Showing papers by "Pompeu Fabra University published in 2013"

GSVA: gene set variation analysis for microarray and RNA-seq data.

Abstract: Gene set enrichment (GSE) analysis is a popular framework for condensing information from gene expression profiles into a pathway or signature summary. The strengths of this approach over single gene analysis include noise and dimension reduction, as well as greater biological interpretability. As molecular profiling experiments move beyond simple case-control studies, robust and flexible GSE methodologies are needed that can model pathway activity within highly heterogeneous data sets. To address this challenge, we introduce Gene Set Variation Analysis (GSVA), a GSE method that estimates variation of pathway activity over a sample population in an unsupervised manner. We demonstrate the robustness of GSVA in a comparison with current state of the art sample-wise enrichment methods. Further, we provide examples of its utility in differential pathway activity and survival analysis. Lastly, we show how GSVA works analogously with data from both microarray and RNA-seq experiments. GSVA provides increased power to detect subtle pathway activity changes over a sample population in comparison to corresponding methods. While GSE methods are generally regarded as end points of a bioinformatic analysis, GSVA constitutes a starting point to build pathway-centric models of biology. Moreover, GSVA contributes to the current need of GSE methods for RNA-seq data. GSVA is an open source software package for R which forms part of the Bioconductor project and can be downloaded at http://www.bioconductor.org .

The cancer genome atlas pan-cancer analysis project

Abstract: The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.

Transcriptome and genome sequencing uncovers functional variation in humans

Abstract: Genome sequencing projects are discovering millions of genetic variants in humans, and interpretation of their functional effects is essential for understanding the genetic basis of variation in human traits. Here we report sequencing and deep analysis of messenger RNA and microRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project--the first uniformly processed high-throughput RNA-sequencing data from multiple human populations with high-quality genome sequences. We discover extremely widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent. Our characterization of causal regulatory variation sheds light on the cellular mechanisms of regulatory and loss-of-function variation, and allows us to infer putative causal variants for dozens of disease-associated loci. Altogether, this study provides a deep understanding of the cellular mechanisms of transcriptome variation and of the landscape of functional variants in the human genome.

Great ape genetic diversity and population history

Abstract: Most great ape genetic variation remains uncharacterized; however, its study is critical for understanding population history, recombination, selection and susceptibility to disease. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria-Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.

Transcriptional regulation by Polycomb group proteins.

Abstract: Polycomb group (PcG) proteins function within Polycomb repressive complexes (PRCs), which modify histones and other proteins and silence target genes. This Review highlights new insights into the role of PcG proteins in gene regulation, specifically in controlling self-renewal and differentiation of embryonic stem cells, and into how PRCs are targeted to chromatin.

Biculturalism and Adjustment A Meta-Analysis

Abstract: Biculturalism (having two cultures) is a growing social phenomenon that has received considerable attention in psychology in the last decade; however, the issue of what impact (if any) biculturalism has on individuals’ adjustment remains empirically unclear. To answer this question, we conducted a meta-analysis that included 83 studies, 322 rs, and 23,197 participants. Results based on the random-effects approach show a significant, strong, and positive association between biculturalism and adjustment (both psychological and sociocultural). This biculturalism- adjustment link is stronger than the association between having one culture (dominant or heritage) and adjustment. Thus, our results clearly invalidate early sociological accounts of this phenomenon, which portrayed bicultural individuals as “marginal” and stumped between two worlds. Analyses also indicate that the association between biculturalism and adjustment is moderated by how acculturation is measured, the adjustment domain, and sample charac...

Assessment of transcript reconstruction methods for RNA-seq

Abstract: We evaluated 25 protocol variants of 14 independent computational methods for exon identification, transcript reconstruction and expression-level quantification from RNA-seq data. Our results show that most algorithms are able to identify discrete transcript components with high success rates but that assembly of complete isoform structures poses a major challenge even when all constituent elements are identified. Expression-level estimates also varied widely across methods, even when based on similar transcript models. Consequently, the complexity of higher eukaryotic genomes imposes severe limitations on transcript recall and splice product discrimination that are likely to remain limiting factors for the analysis of current-generation RNA-seq data.

