Genome Biology Group

Barcelona, Spain

Genome Biology Group

Barcelona, Spain
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Bano-Polo M.,University of Valencia | Baeza-Delgado C.,University of Valencia | Orzaez M.,Research Center Principe Felipe | Marti-Renom M.A.,Genome Biology Group | And 3 more authors.
PLoS ONE | Year: 2012

The vast majority of membrane proteins are anchored to biological membranes through hydrophobic α-helices. Sequence analysis of high-resolution membrane protein structures show that ionizable amino acid residues are present in transmembrane (TM) helices, often with a functional and/or structural role. Here, using as scaffold the hydrophobic TM domain of the model membrane protein glycophorin A (GpA), we address the consequences of replacing specific residues by ionizable amino acids on TM helix insertion and packing, both in detergent micelles and in biological membranes. Our findings demonstrate that ionizable residues are stably inserted in hydrophobic environments, and tolerated in the dimerization process when oriented toward the lipid face, emphasizing the complexity of protein-lipid interactions in biological membranes. © 2012 Bañó-Polo et al.

Le Dily F.,University Pompeu Fabra | Le Dily F.,Genome Biology Group | Bau D.,Genome Biology Group | Pohl A.,University Pompeu Fabra | And 11 more authors.
Genes and Development | Year: 2014

The human genome is segmented into topologically associating domains (TADs), but the role of this conserved organization during transient changes in gene expression is not known. Here we describe the distribution of progestin-induced chromatin modifications and changes in transcriptional activity over TADs in T47D breast cancer cells. Using ChIP-seq (chromatin immunoprecipitation combined with high-throughput sequencing), Hi-C (chromosome capture followed by high-throughput sequencing), and three-dimensional (3D) modeling techniques, we found that the borders of the ∼2000 TADs in these cells are largely maintained after hormone treatment and that up to 20% of the TADs could be considered as discrete regulatory units where the majority of the genes are either transcriptionally activated or repressed in a coordinated fashion. The epigenetic signatures of the TADs are homogeneously modified by hormones in correlation with the transcriptional changes. Hormone-induced changes in gene activity and chromatin remodeling are accompanied by differential structural changes for activated and repressed TADs, as reflected by specific and opposite changes in the strength of intra-TAD interactions within responsive TADs. Indeed, 3D modeling of the Hi-C data suggested that the structure of TADs was modified upon treatment. The differential responses of TADs to progestins and estrogens suggest that TADs could function as “regulons” to enable spatially proximal genes to be coordinately transcribed in response to hormones. © 2014, Le Dily et al.

Serra F.,Research Center Principe Felipe | Serra F.,Genome Biology Group | Becher V.,University of Buenos Aires | Dopazo H.,Institute Genomica Humana Banco Nacional Of Datos Geneticos | Dopazo H.,University of Buenos Aires
PLoS ONE | Year: 2013

It is universally true in ecological communities, terrestrial or aquatic, temperate or tropical, that some species are very abundant, others are moderately common, and the majority are rare. Likewise, eukaryotic genomes also contain classes or "species" of genetic elements that vary greatly in abundance: DNA transposons, retrotransposons, satellite sequences, simple repeats and their less abundant functional sequences such as RNA or genes. Are the patterns of relative species abundance and diversity similar among ecological communities and genomes? Previous dynamical models of genomic diversity have focused on the selective forces shaping the abundance and diversity of transposable elements (TEs). However, ideally, models of genome dynamics should consider not only TEs, but also the diversity of all genetic classes or "species" populating eukaryotic genomes. Here, in an analysis of the diversity and abundance of genetic elements in >500 eukaryotic chromosomes, we show that the patterns are consistent with a neutral hypothesis of genome assembly in virtually all chromosomes tested. The distributions of relative abundance of genetic elements are quite precisely predicted by the dynamics of an ecological model for which the principle of functional equivalence is the main assumption. We hypothesize that at large temporal scales an overarching neutral or nearly neutral process governs the evolution of abundance and diversity of genetic elements in eukaryotic genomes. © 2013 Serra et al.

