displayed a similar root phenotype. Yeast two-hybrid assays identified a cytosolic invertase, CINV1, that interacted with PIP5K9, and the physiological relevance of this interaction was confirmed by coimmunoprecipitation studies using plant extracts. CINV1-deficient plants, cinv1, had reduced activities of both neutral and acid invertases as well as shortened roots. Invertase activities in pip5k9-d seedlings were also reduced, suggesting a negative regulation of CINV1 by PIP5K9. In vitro studies showed that PIP5K9 interaction indeed repressed CINV1 activities. Genome-wide expression studies revealed that genes involved in sugar metabolism and multiple developmental processes were altered in pip5k9-d and cinv1, and the altered sugar metabolism in these mutants was confirmed by metabolite profiling. Together, our results indicate that PIP5K9 interacts with CINV1 to negatively regulate sugar-mediated root cell elongation.

Arabidopsis↗
PubMed1982

The Coffin-Lowry syndrome. Experience from four centres.

The Coffin-Lowry syndrome is an established syndrome of mental retardation, a characteristic facies and skeletal anomalies. This paper describes 12 cases from eight families and compares their findings with those of previously reported patients. The differential diagnosis is considered. Physical findings and pedigree data strongly support X-linked semi-dominant inheritance. The gene appears widely distributed and, as expected, a significant proportion of cases represent new mutations. We cannot confirm the metacarpal-phalangeal profile or fingertip dermatoglyphics as useful diagnostic aids. Skin biopsy studies from four of our patients gave no evidence for a primary disorder of lysosomes or a degenerative disease. Caution is urged before assuming that such patients will all show intellectual deterioration.

Abnormalities, Multiple↗
PubMed1993

Protein and gene structure analysis of an albumin genetic variant: proalbumin Wu Yang (-2 Arg-->His).

An electrophoretically slow genetic variant of human serum albumin was isolated from a patient with bis-albuminemia in Xin Jiang who originated in the province of He Nan, county Wu Yang. Based on the FPLC-CNBr peptide profiles of the variant and normal albumins, the mutated CNBr peptide of the variant was found. Both the mutated and corresponding normal CNBr peptides were further subjected to trypsin digestion. An additional peptide peak from the mutated CNBr peptide was found in the HPLC mapping. The amino acid sequence of this peptide was determined to be Gly-Val-Phe-His-Arg corresponding to the fragment of albumin propeptide from position -5 to -1 with an -2 Arg-->His mutation. The N-terminal sequence of the mutated CNBr peptide was also determined to be Arg-Gly-Val-Phe-His*-Arg-Asp-Ala-His-Lys-, namely the N-terminal part of the mutated proalbumin. According to the known genomic structure of proalbumin, the gene fragments neighbouring the propeptide DNA sequences of the normal and variant albumins were amplified in vitro by polymerase chain reaction. The PCR products with 390 bp were then cloned into M13 vector, respectively. The nucleotide sequence analyses demonstrated that the codon CGT for -2 Arg was mutated to CAT for His. Thus, the point substitution was confirmed both at protein and gene levels. The above genetic variant of albumin was named proalbumin Wu Yang (-2 Arg-->His) being the first instance of the Lille type found in China.

Adolescent↗
PubMed2005

Global epithelial cell transcriptional responses reveal Streptococcus pyogenes Fas regulator activity association with bacterial aggressiveness.

The bacterial human pathogen Streptococcus pyogenes (group A streptococci, GAS) is able to adhere to, internalize into and cross-talk on multiple levels with its host cells. To gain insight into the Fas function in pathogenesis we used Affymetrix human genome DNA-arrays to measure temporal and global transcriptional responses of HEp-2 cells infected with M49 S. pyogenes wild-type bacteria and DeltafasX, an isogenic S. pyogenes two-component-signal-transduction system mutant. A modified stringent statistical analysis method identified a total of 86 HEp-2 cell genes as differentially transcribed upon infection over the investigated time course. Increased expression of genes encoding proteins involved in GAS host cell adherence and internalization (fibronectin, integrin-alpha5) was found as a common response. In contrast to earlier reports investigating other GAS serotype strains, Ras superfamily and RhoA pathways are exploited by M49 GAS, suggesting serotype specific interactions with the host cell cytoskeleton. Despite transcriptional induction, secreted IL-8 levels of deltafasX mutant infected cells were below those of non-infected cells, indicating an absence of Fas expression could be important for GAS tissue colonization and long-term intracellular persistence. Oppositely, activity of the S. pyogenes Fas-system apparently promotes high adherence and internalization rates, massive cytokine gene transcription and cytokine release, host cell apoptosis via a caspase-2 activation pathway, and cytotoxicity. Thus, the S. pyogenes Fas two-component signal transduction system could be involved in local tissue destruction and general bacterial aggressiveness towards host cells.

Apoptosis↗
PubMed1989

The thiol-activated toxin streptolysin O does not require a thiol group for cytolytic activity.

Site-directed mutagenesis of the TGC codon in a cloned streptolysin O (SLO) gene exchanged the single Cys residue in SLO for either Ala or Ser. The parent wild-type SLO (SLO.Cys-530) and the SLO.Ala-530 and SLO.Ser-530 mutant toxins, expressed in Escherichia coli, were purified and analyzed. Wild-type SLO.Cys-530 and the SLO.Ala-530 mutant showed no significant differences in their specific hemolytic activities, while the SLO.Ser-530 mutant had a reduced (ca. 25%), but still considerable, specific hemolytic activity as compared with that of wild-type SLO. The parent and mutant toxins extracted from lysed erythrocyte membranes had similar sedimentation profiles on sucrose density gradients, suggesting that the mutations did not affect the ability of SLO to form oligomers in membranes. These results show that the widely held assumption that the in vitro cytolytic activity of SLO requires an essential Cys residue is not true.

Amino Acid Sequence↗
PubMed2002

Differential regulation of the Bordetella bipA gene: distinct roles for different BvgA binding sites.

The BvgAS signal transduction system of Bordetella controls an entire spectrum of gene expression states in response to differences in environmental conditions. In particular, the Bordetella Bvg-intermediate-phase gene bipA displays a complex regulatory pattern in response to various concentrations of modulators. Expression of bipA is low in the absence of modulating signals, maximal at intermediate concentrations of modulators, and near background levels at high concentrations of modulators. bipA is regulated at the transcriptional level, and the bipA promoter contains multiple BvgA binding sites present both upstream and downstream of the transcriptional initiation site. In vivo transcriptional analyses, utilizing several mutant promoter fusions to the reporter enzyme beta-galactosidase, suggest that the upstream binding site IR1 is essential for expression and that the downstream binding sites IR2 and IR3 are involved in transcriptional repression. Mutations of IR2 or IR3 convert the expression profile of bipA from that of a Bvg-intermediate-specific-phase gene to that of a Bvg(+)-phase gene. To gain insight into the mechanism responsible for differential bipA regulation, DNase I protection studies were conducted with various mutant promoters. These analyses suggest that IR1 and IR2 function as core binding sites and are the primary determinants for the phosphorylation-induced oligomerization of BvgA to the adjacent regions.

Bacterial Outer Membrane Proteins↗