BACKGROUND: Introns are generally removed from primary transcripts to form mature RNA molecules in a post-transcriptional process called splicing. An efficient splicing of primary transcripts is an essential step in gene expression and its misregulation is related to numerous human diseases. Thus, to better understand the dynamics of this process and the perturbations that might be caused by aberrant transcript processing it is important to quantify splicing efficiency. RESULTS: Here, we introduce SPLICE-q, a fast and user-friendly Python tool for genome-wide SPLICing Efficiency quantification. It supports studies focusing on the implications of splicing efficiency in transcript processing dynamics. SPLICE-q uses aligned reads from strand-specific RNA-seq to quantify splicing efficiency for each intron individually and allows the user to select different levels of restrictiveness concerning the introns' overlap with other genomic elements such as exons of other genes. We applied SPLICE-q to globally assess the dynamics of intron excision in yeast and human nascent RNA-seq. We also show its application using total RNA-seq from a patient-matched prostate cancer sample. CONCLUSIONS: Our analyses illustrate that SPLICE-q is suitable to detect a progressive increase of splicing efficiency throughout a time course of nascent RNA-seq and it might be useful when it comes to understanding cancer progression beyond mere gene expression levels. SPLICE-q is available at: https://github.com/vrmelo/SPLICE-q.

Somatic mutations occurring in many cancer types are associated with well-understood processes, such as exposure to tobacco smoking or to ultraviolet (UV) light, but also with mutational processes of so far unknown etiology. Mutational processes can be described in terms of so-called mutational signatures, most often represented as vectors of mutation probabilities which indicate what mutation types are preferentially induced by the mutational processes. In this paper we propose a framework to identify which mutational processes are more likely to harm binding sites of a given transcription factor. Our method starts from the binding site motif and assigns to each mutational signature both a hit score, i.e., the likelihood that the mutational process mutates a binding sequence in at least one nucleotide, and a measure of deleteriousness, i.e., the likelihood that a binding site can be disrupted by mutations belonging to the signature. In a final step, the determined scores can be adjusted according to the strengths with which individual mutational signatures have contributed to the observed mutational load of a tumor. We apply the method to CTCF, a transcription factor that is a core architectural protein dictating the dimensional structure of the genome. Our analysis concentrates on melanoma (skin cancer), for which we show that our framework predicts the disruption of CTCF binding sites by specific UV-light associated mutational signatures, confirming our biological expectations.

BACKGROUND: The somatic mutations found in a tumor have in most cases been caused by multiple mutational processes such as those related to extrinsic carcinogens like cigarette smoke, and those related to intrinsic processes like age-related spontaneous deamination of 5-methylcytosine. The effect of such mutational processes can be modeled by mutational signatures, of which two different conceptualizations exist: the model introduced by Alexandrov et al., Nature 500:415-421, 2013, and the model introduced by Shiraishi et al., PLoS Genetics 11(12):e1005657, 2015. The initial identification and definition of mutational signatures requires large sets of tumor samples. RESULTS: Here, we present decompTumor2Sig, an easy to use R package that can decompose an individual tumor genome into a given set of Alexandrov-type or Shiraishi-type signatures, thus quantifying the contribution of the corresponding mutational processes to the somatic mutations identified in the tumor. Until now, such tools were available only for Alexandrov signatures. We demonstrate the correctness and usefulness of our approach with three test cases, using somatic mutations from 21 breast cancer genomes, from 435 tumor genomes of ten different tumor entities, and from simulated tumor genomes, respectively. CONCLUSIONS: The decompTumor2Sig package is freely available and has been accepted for inclusion in Bioconductor.

