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PubMed2001

Inferring subnetworks from perturbed expression profiles.

Genome-wide expression profiles of genetic mutants provide a wide variety of measurements of cellular responses to perturbations. Typical analysis of such data identifies genes affected by perturbation and uses clustering to group genes of similar function. In this paper we discover a finer structure of interactions between genes, such as causality, mediation, activation, and inhibition by using a Bayesian network framework. We extend this framework to correctly handle perturbations, and to identify significant subnetworks of interacting genes. We apply this method to expression data of S. cerevisiae mutants and uncover a variety of structured metabolic, signaling and regulatory pathways.

Bayes Theorem↗
PubMed2005

Disease gene discovery through integrative genomics.

The availability of complete genome sequences and the wealth of large-scale biological data sets now provide an unprecedented opportunity to elucidate the genetic basis of rare and common human diseases. Here we review some of the emerging genomics technologies and data resources that can be used to infer gene function to prioritize candidate genes. We then describe some computational strategies for integrating these large-scale data sets to provide more faithful descriptions of gene function, and how such approaches have recently been applied to discover genes underlying Mendelian disorders. Finally, we discuss future prospects and challenges for using integrative genomics to systematically discover not only single genes but also entire gene networks that underlie and modify human disease.

Databases, Genetic↗
PubMed2006

Finding biological process modifications in cancer tissues by mining gene expression correlations.

BACKGROUND: Through the use of DNA microarrays it is now possible to obtain quantitative measurements of the expression of thousands of genes from a biological sample. This technology yields a global view of gene expression that can be used in several ways. Functional insight into expression profiles is routinely obtained by using Gene Ontology terms associated to the cellular genes. In this paper, we deal with functional data mining from expression profiles, proposing a novel approach that studies the correlations between genes and their relations to Gene Ontology (GO). By using this "functional correlations comparison" we explore all possible pairs of genes identifying the affected biological processes by analyzing in a pair-wise manner gene expression patterns and linking correlated pairs with Gene Ontology terms. RESULTS: We apply here this "functional correlations comparison" approach to identify the existing correlations in hepatocarcinoma (161 microarray experiments) and to reveal functional differences between normal liver and cancer tissues. The number of well-correlated pairs in each GO term highlights several differences in genetic interactions between cancer and normal tissues. We performed a bootstrap analysis in order to compute false detection rates (FDR) and confidence limits. CONCLUSION: Experimental results show the main advantage of the applied method: it both picks up general and specific GO terms (in particular it shows a fine resolution in the specific GO terms). The results obtained by this novel method are highly coherent with the ones proposed by other cancer biology studies. But additionally they highlight the most specific and interesting GO terms helping the biologist to focus his/her studies on the most relevant biological processes.

Carcinoma, Hepatocellular↗
PubMed2006

DNA barcoding Korean birds.

DNA barcoding, an inventory of DNA sequences from a standardized genomic region, provides a bio-barcode for identifying and discovering species. Several recent studies suggest that the sequence diversity in a 648 bp region of the mitochondrial gene for cytochrome c oxi- dase I (COI) might serve as a DNA barcode for identify- ing animal species such as North American birds, in- sects and fishes. The present study tested the effective- ness of a COI barcode in discriminating Korean bird species. We determined the 5' terminus of the COI bar- code for 92 species of Korean birds and found that spe- cies identification was unambiguous; the genetic differ- ences between closely related species were, on average, 25 times higher than the differences within species. We identified only one misidentified species out of 239 specimens in a genetic resource bank, so confirming the accuracy of species identification in the banking system. We also identified two potential composite species, calling for further investigation using more samples. The finding of large COI sequence differences between species confirms the effectiveness of COI barcodes for identifying Korean bird species. To bring greater reliability to the identification of species, increased in- tra- and interspecies sampling, as well as supplementa- tion of the mitochondrial barcodes with nuclear ones, is needed.

Animals↗
PubMed2006

Polyphasic analysis of Thermus isolates from geothermal areas in Iceland.