Baeza-Delgado C.,University of Valencia | Marti-Renom M.A.,Genome Biology Group | Marti-Renom M.A.,Structural Genomics Group | Mingarro I.,University of Valencia
European Biophysics Journal | Year: 2013

Recent advances in determination of the high-resolution structure of membrane proteins now enable analysis of the main features of amino acids in transmembrane (TM) segments in comparison with amino acids in water-soluble helices. In this work, we conducted a large-scale analysis of the prevalent locations of amino acids by using a data set of 170 structures of integral membrane proteins obtained from the MPtopo database and 930 structures of water-soluble helical proteins obtained from the protein data bank. Large hydrophobic amino acids (Leu, Val, Ile, and Phe) plus Gly were clearly prevalent in TM helices whereas polar amino acids (Glu, Lys, Asp, Arg, and Gln) were less frequent in this type of helix. The distribution of amino acids along TM helices was also examined. As expected, hydrophobic and slightly polar amino acids are commonly found in the hydrophobic core of the membrane whereas aromatic (Trp and Tyr), Pro, and the hydrophilic amino acids (Asn, His, and Gln) occur more frequently in the interface regions. Charged amino acids are also statistically prevalent outside the hydrophobic core of the membrane, and whereas acidic amino acids are frequently found at both cytoplasmic and extra-cytoplasmic interfaces, basic amino acids cluster at the cytoplasmic interface. These results strongly support the experimentally demonstrated biased distribution of positively charged amino acids (that is, the so-called the positive-inside rule) with structural data. © 2012 European Biophysical Societies' Association.

Martinez-Jimenez F.,Genome Biology Group | Martinez-Jimenez F.,Center for Genomic Regulation | Papadatos G.,European Bioinformatics Institute | Yang L.,Glaxosmithkline | And 8 more authors.
PLoS Computational Biology | Year: 2013

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects an estimated two billion people worldwide and is the leading cause of mortality due to infectious disease. The development of new anti-TB therapeutics is required, because of the emergence of multi-drug resistance strains as well as co-infection with other pathogens, especially HIV. Recently, the pharmaceutical company GlaxoSmithKline published the results of a high-throughput screen (HTS) of their two million compound library for anti-mycobacterial phenotypes. The screen revealed 776 compounds with significant activity against the M. tuberculosis H37Rv strain, including a subset of 177 prioritized compounds with high potency and low in vitro cytotoxicity. The next major challenge is the identification of the target proteins. Here, we use a computational approach that integrates historical bioassay data, chemical properties and structural comparisons of selected compounds to propose their potential targets in M. tuberculosis. We predicted 139 target - compound links, providing a necessary basis for further studies to characterize the mode of action of these compounds. The results from our analysis, including the predicted structural models, are available to the wider scientific community in the open source mode, to encourage further development of novel TB therapeutics. © 2013 Martínez-Jiménez et al.

Mensch J.,University of Buenos Aires | Serra F.,Research Center Principe Felipe | Serra F.,Genome Biology Group | Lavagnino N.J.,University of Buenos Aires | And 2 more authors.
Genome Biology and Evolution | Year: 2013

Developmental conservation among related species is a common generalization known as von Baer's third law and implies that early stages of development are the most refractory to change. The "hourglass model" is an alternative view that proposes that middle stages are the most constrained during development. To investigate this issue, we undertook a genomic approach and provide insights into how natural selection operates on genes expressed during the first 24 h of Drosophila ontogeny in the six species of the melanogaster group for which whole genome sequences are available. Having studied the rate of evolution of more than 2,000 developmental genes, our results showed differential selective pressures at different moments of embryogenesis. In many Drosophila species, early zygotic genes evolved slower than maternal genes indicating that mid-embryogenesis is the stage most refractory to evolutionary change. Interestingly, positively selected genes were found in all embryonic stages even during the period with the highest developmental constraint, emphasizing that positive selection and negative selection are not mutually exclusive as it is often mistakenly considered. Among the fastest evolving genes, we identified a network of nucleoporins (Nups) as part of the maternal transcriptome. Specifically, the acceleration of Nups was driven by positive selection only in the more recently diverged species. Because many Nups are involved in hybrid incompatibilities between species of the Drosophila melanogaster subgroup, our results link rapid evolution of early developmental genes with reproductive isolation. In summary, our study revealed that even within functional groups of genes evolving under strong negative selection many positively selected genes could be recognized. Understanding these exceptions to the broad evolutionary conservation of early expressed developmental genes can shed light into relevant processes driving the evolution of species divergence. © The Author(s) 2013. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Trussart M.,EMBL CRG Systems Biology Research Unit | Trussart M.,University Pompeu Fabra | Serra F.,Center for Genomic Regulation | Serra F.,Genome Biology Group | And 10 more authors.
Nucleic Acids Research | Year: 2015