Systematic evaluation of spliced alignment programs for RNA-seq data

Abstract: High-throughput RNA sequencing is an increasingly accessible method for studying gene structure and activity on a genome-wide scale. A critical step in RNA-seq data analysis is the alignment of partial transcript reads to a reference genome sequence. To assess the performance of current mapping software, we invited developers of RNA-seq aligners to process four large human and mouse RNA-seq data sets. In total, we compared 26 mapping protocols based on 11 programs and pipelines and found major performance differences between methods on numerous benchmarks, including alignment yield, basewise accuracy, mismatch and gap placement, exon junction discovery and suitability of alignments for transcript reconstruction. We observed concordant results on real and simulated RNA-seq data, confirming the relevance of the metrics employed. Future developments in RNA-seq alignment methods would benefit from improved placement of multimapped reads, balanced utilization of existing gene annotation and a reduced false discovery rate for splice junctions.

IntOGen-mutations identifies cancer drivers across tumor types

Abstract: The IntOGen-mutations platform (http://www.intogen.org/mutations/) summarizes somatic mutations, genes and pathways involved in tumorigenesis. It identifies and visualizes cancer drivers, analyzing 4,623 exomes from 13 cancer sites. It provides support to cancer researchers, aids the identification of drivers across tumor cohorts and helps rank mutations for better clinical decision-making.

Resting-State Functional Connectivity Emerges from Structurally and Dynamically Shaped Slow Linear Fluctuations

Abstract: Brain fluctuations at rest are not random but are structured in spatial patterns of correlated activity across different brain areas. The question of how resting-state functional connectivity (FC) emerges from the brain's anatomical connections has motivated several experimental and computational studies to understand structure-function relationships. However, the mechanistic origin of resting state is obscured by large-scale models' complexity, and a close structure-function relation is still an open problem. Thus, a realistic but simple enough description of relevant brain dynamics is needed. Here, we derived a dynamic mean field model that consistently summarizes the realistic dynamics of a detailed spiking and conductance-based synaptic large-scale network, in which connectivity is constrained by diffusion imaging data from human subjects. The dynamic mean field approximates the ensemble dynamics, whose temporal evolution is dominated by the longest time scale of the system. With this reduction, we demonstrated that FC emerges as structured linear fluctuations around a stable low firing activity state close to destabilization. Moreover, the model can be further and crucially simplified into a set of motion equations for statistical moments, providing a direct analytical link between anatomical structure, neural network dynamics, and FC. Our study suggests that FC arises from noise propagation and dynamical slowing down of fluctuations in an anatomically constrained dynamical system. Altogether, the reduction from spiking models to statistical moments presented here provides a new framework to explicitly understand the building up of FC through neuronal dynamics underpinned by anatomical connections and to drive hypotheses in task-evoked studies and for clinical applications.

Functional and evolutionary implications of gene orthology

Abstract: The concepts of orthology and paralogy are fundamental to comparative genomics and are also frequently used for the functional annotation of uncharacterized genes. However, assumptions regarding function have recently been challenged, and the implications of assigning genes as orthologues or paralogues are far from straightforward.

Comprehensive identification of mutational cancer driver genes across 12 tumor types

Abstract: With the ability to fully sequence tumor genomes/exomes, the quest for cancer driver genes can now be undertaken in an unbiased manner. However, obtaining a complete catalog of cancer genes is difficult due to the heterogeneous molecular nature of the disease and the limitations of available computational methods. Here we show that the combination of complementary methods allows identifying a comprehensive and reliable list of cancer driver genes. We provide a list of 291 high-confidence cancer driver genes acting on 3,205 tumors from 12 different cancer types. Among those genes, some have not been previously identified as cancer drivers and 16 have clear preference to sustain mutations in one specific tumor type. The novel driver candidates complement our current picture of the emergence of these diseases. In summary, the catalog of driver genes and the methodology presented here open new avenues to better understand the mechanisms of tumorigenesis.

