Learning the optimal scale for GWAS through hierarchical SNP aggregation.

BACKGROUND: Genome-Wide Association Studies (GWAS) seek to identify causal genomic variants associated with rare human diseases. The classical statistical approach for detecting these variants is based on univariate hypothesis testing, with healthy individuals being tested against affected individuals at each locus. Given that an individual's genotype is characterized by up to one million SNPs, this approach lacks precision, since it may yield a large number of false positives that can lead to erroneous conclusions about genetic associations with the disease. One way to improve the detection of true genetic associations is to reduce the number of hypotheses to be tested by grouping SNPs. RESULTS: We propose a dimension-reduction approach which can be applied in the context of GWAS by making use of the haplotype structure of the human genome. We compare our method with standard univariate and group-based approaches on both synthetic and real GWAS data. CONCLUSION: We show that reducing the dimension of the predictor matrix by aggregating SNPs gives a greater precision in the detection of associations between the phenotype and genomic regions.

DOMIRE: a web server for identifying structural domains and their neighbors in proteins.

SUMMARY: The DOMIRE web server implements a novel, automatic, protein structural domain assignment procedure based on 3D substructures of the query protein which are also found within structures of a non-redundant protein database. These common 3D substructures are transformed into a co-occurrence matrix that offers a global view of the protein domain organization. Three different algorithms are employed to define structural domain boundaries from this co-occurrence matrix. For each query, a list of structural neighbors and their alignments are provided. DOMIRE, by displaying the protein structural domain organization, can be a useful tool for defining protein common cores and for unravelling the evolutionary relationship between different proteins. AVAILABILITY: http://genome.jouy.inra.fr/domire CONTACT: jean.garnier@jouy.inra.fr.

YeastIP: a database for identification and phylogeny of Saccharomycotina yeasts.

With the advances in sequencing techniques, identification of ascomycetous yeasts to the species level and phylogeny reconstruction increasingly require curated and updated taxonomic information. A specific database with nucleotide sequences of the most common markers used for yeast taxonomy and phylogeny and a user-friendly interface allowing identification, taxonomy and phylogeny of yeasts species was developed. By 1 September 2012, the YeastIP database contained all the described Saccharomycotina species for which sequences used for taxonomy and phylogeny, such as D1/D2 rDNA and ITS, are available. The database interface was developed to provide a maximum of relevant information and data mining tools, including the following features: (1) the blast n program for the sequences of the YeastIP database; (2) easy retrieval of selected sequences; (3) display of the available markers for each selected group of species; and (4) a tool to concatenate marker sequences, including those provided by the user. The concatenation tool allows phylogeny reconstruction through a direct link to the Phylogeny.fr platform. YeastIP is thus a unique database in that it provides taxonomic information and guides users in their taxonomic analyses. YeastIP facilitates multigenic analysis to encourage good practice in ascomycetous yeast phylogeny (URL: http://genome.jouy.inra.fr/yeastip.).

The Transposable Element Environment of Human Genes Differs According to Their Duplication Status and Essentiality.

Transposable elements (TEs) are major components of eukaryotic genomes and represent approximately 45% of the human genome. TEs can be important sources of novelty in genomes and there is increasing evidence that TEs contribute to the evolution of gene regulation in mammals. Gene duplication is an evolutionary mechanism that also provides new genetic material and opportunities to acquire new functions. To investigate how duplicated genes are maintained in genomes, here, we explored the TE environment of duplicated and singleton genes. We found that singleton genes have more short-interspersed nuclear elements and DNA transposons in their vicinity than duplicated genes, whereas long-interspersed nuclear elements and long-terminal repeat retrotransposons have accumulated more near duplicated genes. We also discovered that this result is highly associated with the degree of essentiality of the genes with an unexpected accumulation of short-interspersed nuclear elements and DNA transposons around the more-essential genes. Our results underline the importance of taking into account the TE environment of genes to better understand how duplicated genes are maintained in genomes.

AI-based mobile application to fight antibiotic resistance.

Antimicrobial resistance is a major global health threat and its development is promoted by antibiotic misuse. While disk diffusion antibiotic susceptibility testing (AST, also called antibiogram) is broadly used to test for antibiotic resistance in bacterial infections, it faces strong criticism because of inter-operator variability and the complexity of interpretative reading. Automatic reading systems address these issues, but are not always adapted or available to resource-limited settings. We present an artificial intelligence (AI)-based, offline smartphone application for antibiogram analysis. The application captures images with the phone's camera, and the user is guided throughout the analysis on the same device by a user-friendly graphical interface. An embedded expert system validates the coherence of the antibiogram data and provides interpreted results. The fully automatic measurement procedure of our application's reading system achieves an overall agreement of 90% on susceptibility categorization against a hospital-standard automatic system and 98% against manual measurement (gold standard), with reduced inter-operator variability. The application's performance showed that the automatic reading of antibiotic resistance testing is entirely feasible on a smartphone. Moreover our application is suited for resource-limited settings, and therefore has the potential to significantly increase patients' access to AST worldwide.

FLAGdb++: a database for the functional analysis of the Arabidopsis genome.