MOTIVATION: The computational evaluation of candidate genes for hereditary disorders is a non-trivial task. Several excellent methods for disease-gene prediction have been developed in the past 2 decades, exploiting widely differing data sources to infer disease-relevant functional relationships between candidate genes and disorders. We have shown recently that spatially mapped, i.e. 3D, gene expression data from the mouse brain can be successfully used to prioritize candidate genes for human Mendelian disorders of the central nervous system. RESULTS: We improved our previous work 2-fold: (i) we demonstrate that condition-independent transcription factor binding affinities of the candidate genes' promoters are relevant for disease-gene prediction and can be integrated with our previous approach to significantly enhance its predictive power; and (ii) we define a novel similarity measure-termed Relative Intensity Overlap-for both 3D gene expression patterns and binding affinity profiles that better exploits their disease-relevant information content. Finally, we present novel disease-gene predictions for eight loci associated with different syndromes of unknown molecular basis that are characterized by mental retardation.

MOTIVATION: The identification of genes involved in specific phenotypes, such as human hereditary diseases, often requires the time-consuming and expensive examination of a large number of positional candidates selected by genome-wide techniques such as linkage analysis and association studies. Even considering the positive impact of next-generation sequencing technologies, the prioritization of these positional candidates may be an important step for disease-gene identification. RESULTS: Here, we report a large-scale analysis of spatial, i.e. 3D, gene-expression data from an entire organ (the mouse brain) for the purpose of evaluating and ranking positional candidate genes, showing that the spatial gene-expression patterns can be successfully exploited for the prediction of gene-phenotype associations not only for mouse phenotypes, but also for human central nervous system-related Mendelian disorders. We apply our method to the case of X-linked mental retardation, compare the predictions to the results obtained from a previous large-scale resequencing study of chromosome X and discuss some promising novel candidates.

BACKGROUND: Even in the post-genomic era, the identification of candidate genes within loci associated with human genetic diseases is a very demanding task, because the critical region may typically contain hundreds of positional candidates. Since genes implicated in similar phenotypes tend to share very similar expression profiles, high throughput gene expression data may represent a very important resource to identify the best candidates for sequencing. However, so far, gene coexpression has not been used very successfully to prioritize positional candidates. METHODOLOGY/PRINCIPAL FINDINGS: We show that it is possible to reliably identify disease-relevant relationships among genes from massive microarray datasets by concentrating only on genes sharing similar expression profiles in both human and mouse. Moreover, we show systematically that the integration of human-mouse conserved coexpression with a phenotype similarity map allows the efficient identification of disease genes in large genomic regions. Finally, using this approach on 850 OMIM loci characterized by an unknown molecular basis, we propose high-probability candidates for 81 genetic diseases. CONCLUSION: Our results demonstrate that conserved coexpression, even at the human-mouse phylogenetic distance, represents a very strong criterion to predict disease-relevant relationships among human genes.

Tracing resource usage by Grid users is of utmost importance especially in the context of large-scale scientific collaborations such as within the High Energy Physics (HEP) community to guarantee fairness of resource sharing, but many difficulties can arise when tracing the resource usage of distributed applications over heterogeneous Grid platforms. These difficulties are often related to a lack of interoperability of the accounting components across middlewares. This paper brie y describes the architecture and workflow of the Distributed Grid Accounting System (DGAS) [1] and evaluates the possibility to extend it with a Resource Usage Service (RUS) [2, 3] interface according to the Open Grid Forum (OGF) sped cation that allows to store and retrieve OGF Usage Records (URs) [4, 5] via Web Services. In this context the OGF RUS and UR sped cations are critically analyzed. Furthermore, a prototype of a RUS interface for DGAS (DGAS-RUS) is presented and the most recent test results towards a full interoperability between heterogeneous Grid platforms are outlined.

Abstract The DGAS‐Sim(ulator) simulates the components of the Grid middleware that are involved in the job scheduling process, reflecting the architecture of the Workload Management System of the European DataGrid project. Its purpose is to study the impact of different resource pricing schemes and resource brokering strategies on workload balancing. In this paper we present further simulation results for a price‐sensitive utility function (the resource broker always chooses the most economic computing element) and the Hybrid Pricing Model (fixed base prices and linear price adjustments within fixed variation limits to reflect the current workload of the computing element). We specifically consider a Grid economy scenario with widely overlapping domains of the prices of the single resources and compare the outcome with our previously presented results. Copyright © 2005 John Wiley & Sons, Ltd.