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Abstract: Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.

The impact of transposable elements in environmental adaptation

Abstract: Transposable elements (TEs) play an important role in the responsive capacity of their hosts in the face of environmental challenges. The variety of mechanisms by which TEs influence the capacity of adaptation of the host is as large as the variety of TEs and host genomes. For example, TEs might directly affect the function of individual genes, provide a mechanism for rapidly acquiring new genetic material and disseminate regulatory elements that can lead to the creation of stress-inducible regulatory networks. In this review, we summarize recent examples that are part of an increasing body of evidence suggesting a significant role of TEs in the host response to an ever-changing environment, both in prokaryote and in eukaryote organisms. We argue that in the near future, the increasing availability of genome sequences and the development of new tools to discover and analyse TE insertions will further show the relevant role of TEs in environmental adaptation.

Fundamental Limits of Cooperation

Abstract: Cooperation is viewed as a key ingredient for interference management in wireless networks. This paper shows that cooperation has fundamental limitations. First, it is established that in systems that rely on pilot-assisted channel estimation, the spectral efficiency is upper-bounded by a quantity that does not depend on the transmit powers; in this framework, cooperation is possible only within clusters of limited size, which are subject to out-of-cluster interference whose power scales with that of the in-cluster signals. Second, an upper bound is also shown to exist if the cooperation extends to an entire (large) system operating as a single cluster; here, pilot-assisted transmission is necessarily transcended. Altogether, it is concluded that cooperation cannot in general change an interference-limited network to a noise-limited one. Consequently, the existing literature that routinely assumes that the high-power spectral efficiency scales with the log-scale transmit power provides only a partial characterization. The complete characterization proposed in this paper subdivides the high-power regime into a degree-of-freedom regime, where the scaling with the log-scale transmit power holds approximately, and a saturation regime, where the spectral efficiency hits a ceiling that is independent of the power. Using a cellular system as an example, it is demonstrated that the spectral efficiency saturates at power levels of operational relevance.

Targeting the Circulating MicroRNA Signature of Obesity

Abstract: Background: Genomic studies have yielded important insights into the pathogenesis of obesity. Circulating microRNAs (miRNAs) are valuable biomarkers of systemic diseases and potential therapeutic targets. We sought to define the circulating pattern of miRNAs in obesity and examine changes after weight loss. Methods: We assessed the genome-wide circulating miRNA profile cross-sectionally in 32 men and after surgery-induced weight loss in 6 morbidly obese patients. The most relevant miRNAs were cross-sectionally validated in 80 men and longitudinally in 22 patients (after surgery-induced weight loss). We evaluated the effects of diet-induced weight loss in 9 obese patients. Thirty-six circulating miRNAs were associated with anthropometric variables in the initial sample. Results: In the validation study, morbidly obese patients showed a marked increase of miR-140-5p, miR-142-3p (both P < 0.0001), and miR-222 ( P = 0.0002) and decreased levels of miR-532–5p, miR-125b, miR-130b, miR-221, miR-15a, miR-423-5p, and miR-520c-3p ( P < 0.0001 for all). Interestingly, in silico targets leukemia inhibitory factor receptor (LIFR) and transforming growth factor receptor (TGFR) of miR-140-5p, miR-142-3p, miR-15a, and miR-520c-3p circulated in association with their corresponding miRNAs. Moreover, a discriminant function of 3 miRNAs (miR-15a, miR-520c-3p, and miR-423-5p) was specific for morbid obesity, with an accuracy of 93.5%. Surgery-induced (but not diet-induced) weight loss led to a marked decrease of miR-140-5p, miR-122, miR-193a-5p, and miR-16-1 and upregulation of miR-221 and miR-199a-3p ( P < 0.0001 for all). Conclusions: Circulating miRNAs are deregulated in severe obesity. Weight loss–induced changes in this profile and the study of in silico targets support this observation and suggest a potential mechanistic relevance.

