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PubMed2006

Functional mapping in pea, as an aid to the candidate gene selection and for investigating synteny with the model legume Medicago truncatula.

The identification of the molecular polymorphisms giving rise to phenotypic trait variability-both quantitative and qualitative-is a major goal of the present agronomic research. Various approaches such as positional cloning or transposon tagging, as well as the candidate gene strategy have been used to discover the genes underlying this variation in plants. The construction of functional maps, i.e. composed of genes of known function, is an important component of the candidate gene approach. In the present paper we report the development of 63 single nucleotide polymorphism markers and 15 single-stranded conformation polymorphism markers for genes encoding enzymes mainly involved in primary metabolism, and their genetic mapping on a composite map using two pea recombinant inbred line populations. The complete genetic map covers 1,458 cM and comprises 363 loci, including a total of 111 gene-anchored markers: 77 gene-anchored markers described in this study, 7 microsatellites located in gene sequences, 16 flowering time genes, the Tri gene, 5 morphological markers, and 5 other genes. The mean spacing between adjacent markers is 4 cM and 90% of the markers are closer than 10 cM to their neighbours. We also report the genetic mapping of 21 of these genes in Medicago truncatula and add 41 new links between the pea and M. truncatula maps. We discuss the use of this new composite functional map for future candidate gene approaches in pea.

Chromosome Mapping↗
PubMed1996

Genetic activity profiles of anticancer drugs.

The results from short-term tests for genetic and related effects, abstracted from the open literature for 36 anticancer drugs, are examined in this review. Data for 27 of these agents are available in the EPA/IARC Genetic Activity Profile (GAP) database. Data summaries, including data listings and activity profiles, are presented for nine anticancer drugs added to the GAP database for this analysis. Genetic toxicity data from the recent literature are included for the additional agents to provide a broader representation of the categories of drugs being evaluated. These categories, based on the chemical mode of action, are covalent and noncovalent DNA-binding drugs, topoisomerase II inhibitors, antimetabolites, mitotic spindle inhibitors, and drugs which affect endocrine function. The qualitative data for all 36 drugs are summarized in this report and findings are presented from pair-wise matching of genetic activity profiles, based on test results in common, for some chemical analogs. The significance of germ cell test results for some of these drugs and their implication in assessing risk of heritable genetic disease are discussed.

Animals↗
PubMedDate not supplied

Variable selection and interpretation in structure-affinity correlation modeling of estrogen receptor binders.

A computational approach for the identification and investigation of correlations between a chemical structure and a selected biological property is described. It is based on a set of 132 compounds of known chemical structures, which were tested for their binding affinities to the estrogen receptor. Different multivariate modeling methods, i.e., partial least-squares regression, counterpropagation neural network, and error-back-propagation neural network, were applied, and the prediction ability of each model was tested in order to compare the results of the obtained models. To reduce the extensive set of calculated structural descriptors, two types of variable selection methods were applied, depending on the modeling approach used. In particular, the final partial least-squares regression model was built using the "variable importance in projection" variable selection method, while genetic algorithms were applied in neural network modeling to select the optimal set of descriptors. A thorough statistical study of the variables selected by genetic algorithms is shown. The results were assessed with the aim to get insight to the mechanisms involved in the binding of estrogenic compounds to the receptor. The variable selection on the basis of genetic algorithm was controlled with the test set of compounds, extracted from the data set available. To compare the predictive ability of all the optimized models, a leave-one-out cross-validation procedure was applied, the best model being the nonlinear neural network model based on error back-propagation algorithm, which resulted in R2= 92.2% and Q2= 70.8%.

Algorithms↗
PubMed2006

Assessment of automated genotyping protocols as tools for surveillance of HIV-1 genetic diversity.