FLAGdb++ is dedicated to the integration and visualization of data for high-throughput functional analysis of a fully sequenced genome, as illustrated for Arabidopsis. FLAGdb++ displays the predicted or experimental data in a position-dependent way and displays correlations and relationships between different features. FLAGdb++ provides for a given genome region, summarized characteristics of experimental materials like probe lengths, locations and specificities having an impact upon the confidence we will put in the experimental results. A selected subset of the available information is linked to a locus represented on an easy-to-interpret and memorable graphical display. Data are curated, processed and formatted before their integration into FLAGdb++. FLAGdb++ contains different options for easy back and forth navigation through many loci selected at the start of a session. It includes an original two-component visualization of the data, a genome-wide and a local view, which are permanently linked and display complementary information. Density curves along the chromosomes may be displayed in parallel for suggesting correlations between different structural and functional data. FLAGdb++ is fully accessible at http://genoplante-info.infobiogen.fr/FLAGdb/.

Genome-Wide Study of Structural Variants in Bovine Holstein, Montbéliarde and Normande Dairy Breeds.

High-throughput sequencing technologies have offered in recent years new opportunities to study genome variations. These studies have mostly focused on single nucleotide polymorphisms, small insertions or deletions and on copy number variants. Other structural variants, such as large insertions or deletions, tandem duplications, translocations, and inversions are less well-studied, despite that some have an important impact on phenotypes. In the present study, we performed a large-scale survey of structural variants in cattle. We report the identification of 6,426 putative structural variants in cattle extracted from whole-genome sequence data of 62 bulls representing the three major French dairy breeds. These genomic variants affect DNA segments greater than 50 base pairs and correspond to deletions, inversions and tandem duplications. Out of these, we identified a total of 547 deletions and 410 tandem duplications which could potentially code for CNVs. Experimental validation was carried out on 331 structural variants using a novel high-throughput genotyping method. Out of these, 255 structural variants (77%) generated good quality genotypes and 191 (75%) of them were validated. Gene content analyses in structural variant regions revealed 941 large deletions removing completely one or several genes, including 10 single-copy genes. In addition, some of the structural variants are located within quantitative trait loci for dairy traits. This study is a pan-genome assessment of genomic variations in cattle and may provide a new glimpse into the bovine genome architecture. Our results may also help to study the effects of structural variants on gene expression and consequently their effect on certain phenotypes of interest.

Condition-dependent transcriptome reveals high-level regulatory architecture in Bacillus subtilis.

Bacteria adapt to environmental stimuli by adjusting their transcriptomes in a complex manner, the full potential of which has yet to be established for any individual bacterial species. Here, we report the transcriptomes of Bacillus subtilis exposed to a wide range of environmental and nutritional conditions that the organism might encounter in nature. We comprehensively mapped transcription units (TUs) and grouped 2935 promoters into regulons controlled by various RNA polymerase sigma factors, accounting for ~66% of the observed variance in transcriptional activity. This global classification of promoters and detailed description of TUs revealed that a large proportion of the detected antisense RNAs arose from potentially spurious transcription initiation by alternative sigma factors and from imperfect control of transcription termination.

Exploration of plant genomes in the FLAGdb++ environment.

BACKGROUND: In the contexts of genomics, post-genomics and systems biology approaches, data integration presents a major concern. Databases provide crucial solutions: they store, organize and allow information to be queried, they enhance the visibility of newly produced data by comparing them with previously published results, and facilitate the exploration and development of both existing hypotheses and new ideas. RESULTS: The FLAGdb++ information system was developed with the aim of using whole plant genomes as physical references in order to gather and merge available genomic data from in silico or experimental approaches. Available through a JAVA application, original interfaces and tools assist the functional study of plant genes by considering them in their specific context: chromosome, gene family, orthology group, co-expression cluster and functional network. FLAGdb++ is mainly dedicated to the exploration of large gene groups in order to decipher functional connections, to highlight shared or specific structural or functional features, and to facilitate translational tasks between plant species (Arabidopsis thaliana, Oryza sativa, Populus trichocarpa and Vitis vinifera). CONCLUSION: Combining original data with the output of experts and graphical displays that differ from classical plant genome browsers, FLAGdb++ presents a powerful complementary tool for exploring plant genomes and exploiting structural and functional resources, without the need for computer programming knowledge. First launched in 2002, a 15th version of FLAGdb++ is now available and comprises four model plant genomes and over eight million genomic features.

T-DNA integration into the Arabidopsis genome depends on sequences of pre-insertion sites.

A statistical analysis of 9000 flanking sequence tags characterizing transferred DNA (T-DNA) transformants in Arabidopsis sheds new light on T-DNA insertion by illegitimate recombination. T-DNA integration is favoured in plant DNA regions with an A-T-rich content. The formation of a short DNA duplex between the host DNA and the left end of the T-DNA sets the frame for the recombination. The sequence immediately downstream of the plant A-T-rich region is the master element for setting up the DNA duplex, and deletions into the left end of the integrated T-DNA depend on the location of a complementary sequence on the T-DNA. Recombination at the right end of the T-DNA with the host DNA involves another DNA duplex, 2-3 base pairs long, that preferentially includes a G close to the right end of the T-DNA.