Cospeciation vs host-shift speciation: methods for testing, evidence from natural associations and relation to coevolution

Abstract: 'Summary' 347 I. 'Introduction' 348 II. 'Origin of the cospeciation concept' 349 III. 'Theoretical framework and methods for testing for cospeciation' 349 IV. 'Studies of natural associations reveal the prevalence of host shifts' 355 V. 'Relationship between host–symbiont coevolution and symbiont speciation' 378 VI. 'Conclusion' 381 'Acknowledgements' 381 References 381 Glossary 379 Summary Hosts and their symbionts are involved in intimate physiological and ecological interactions. The impact of these interactions on the evolution of each partner depends on the time-scale considered. Short-term dynamics – ‘coevolution’ in the narrow sense – has been reviewed elsewhere. We focus here on the long-term evolutionary dynamics of cospeciation and speciation following host shifts. Whether hosts and their symbionts speciate in parallel, by cospeciation, or through host shifts, is a key issue in host–symbiont evolution. In this review, we first outline approaches to compare divergence between pairwise associated groups of species, their advantages and pitfalls. We then consider recent insights into the long-term evolution of host–parasite and host–mutualist associations by critically reviewing the literature. We show that convincing cases of cospeciation are rare (7%) and that cophylogenetic methods overestimate the occurrence of such events. Finally, we examine the relationships between short-term coevolutionary dynamics and long-term patterns of diversification in host–symbiont associations. We review theoretical and experimental studies showing that short-term dynamics can foster parasite specialization, but that these events can occur following host shifts and do not necessarily involve cospeciation. Overall, there is now substantial evidence to suggest that coevolutionary dynamics of hosts and parasites do not favor long-term cospeciation.

Essentia: An Audio Analysis Library for Music Information Retrieval.

Abstract: Comunicacio presentada a la 14th International Society for Music Information Retrieval Conference, celebrada a Curitiba (Brasil) els dies 4 a 8 de novembre de 2013.

EsPal: One-stop shopping for Spanish word properties

Abstract: This article introduces EsPal: a Web-accessible repository containing a comprehensive set of properties of Spanish words. EsPal is based on an extensible set of data sources, beginning with a 300 million token written database and a 460 million token subtitle database. Properties available include word frequency, orthographic structure and neighborhoods, phonological structure and neighborhoods, and subjective ratings such as imageability. Subword structure properties are also available in terms of bigrams and trigrams, biphones, and bisyllables. Lemma and part-of-speech information and their corresponding frequencies are also indexed. The website enables users either to upload a set of words to receive their properties or to receive a set of words matching constraints on the properties. The properties themselves are easily extensible and will be added over time as they become available. It is freely available from the following website: http://www.bcbl.eu/databases/espal/ .

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Abstract: Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

Sovereign Default, Domestic Banks and Financial Institutions

Abstract: We present a model of sovereign debt in which, contrary to conventional wisdom, government defaults are costly because they destroy the balance sheets of domestic banks. In our model, better financial institutions allow banks to be more leveraged, thereby making them more vulnerable to sovereign defaults. Our predictions: government defaults should lead to declines in private credit, and these declines should be larger in countries where financial institutions are more developed and banks hold more government bonds. In these same countries, government defaults should be less likely. Using a large panel of countries, we find evidence consistent with these predictions.

Genome structure and metabolic features in the red seaweed Chondrus crispus shed light on evolution of the Archaeplastida.