BACKGROUND: The routine use of drug resistance testing provides an abundant source of HIV-1 sequence data. However, it is not clear how reliable standard genotyping of these sequences is for describing HIV-1 genetic variation and for detecting novel genetic variants and epidemiological trends. OBJECTIVES: To compare assignment of HIV-1 resistance test sequences to reference strains across commonly used genotyping protocols. METHODS: Subtype assignments were compared across three standard genotyping protocols for 10 537 resistance test sequences, representing approximately one-fifth of all reported infections in the United Kingdom. Sequences that were inconsistently genotyped across methods, or that were unassigned by at least one method, were examined for evidence of recombination using sliding-window-based approaches. RESULTS: Although agreement across methods was high for subtypes B, C and H, it was generally much lower (< 50%) for other subtypes. Disagreement between methods typically involved closely related, but epidemiologically distinct, groups or involved a significant proportion ( approximately 12%) of divergent sequences in which analysis revealed widespread evidence of recombination and a remarkable diversity of unusual recombinant forms. CONCLUSIONS: With frequent long-distance transfer of viral strains and widespread recombination between them, genetic and epidemiological relationships within HIV-1 are becoming increasingly complex. Current methods of subtype assignment vary in their ability to identify novel genetic variants and to distinguish epidemiologically distinct strains. Capturing meaningful epidemiological information from resistance test data will require a critical understanding of the methodologies used in order to appreciate the possible sources of error and misclassification.

Databases, Genetic↗
PubMed2000

Bioinformatics tools for whole genomes.

The advent of whole-genome data resources--not only sequence but also other genome-scale data collections such as gene expression, protein interaction, and genetic variation--is having two marked, complementary effects on the relatively new discipline of bioinformatics. First, the veritable flood of data is creating a need and demand for new tools for dealing adequately with the deluge, and, second, the unprecedented extent, diversity, and impending completeness of the data sets are creating opportunities for new approaches to discovery based on computational methods.

Algorithms↗
PubMed2004

Ancient adaptive evolution of the primate antiviral DNA-editing enzyme APOBEC3G.

Host genomes have adopted several strategies to curb the proliferation of transposable elements and viruses. A recently discovered novel primate defense against retroviral infection involves a single-stranded DNA-editing enzyme, APOBEC3G, that causes hypermutation of HIV. The HIV-encoded virion infectivity factor (Vif) protein targets APOBEC3G for destruction, setting up a genetic conflict between the APOBEC3G and Vif genes. This kind of conflict leads to rapid fixation of mutations that alter amino acids at the protein-protein interface, referred to as positive selection. We show that the APOBEC3G gene has been subject to strong positive selection throughout the history of primate evolution. Unexpectedly, this selection appears more ancient than, and is likely only partially caused by, modern lentiviruses. Furthermore, five additional APOBEC genes in the human genome appear to be engaged in similar genetic conflicts, displaying some of the highest signals for positive selection in the human genome. Despite being only recently discovered, editing of RNA and DNA may thus represent an ancient form of host defense in primate genomes.

APOBEC Deaminases↗
PubMed2006

Comparison of gene coverage of mouse oligonucleotide microarray platforms.

BACKGROUND: The increasing use of DNA microarrays for genetical genomics studies generates a need for platforms with complete coverage of the genome. We have compared the effective gene coverage in the mouse genome of different commercial and noncommercial oligonucleotide microarray platforms by performing an in-house gene annotation of probes. We only used information about probes that is available from vendors and followed a process that any researcher may take to find the gene targeted by a given probe. In order to make consistent comparisons between platforms, probes in each microarray were annotated with an Entrez Gene id and the chromosomal position for each gene was obtained from the UCSC Genome Browser Database. Gene coverage was estimated as the percentage of Entrez Genes with a unique position in the UCSC Genome database that is tested by a given microarray platform. RESULTS: A MySQL relational database was created to store the mapping information for 25,416 mouse genes and for the probes in five microarray platforms (gene coverage level in parenthesis): Affymetrix430 2.0 (75.6%), ABI Genome Survey (81.24%), Agilent (79.33%), Codelink (78.09%), Sentrix (90.47%); and four array-ready oligosets: Sigma (47.95%), Operon v.3 (69.89%), Operon v.4 (84.03%), and MEEBO (84.03%). The differences in coverage between platforms were highly conserved across chromosomes. Differences in the number of redundant and unspecific probes were also found among arrays. The database can be queried to compare specific genomic regions using a web interface. The software used to create, update and query the database is freely available as a toolbox named ArrayGene. CONCLUSION: The software developed here allows researchers to create updated custom databases by using public or proprietary information on genes for any organisms. ArrayGene allows easy comparisons of gene coverage between microarray platforms for any region of the genome. The comparison presented here reveals that the commercial microarray Sentrix, which is based on the MEEBO public oligoset, showed the best mouse genome coverage currently available. We also suggest the creation of guidelines to standardize the minimum set of information that vendors should provide to allow researchers to accurately evaluate the advantages and disadvantages of using a given platform.