Genetic relationships and diversity of 101 Thermus isolates from different geothermal regions in Iceland were investigated by using multilocus enzyme electrophoresis (MLEE) and small subunit ribosomal rRNA (SSU rRNA) sequence analysis. Ten polymorphic enzymes were used and seven distinct and genetically highly divergent lineages of Thermus were observed. Six of seven lineages could be assigned to species whose names have been validated. The most diverse lineage was Thermus scotoductus. In contrast to the other lineages, this lineage was divided into very distinct genetic sublineages that may represent subspecies with different habitat preferences. The least diverse lineage was Thermus brockianus. Phenotypic and physiological analysis was carried out on a subset of the isolates. No relationship was found between growth on specific single carbon source to the grouping obtained by the isoenzyme analysis. The response to various salts was distinguishing in a few cases. No relationship was found between temperature at the isolation site and the different lineages, but pH indicated a relation to specific lineages.

Adaptation, Physiological↗
PubMed2005

FlyBase: genes and gene models.

FlyBase (http://flybase.org) is the primary repository of genetic and molecular data of the insect family Drosophilidae. For the most extensively studied species, Drosophila melanogaster, a wide range of data are presented in integrated formats. Data types include mutant phenotypes, molecular characterization of mutant alleles and aberrations, cytological maps, wild-type expression patterns, anatomical images, transgenic constructs and insertions, sequence-level gene models and molecular classification of gene product functions. There is a growing body of data for other Drosophila species; this is expected to increase dramatically over the next year, with the completion of draft-quality genomic sequences of an additional 11 Drosophila species.

Animals↗
PubMed2004

Ethical implications of pharmacogenetics--do slippery slope arguments matter?

Pharmacogenetics is a rapidly expanding area of research exploring the relationship between inter-individual genetic variation and drug response, with the goal of developing genetically optimised therapies. Slippery slope arguments claim that a particular action should be rejected (or supported) because it might be the first step onto a slippery slope leading to undesirable (or desirable) consequences. In this article, several slippery slope arguments relevant to the context of pharmacogenetics are evaluated under consideration of underlying reasons for their popularity. The author concludes that although the examined arguments are unconvincing as slippery slope arguments, they do matter in this context. While positive slippery slope arguments serve as a driving force to fuel the development of pharmacogenetics, their negative counterparts play an important role to sensitise policy makers and the public to potential problems.

Databases, Genetic↗
PubMed2005

EU-OSTID: a collection of transposon insertional mutants for functional genomics in rice.

A collection of 1373 unique flanking sequence tags (FSTs), generated from Ac/Ds and Ac transposon lines for reverse genetics studies, were produced in japonica and indica rice, respectively. The Ds and Ac FSTs together with the original T-DNAs were assigned a position in the rice genome sequence represented as assembled pseudomolecules, and found to be distributed evenly over the entire rice genome with a distinct bias for predicted gene-rich regions. The bias of the Ds and Ac transposon inserts for genes was exemplified by the presence of 59% of the inserts in genes annotated on the rice chromosomes and 41% present in genes transcribed as disclosed by their homology to cDNA clones. In a screen for inserts in a set of 75 well annotated transcription factors, including homeobox-containing genes, we found six Ac/Ds inserts. This high frequency of Ds and Ac inserts in genes suggests that saturated knockout mutagenesis in rice using this strategy will be efficient and possible with a lower number of inserts than expected. These FSTs and the corresponding plant lines are publicly available through OrygenesDB database and from the EU consortium members.

Binding Sites↗
PubMed2005

Global landscape of recent inferred Darwinian selection for Homo sapiens.

By using the 1.6 million single-nucleotide polymorphism (SNP) genotype data set from Perlegen Sciences [Hinds, D. A., Stuve, L. L., Nilsen, G. B., Halperin, E., Eskin, E., Ballinger, D. G., Frazer, K. A. & Cox, D. R. (2005) Science 307, 1072-1079], a probabilistic search for the landscape exhibited by positive Darwinian selection was conducted. By sorting each high-frequency allele by homozygosity, we search for the expected decay of adjacent SNP linkage disequilibrium (LD) at recently selected alleles, eliminating the need for inferring haplotype. We designate this approach the LD decay (LDD) test. By these criteria, 1.6% of Perlegen SNPs were found to exhibit the genetic architecture of selection. These results were confirmed on an independently generated data set of 1.0 million SNP genotypes (International Human Haplotype Map Phase I freeze). Simulation studies indicate that the LDD test, at the megabase scale used, effectively distinguishes selection from other causes of extensive LD, such as inversions, population bottlenecks, and admixture. The approximately 1,800 genes identified by the LDD test were clustered according to Gene Ontology (GO) categories. Based on overrepresentation analysis, several predominant biological themes are common in these selected alleles, including host-pathogen interactions, reproduction, DNA metabolism/cell cycle, protein metabolism, and neuronal function.