Abstract: Red seaweeds are key components of coastal ecosystems and are economically important as food and as a source of gelling agents, but their genes and genomes have received little attention. Here we report the sequencing of the 105-Mbp genome of the florideophyte Chondrus crispus (Irish moss) and the annotation of the 9,606 genes. The genome features an unusual structure characterized by gene-dense regions surrounded by repeat-rich regions dominated by transposable elements. Despite its fairly large size, this genome shows features typical of compact genomes, e.g., on average only 0.3 introns per gene, short introns, low median distance between genes, small gene families, and no indication of large-scale genome duplication. The genome also gives insights into the metabolism of marine red algae and adaptations to the marine environment, including genes related to halogen metabolism, oxylipins, and multicellularity (microRNA processing and transcription factors). Particularly interesting are features related to carbohydrate metabolism, which include a minimalistic gene set for starch biosynthesis, the presence of cellulose synthases acquired before the primary endosymbiosis showing the polyphyly of cellulose synthesis in Archaeplastida, and cellulases absent in terrestrial plants as well as the occurrence of a mannosylglycerate synthase potentially originating from a marine bacterium. To explain the observations on genome structure and gene content, we propose an evolutionary scenario involving an ancestral red alga that was driven by early ecological forces to lose genes, introns, and intergenetic DNA; this loss was followed by an expansion of genome size as a consequence of activity of transposable elements.

Architecture and evolution of a minute plant genome

Abstract: It has been argued that the evolution of plant genome size is principally unidirectional and increasing owing to the varied action of wholegenome duplications (WGDs) and mobile element proliferation 1 . However, extreme genome size reductions have been reported in the angiosperm family tree. Here we report the sequence of the 82megabase genome of the carnivorous bladderwort plant Utricularia gibba. Despite its tiny size, the U. gibba genome accommodates a typical number of genes for a plant, with the main difference from other plant genomes arising from a drastic reduction in non-genic DNA. Unexpectedly, we identified at least three rounds of WGD in U. gibba since common ancestry with tomato (Solanum) and grape (Vitis). The compressed architecture of the U. gibba genome indicates that a small fraction of intergenic DNA, with few or no active retrotransposons, is sufficient to regulate and integrate all the processes required for the development and reproduction of a complex organism. Like other carnivorous plants, Utricularia (Lentibulariaceae) species derive nitrogen and phosphorus supplements by trapping and digesting prey organisms 2,3 . Lentibulariaceae are asterid angiosperms closely related to the model plants snapdragon (Antirrhinum) and monkey

Freesound technical demo

Abstract: Freesound is an online collaborative sound database where people with diverse interests share recorded sound samples under Creative Commons licenses. It was started in 2005 and it is being maintained to support diverse research projects and as a service to the overall research and artistic community. In this demo we want to introduce Freesound to the multimedia community and show its potential as a research resource. We begin by describing some general aspects of Freesound, its architecture and functionalities, and then explain potential usages that this framework has for research applications.

A Concise Introduction to Models and Methods for Automated Planning

Abstract: Planning is the model-based approach to autonomous behavior where the agent behavior is derived automatically from a model of the actions, sensors, and goals. The main challenges in planning are computational as all models, whether featuring uncertainty and feedback or not, are intractable in the worst case when represented in compact form. In this book, we look at a variety of models used in AI planning, and at the methods that have been developed for solving them. The goal is to provide a modern and coherent view of planning that is precise, concise, and mostly self-contained, without being shallow. For this, we make no attempt at covering the whole variety of planning approaches, ideas, and applications, and focus on the essentials. The target audience of the book are students and researchers interested in autonomous behavior and planning from an AI, engineering, or cognitive science perspective. Table of Contents: Preface / Planning and Autonomous Behavior / Classical Planning: Full Information and Deterministic Actions / Classical Planning: Variations and Extensions / Beyond Classical Planning: Transformations / Planning with Sensing: Logical Models / MDP Planning: Stochastic Actions and Full Feedback / POMDP Planning: Stochastic Actions and Partial Feedback / Discussion / Bibliography / Author's Biography