Animals↗
PubMed2002

Functional genomics of the social amoebae, Dictyostelium discoideum.

Dictyostelium discoideum is one of the simplest organisms to form a multicellular structure, and it offers several advantages as a model. In order to understand the genetic basis of the multicellular development, a comprehensive analysis of cDNAs is being performed. To date, about 75,000 ESTs have been collected at different stages of development. They have been assembled into about 6,400 independent sequences that represent 70-80% of all of the expected genes in D. discoideum. The results are available on the Internet. In addition to structural analyses, functional analyses of the temporal and spatial expression patterns and gene targeting are being carried out. Furthermore, there are plans to combine the information that is obtained from the cDNA, Genome, and Proteome Projects, as well as the published results, into an integrated database, DictyBase.

Animals↗
PubMed2005

Multiple-locus variable number tandem repeats analysis for genetic fingerprinting of pathogenic bacteria.

DNA fingerprinting has attracted considerable interest as means for identifying, tracing and preventing the dissemination of infectious agents. Various methods have been developed for typing of pathogenic bacteria, which differ in discriminative power, reproducibility and ease of interpretation. During recent years a typing method, which uses the information provided by whole genome sequencing of bacterial species, has gained increased attention. Short sequence repeat (SSR) motifs are known to undergo frequent variation in the number of repeated units through cellular mechanisms most commonly active during chromosome replication. A class of SSRs, named variable number of tandem repeats (VNTRs), has proven to be a suitable target for assessing genetic polymorphisms within bacterial species. This review attempts to give an overview of bacterial agents where VNTR-based typing, or multiple-locus variant-repeat analysis (MLVA) has been developed for typing purposes, together with addressing advantages and drawbacks associated with the use of tandem repeated DNA motifs as targets for bacterial typing and identification.

Bacillus anthracis↗
PubMed2006

Phylogenetic profiles for the prediction of protein-protein interactions: how to select reference organisms?

The phylogenetic profile method has been widely applied in the prediction of protein-protein interactions (PPIs). Studies often use all of the available complete genomes for this method. With more than 400 genomes complete and new ones on the horizon, it remains unclear how to select reference organisms for profile construction and then influence the PPI prediction. Here, we performed a systematic assessment of reference organism selection from 225 complete genomes with their evolutionary tree. Our results suggest that reference organisms should be selected from moderately and highly genetically distant organisms, from all three domains (Bacteria, Archaea, and Eukarya), and by their even distribution at the fifth hierarchical level in the evolutionary tree. Our study provides important guidance on the construction of phylogenetic profiles for PPI prediction and functional genomics, which has become challenging due to the large and increasing number of available candidate organisms.

Algorithms↗
PubMed2005

Calculation of multipoint likelihoods using flanking marker data: a simulation study.