Alleles↗
PubMed2006

Argument-predicate distance as a filter for enhancing precision in extracting predications on the genetic etiology of disease.

BACKGROUND: Genomic functional information is valuable for biomedical research. However, such information frequently needs to be extracted from the scientific literature and structured in order to be exploited by automatic systems. Natural language processing is increasingly used for this purpose although it inherently involves errors. A postprocessing strategy that selects relations most likely to be correct is proposed and evaluated on the output of SemGen, a system that extracts semantic predications on the etiology of genetic diseases. Based on the number of intervening phrases between an argument and its predicate, we defined a heuristic strategy to filter the extracted semantic relations according to their likelihood of being correct. We also applied this strategy to relations identified with co-occurrence processing. Finally, we exploited postprocessed SemGen predications to investigate the genetic basis of Parkinson's disease. RESULTS: The filtering procedure for increased precision is based on the intuition that arguments which occur close to their predicate are easier to identify than those at a distance. For example, if gene-gene relations are filtered for arguments at a distance of 1 phrase from the predicate, precision increases from 41.95% (baseline) to 70.75%. Since this proximity filtering is based on syntactic structure, applying it to the results of co-occurrence processing is useful, but not as effective as when applied to the output of natural language processing. In an effort to exploit SemGen predications on the etiology of disease after increasing precision with postprocessing, a gene list was derived from extracted information enhanced with postprocessing filtering and was automatically annotated with GFINDer, a Web application that dynamically retrieves functional and phenotypic information from structured biomolecular resources. Two of the genes in this list are likely relevant to Parkinson's disease but are not associated with this disease in several important databases on genetic disorders. CONCLUSION: Information based on the proximity postprocessing method we suggest is of sufficient quality to be profitably used for subsequent applications aimed at uncovering new biomedical knowledge. Although proximity filtering is only marginally effective for enhancing the precision of relations extracted with co-occurrence processing, it is likely to benefit methods based, even partially, on syntactic structure, regardless of the relation.

Genetic Diseases, Inborn↗
PubMed2006

Integrated maps in quail (Coturnix japonica) confirm the high degree of synteny conservation with chicken (Gallus gallus) despite 35 million years of divergence.

BACKGROUND: By comparing the quail genome with that of chicken, chromosome rearrangements that have occurred in these two galliform species over 35 million years of evolution can be detected. From a more practical point of view, the definition of conserved syntenies helps to predict the position of genes in quail, based on information taken from the chicken sequence, thus enhancing the utility of this species in biological studies through a better knowledge of its genome structure. A microsatellite and an Amplified Fragment Length Polymorphism (AFLP) genetic map were previously published for quail, as well as comparative cytogenetic data with chicken for macrochromosomes. Quail genomics will benefit from the extension and the integration of these maps. RESULTS: The integrated linkage map presented here is based on segregation analysis of both anonymous markers and functional gene loci in 1,050 quail from three independent F2 populations. Ninety-two loci are resolved into 14 autosomal linkage groups and a Z chromosome-specific linkage group, aligned with the quail AFLP map. The size of linkage groups ranges from 7.8 cM to 274.8 cM. The total map distance covers 904.3 cM with an average spacing of 9.7 cM between loci. The coverage is not complete, as macrochromosome CJA08, the gonosome CJAW and 23 microchromosomes have no marker assigned yet. Significant sequence identities of quail markers with chicken enabled the alignment of the quail linkage groups on the chicken genome sequence assembly. This, together with interspecific Fluorescence In Situ Hybridization (FISH), revealed very high similarities in marker order between the two species for the eight macrochromosomes and the 14 microchromosomes studied. CONCLUSION: Integrating the two microsatellite and the AFLP quail genetic maps greatly enhances the quality of the resulting information and will thus facilitate the identification of Quantitative Trait Loci (QTL). The alignment with the chicken chromosomes confirms the high conservation of gene order that was expected between the two species for macrochromosomes. By extending the comparative study to the microchromosomes, we suggest that a wealth of information can be mined in chicken, to be used for genome analyses in quail.