The calculation of multipoint likelihoods is computationally challenging, with the exact calculation of multipoint probabilities only possible on small pedigrees with many markers or large pedigrees with few markers. This paper explores the utility of calculating multipoint likelihoods using data on markers flanking a hypothesized position of the trait locus. The calculation of such likelihoods is often feasible, even on large pedigrees with missing data and complex structures. Performance characteristics of the flanking marker procedure are assessed through the calculation of multipoint heterogeneity LOD scores on data simulated for Genetic Analysis Workshop 14 (GAW14). Analysis is restricted to data on the Aipotu population on chromosomes 1, 3, and 4, where chromosomes 1 and 3 are known to contain disease loci. The flanking marker procedure performs well, even when missing data and genotyping errors are introduced.

Chromosome Mapping↗
PubMed2004

Loss of heterozygosity analysis of benign, atypical, and anaplastic meningiomas.

OBJECTIVE: Up to 70% of typical meningiomas demonstrate allelic loss at chromosome 22q. Allelic loss at additional chromosomal loci is associated with atypia and anaplasia in meningiomas. The pattern of allelic loss or loss of heterozygosity (LOH) follows a nonrandom, multistep pattern. METHODS: All surgical meningioma samples obtained from 1991 to 1992 at the University of Pittsburgh Medical Center were analyzed according to current World Health Organization criteria. Samples without constitutional deoxyribonucleic acid (DNA) were excluded from this analysis. Individual hematoxylin and eosin slides from 43 patients were microdissected, and the DNA was harvested and amplified in the presence of 24 pairs of polymerase chain reaction primers, representing 24 microsatellite loci. The polymerase chain reaction products were subjected to capillary gel electrophoresis and a fluorescence-based DNA analysis system. LOH was defined as ratios of allelic peak heights falling within a conservative threshold of less than 0.5 or more than 2.0. Fisher's exact test and receiver operator characteristic curves were used to test the relationship between benign versus atypical and malignant pathological features and LOH at specific loci or combinations of loci. RESULTS: On review by two independent pathologists, 34 benign meningiomas, 6 atypical meningiomas, and 3 anaplastic meningiomas were identified. The mean number of alleles with LOH was 1.5 +/- 1.2 for benign meningiomas, 6.7 +/- 2.7 for atypical meningiomas, and 8.3 +/- 2.3 for anaplastic meningiomas (P < 0.001). The most important individual loci to predict malignancy were D1S407 (P = 0.006), L-myc (P < 0.001), D10S520 (P = 0.003), D10S1173 (P = 0.042), D11S1920 (P < 0.001), D14S555 (P = 0.041), D17S1289 (P < 0.001), D22S417 (P = 0.001), D22S431 (P = 0.019), and D22S532 (P = 0.028). Combining the LOH data across loci, the area under the receiver operator characteristic curve was 0.993, corresponding to virtually perfect prediction of pathological characteristics. CONCLUSION: Microsatellite marker analysis of allelic loss is a useful method of predicting atypia and anaplasia in meningiomas. More regions of allelic loss are seen in anaplastic and atypical meningiomas as compared with benign meningiomas. This study confirms previously reported chromosomal regions of allelic loss in atypical and anaplastic meningiomas and suggests additional chromosomal regions that may represent heretofore uncharacterized deletions within meningiomas. This type of genetic fingerprint ultimately may serve both a diagnostic and therapeutic role.

Alleles↗
PubMed2006

iHAP--integrated haplotype analysis pipeline for characterizing the haplotype structure of genes.

BACKGROUND: The advent of genotype data from large-scale efforts that catalog the genetic variants of different populations have given rise to new avenues for multifactorial disease association studies. Recent work shows that genotype data from the International HapMap Project have a high degree of transferability to the wider population. This implies that the design of genotyping studies on local populations may be facilitated through inferences drawn from information contained in HapMap populations. RESULTS: To facilitate analysis of HapMap data for characterizing the haplotype structure of genes or any chromosomal regions, we have developed an integrated web-based resource, iHAP. In addition to incorporating genotype and haplotype data from the International HapMap Project and gene information from the UCSC Genome Browser Database, iHAP also provides capabilities for inferring haplotype blocks and selecting tag SNPs that are representative of haplotype patterns. These include block partitioning algorithms, block definitions, tag SNP definitions, as well as SNPs to be "force included" as tags. Based on the parameters defined at the input stage, iHAP performs on-the-fly analysis and displays the result graphically as a webpage. To facilitate analysis, intermediate and final result files can be downloaded. CONCLUSION: The iHAP resource, available at http://ihap.bii.a-star.edu.sg, provides a convenient yet flexible approach for the user community to analyze HapMap data and identify candidate targets for genotyping studies.

Algorithms↗
PubMed2005

The THAP domain of THAP1 is a large C2CH module with zinc-dependent sequence-specific DNA-binding activity.

We have recently described an evolutionarily conserved protein motif, designated the THAP domain, which defines a previously uncharacterized family of cellular factors (THAP proteins). The THAP domain exhibits similarities to the site-specific DNA-binding domain of Drosophila P element transposase, including a putative metal-coordinating C2CH signature (CX(2-4)CX(35-53)CX(2)H). In this article, we report a comprehensive list of approximately 100 distinct THAP proteins in model animal organisms, including human nuclear proapoptotic factors THAP1 and DAP4/THAP0, transcriptional repressor THAP7, zebrafish orthologue of cell cycle regulator E2F6, and Caenorhabditis elegans chromatin-associated protein HIM-17 and cell-cycle regulators LIN-36 and LIN-15B. In addition, we demonstrate the biochemical function of the THAP domain as a zinc-dependent sequence-specific DNA-binding domain belonging to the zinc-finger superfamily. In vitro binding-site selection allowed us to identify an 11-nucleotide consensus DNA-binding sequence specifically recognized by the THAP domain of human THAP1. Mutations of single nucleotide positions in this sequence abrogated THAP-domain binding. Experiments with the zinc chelator 1,10-o-phenanthroline revealed that the THAP domain is a zinc-dependent DNA-binding domain. Site-directed mutagenesis of single cysteine or histidine residues supported a role for the C2CH motif in zinc coordination and DNA-binding activity. The four other conserved residues (P, W, F, and P), which define the THAP consensus sequence, were also found to be required for DNA binding. Together with previous genetic data obtained in C. elegans, our results suggest that cellular THAP proteins may function as zinc-dependent sequence-specific DNA-binding factors with roles in proliferation, apoptosis, cell cycle, chromosome segregation, chromatin modification, and transcriptional regulation.

Amino Acid Motifs↗
PubMed1998

A gene for autosomal recessive limb-girdle muscular dystrophy in Manitoba Hutterites maps to chromosome region 9q31-q33: evidence for another limb-girdle muscular dystrophy locus.

Characterized by proximal muscle weakness and wasting, limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of clinical disorders. Previous reports have documented either autosomal dominant or autosomal recessive modes of inheritance, with genetic linkage studies providing evidence for the existence of at least 12 distinct loci. Gene products have been identified for five genes responsible for autosomal recessive forms of the disorder. We performed a genome scan using pooled DNA from a large Hutterite kindred in which the affected members display a mild form of autosomal recessive LGMD. A total of 200 markers were used to screen pools of DNA from patients and their siblings. Linkage between the LGMD locus and D9S302 (maximum LOD score 5.99 at recombination fraction .03) was established. Since this marker resides within the chromosomal region known to harbor the gene causing Fukuyama congenital muscular dystrophy (FCMD), we expanded our investigations, to include additional markers in chromosome region 9q31-q34.1. Haplotype analysis revealed five recombinations that place the LGMD locus distal to the FCMD locus. The LGMD locus maps close to D9S934 (maximum multipoint LOD score 7.61) in a region that is estimated to be approximately 4.4 Mb (Genetic Location Database composite map). On the basis of an inferred ancestral recombination, the gene may lie in a 300-kb region between D9S302 and D9S934. Our results provide compelling evidence that yet another gene is involved in LGMD; we suggest that it be named "LGMD2H."

Chromosome Mapping↗
PubMed2006

ISAG/IUIS-VIC Comparative MHC Nomenclature Committee report, 2005.