Animals↗
PubMed2002

Genomic pathways to antifungal discovery.

The limitations of the therapeutic antifungals are becoming increasingly apparent in the clinic due to their modest efficacy against life-threatening systemic fungal infections. These antifungals belong to only a few structural classes that affect a small range of targets, some are quite toxic in humans while the use of others, particularly the azole drugs, has encouraged the emergence of resistant clinical isolates and the selection of innately resistant fungal pathogens. Only a few new drugs based on novel targets are in clinical development, and these may be insufficient to overcome the changing tide of fungal disease. In parallel with the successful completion of the Saccharomyces cerevisiae and human genome sequencing projects, an increasing number of genome sequencing projects are being initiated and completed for significant fungal pathogens. The growing repository of genomic information, which is complemented by decades of genetic and biochemical study, is now available for genome-wide analysis of gene function and for incisive inter-genomic comparison, with the S. cerevisiae and human genomes providing key points of reference. Functional genomic and comparative genomic techniques, many of which were developed with S. cerevisiae, are being applied to fungal pathogens with the aim of obtaining an integrated view of fungal biology and to extract targets suitable for drug discovery. This review describes some of these techniques, their limitations and their increasing contribution to the antifungal discovery process through effective gene annotation, target identification and prioritization, and in the optimization of antifungal leads.

Antifungal Agents↗
PubMed2005

Ascertainment bias in studies of human genome-wide polymorphism.

Large-scale SNP genotyping studies rely on an initial assessment of nucleotide variation to identify sites in the DNA sequence that harbor variation among individuals. This "SNP discovery" sample may be quite variable in size and composition, and it has been well established that properties of the SNPs that are found are influenced by the discovery sampling effort. The International HapMap project relied on nearly any piece of information available to identify SNPs-including BAC end sequences, shotgun reads, and differences between public and private sequences-and even made use of chimpanzee data to confirm human sequence differences. In addition, the ascertainment criteria shifted from using only SNPs that had been validated in population samples, to double-hit SNPs, to finally accepting SNPs that were singletons in small discovery samples. In contrast, Perlegen's primary discovery was a resequencing-by-hybridization effort using the 24 people of diverse origin in the Polymorphism Discovery Resource. Here we take these two data sets and contrast two basic summary statistics, heterozygosity and F(ST), as well as the site frequency spectra, for 500-kb windows spanning the genome. The magnitude of disparity between these samples in these measures of variability indicates that population genetic analysis on the raw genotype data is ill advised. Given the knowledge of the discovery samples, we perform an ascertainment correction and show how the post-correction data are more consistent across these studies. However, discrepancies persist, suggesting that the heterogeneity in the SNP discovery process of the HapMap project resulted in a data set resistant to complete ascertainment correction. Ascertainment bias will likely erode the power of tests of association between SNPs and complex disorders, but the effect will likely be small, and perhaps more importantly, it is unlikely that the bias will introduce false-positive inferences.

Databases, Genetic↗
PubMed2006

Eye development at the Houston "Fly Meeting".

The 47th Annual Drosophila Research Conference or "Fly Meeting" took place at Houston, Texas, USA from March 29th- April 2nd, 2006, under the aegis of the Genetics Society of America. The Fly Meeting provides an excellent opportunity for fly researchers to present their work and to get a snapshot of recent developments and upcoming trends in their research field. The fruit fly, Drosophila melanogaster is a very versatile model to study growth, patterning, neural development, evolution, systemetics and various other facets of biomedical science. The topics presented in the meeting covered a very broad spectrum of fly research. In this commentary, I have focused mainly on the presentations related to two fields: 1) research in various fields that use the Drosophila eye as a model system, and 2) the community resources available to all fly researchers.

Animals↗
PubMed2003

Refined mapping of the HMSNR critical gene region--construction of a high-density integrated genetic and physical map.

Hereditary motor and sensory neuropathy russe, a form of autosomal recessive Charcot-Marie-Tooth disease, is a rare disorder found in several Roma families from Europe. The gene has been mapped to a 1Mb region on 10q22. Detailed analysis led to the exclusion of 22 candidate genes and the assembly of a high-density genetic map comprising 141 polymorphic markers. Extensive genotyping in an extended sample of affected families resulted in a 10-fold reduction of the critical hereditary motor and sensory neuropathy russe gene region, which is now contained within a single completely sequenced BAC clone. The fact that no sequence variant has been detected in the known genes in the critical region indicates that the hereditary motor and sensory neuropathy russe mutation affects a novel gene that remains to be identified.

Charcot-Marie-Tooth Disease↗
PubMed2005

Heritability, correlations and in silico mapping of locomotor behavior and neurochemistry in inbred strains of mice.

The midbrain dopamine system mediates normal and pathologic behaviors related to motor activity, attention, motivation/reward and cognition. These are complex, quantitative traits whose variation among individuals is modulated by genetic, epigenetic and environmental factors. Conventional genetic methods have identified several genes important to this system, but the majority of factors contributing to the variation remain unknown. To understand these genetic and environmental factors, we initiated a study measuring 21 behavioral and neurochemical traits in 15 common inbred mouse strains. We report trait data, heritabilities and genetic and non-genetic correlations between pheno-types. In general, the behavioral traits were more heritable than neurochemical traits, and both genetic and non-genetic correlations within these trait sets were high. Surprisingly, there were few significant correlations between the behavioral and the individual neurochemical traits. However, striatal serotonin and one measure of dopamine turnover (DOPAC/DA) were highly correlated with most behavioral measures. The variable accounting for the most variation in behavior was mouse strain and not a specific neurochemical measure, suggesting that additional genetic factors remain to be determined to account for these behavioral differences. We also report the prospective use of the in silico method of quantitative trait loci (QTL) analysis and demonstrate difficulties in the use of this method, which failed to detect significant QTLs for the majority of these traits. These data serve as a framework for further studies of correlations between different midbrain dopamine traits and as a guide for experimental cross designs to identify QTLs and genes that contribute to these traits.

Animals↗
PubMed2005

Analysis of alcoholism data using support vector machines.

A supervised learning method, support vector machine, was used to analyze the microsatellite marker dataset of the Collaborative Study on the Genetics of Alcoholism Problem 1 for the Genetic Analysis Workshop 14. Twelve binary-valued phenotype variables were chosen for analyses using the markers from all autosomal chromosomes. Using various polynomial kernel functions of the support vector machine and randomly divided genome regions, we were able to observe the association of some marker sets with the chosen phenotypes and thus reduce the size of the dataset. The successful classifications established with the chosen support vector machine kernel function had high levels of correctness for each prediction, e.g., 96% in the fourfold cross-validations. However, owing to the limited sample data, we were not able to test the predictions of the classifiers in the new sample data.

Alcoholism↗
PubMed2006

A clearing house for diagnostic testing: the solution to ensure access to and use of patented genetic inventions?

In genetic diagnostics, the emergence of a so-called "patent thicket" is imminent. Such an overlapping set of patent rights may have restrictive effects on further research and development of diagnostic tests, and the provision of clinical diagnostic services. Currently, two models that may facilitate access to and use of patented genetic inventions are attracting much debate in various national and international fora: patent pools and clearing houses. In this article, we explore the concept of clearing houses. Several types of clearing houses are identified. First, we describe and discuss two types that would provide access to information on the patented inventions: the information clearing house and the technology exchange clearing house. Second, three types of clearing houses are analysed that not only offer access to information but also provide an instrument to facilitate the use of the patented inventions: the open access clearing house, the standardized licences clearing house and the royalty collection clearing house. A royalty collection clearing house for genetic diagnostic testing would be the most comprehensive as it would serve several functions: identifying patents and patent claims essential to diagnostic testing, matching licensees with licensors, developing and supplying standardized licences, collecting royalties, monitoring whether users respect licensing conditions, and providing dispute resolution services such as mediation and arbitration. In this way, it might function as an effective model for users to facilitate access to and use of the patented inventions. However, it remains to be seen whether patent holders with a strong patent portfolio will be convinced by the advantages of the royalty collection clearing house and be willing to participate.

Access to Information↗