Nomenclature for Major Histocompatibility Complex (MHC) genes and alleles in species other than humans and mice has historically been overseen either informally by groups generating sequences, or by formal nomenclature committees set up by the International Society for Animal Genetics (ISAG). The suggestion for a Comparative MHC Nomenclature Committee was made at the ISAG meeting held in Göttingen, Germany (2002), and the committee met for the first time at the Institute for Animal Health, Compton, UK in January 2003. To publicize its activity and extend its scope, the committee organized a workshop at the International Veterinary Immunology Symposium (IVIS) in Quebec (2004) where it was decided to affiliate with the Veterinary Immunology Committee (VIC) of the International Union of Immunological Societies (IUIS). The goals of the committee are to establish a common framework and guidelines for MHC nomenclature in any species; to demonstrate this in the form of a database that will ensure that in the future, researchers can easily access a source of validated MHC sequences for any species; to facilitate discussion on this area between existing groups and nomenclature committees. A further meeting of the committee was held in September 2005 in Glasgow, UK. This was attended by most of the existing committee members with some additional invited participants (Table 1). The aims of this meeting were to facilitate the inclusion of new species onto the database, to discuss extension, improvement and funding of the database, and to address a number of nomenclature issues raised at the previous workshop.

Advisory Committees↗
PubMed2006

Tackling community concerns about commercialisation and genetic research: a modest interdisciplinary proposal.

In recent years, there has been a rise in the creation of DNA databases promising a range of health benefits to individuals and populations. This development has been accompanied by an interest in, and concern for the ethical, legal and social aspects of such collections. In terms of policy solutions, much of the focus of these debates has been on issues of consent, confidentiality and research governance. However, there are broader concerns, such as those associated with commercialisation, which cannot be adequately addressed by these foci. In this article, we focus on the health-wealth benefits that DNA databases promise by considering the views of 10 focus groups on Generation Scotland, Scotland's first national genetic database. As in previous studies, our qualitative research on public/s and stakeholders' views of DNA databases show the prospect of utilising donated samples and information derived for wealth-related ends (i.e. for private profit), irrespective of whether there is an associated health-related benefit, arouses considerable reaction. While health-wealth benefits are not mutually exclusive ideals, the tendency has been to cast 'public' benefits as exclusively health-related, while 'private' commercial benefits for funders and/or researchers are held out as a necessary pay-off. We argue for a less polarised approach that reconsiders what is meant by 'public benefits' and questions the exclusivity of commercial interests. We believe accommodation can be achieved via the mobilisation of a grass roots solution known as 'benefit-sharing' or a 'profit pay-off'. We propose a sociologically informed model that has a pragmatic, legal framework, which responds seriously to public concerns.

Commerce↗
PubMed2004

BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer.

In order to evaluate the role of BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer, 97 patients with sporadic breast cancer were analyzed for mutations in the BRCA1 and BRCA2 coding regions, by using a combination of fluorescent-conformation sensitive gel electrophoresis (F-CSGE) and direct sequencing. Fifty-five distinct sequence variants were detected, which included three pathogenic truncating mutations, 15 missense mutations, 16 polymorphisms, and 21 intronic variants. Twenty-six of these variants have never been previously reported and may be of Korean-specific origin. Two pathogenic BRCA1 mutations (c.922_924delinsT, c.5445G>A) and one pathogenic BRCA2 mutation (c.2259delT) were observed, and two of these (BRCA1 c.5445G>A and BRCA2 c.2259delT) are novel. The total prevalence of germline pathogenic mutations in BRCA1 and/or BRCA2 in Korean sporadic breast cancer is estimated to be about 3.1%. Considering that the majority of breast cancer cases are sporadic, the present study will be helpful in the evaluation of the need for the genetic screening of germline BRCA mutations in sporadic breast cancer patients. Further study using a larger sample size is required to determine the merits of genetic diagnosis and counseling in breast cancer patients.

Adult↗