Restraint-based modeling of genomes has been recently explored with the advent of Chromosome Conformation Capture (3C-based) experiments. We previously developed a reconstruction method to resolve the 3D architecture of both prokaryotic and eukaryotic genomes using 3C-based data. These models were congruent with fluorescent imaging validation. However, the limits of such methods have not systematically been assessed. Here we propose the first evaluation of a mean-field restraint-based reconstruction of genomes by considering diverse chromosome architectures and different levels of data noise and structural variability. The results show that: first, current scoring functions for 3D reconstruction correlate with the accuracy of the models; second, reconstructed models are robust to noise but sensitive to structural variability; third, the local structure organization of genomes, such as Topologically Associating Domains, results in more accurate models; fourth, to a certain extent, the models capture the intrinsic structural variability in the input matrices and fifth, the accuracy of the models can be a priori predicted by analyzing the properties of the interaction matrices. In summary, our work provides a systematic analysis of the limitations of a mean-field restrain-based method, which could be taken into consideration in further development of methods as well as their applications. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Dekker J.,University of Massachusetts Medical School | Marti-Renom M.A.,Genome Biology Group | Marti-Renom M.A.,Center for Genomic Regulation | Mirny L.A.,Massachusetts Institute of Technology
Nature Reviews Genetics | Year: 2013

How DNA is organized in three dimensions inside the cell nucleus and how this affects the ways in which cells access, read and interpret genetic information are among the longest standing questions in cell biology. Using newly developed molecular, genomic and computational approaches based on the chromosome conformation capture technology (such as 3C, 4C, 5C and Hi-C), the spatial organization of genomes is being explored at unprecedented resolution. Interpreting the increasingly large chromatin interaction data sets is now posing novel challenges. Here we describe several types of statistical and computational approaches that have recently been developed to analyse chromatin interaction data. © 2013 Macmillan Publishers Limited.

Dufour D.,Genome Biology Group | Marti-Renom M.A.,Catalan Institution for Research and Advanced Studies
Wiley Interdisciplinary Reviews: Computational Molecular Science | Year: 2015

RNA is not regarded anymore as a simple transfer molecule between DNA and proteins. Indeed, over the past decades a plethora of new functional roles have been assigned to RNA molecules. Such functions are carried out either by RNA molecules alone or through interactions with DNA, other RNA molecules, or proteins. In all cases, the structure that the RNA molecule adopts will impact its function, as it happens with proteins. Therefore, to fully characterize the function of an RNA molecule, its structure needs to be either determined by experiments or predicted by computation. Unfortunately, our knowledge of the atomic mechanism by which RNA molecules adopt their biological active structures is still limited. Such hurdle is now being addressed by the development of new computational methods for RNA structure prediction, which complement experimental methods such as X-ray crystallography, nuclear magnetic resonance, small-angle X-ray scattering, and cryo-electron microscopy. This software focus is not dedicated to a single computational method but aims at outlining the most adopted methods for computational RNA structure prediction. © 2014 John Wiley & Sons, Ltd.

Bau D.,Genome Biology Group | Marti-Renom M.A.,Genome Biology Group
Methods | Year: 2012

The three-dimensional (3D) architecture of a genome determines the spatial localization of regulatory elements and the genes they regulate. Thus, elucidating the 3D structure of a genome may result in significant insights about how genes are regulated. The current state-of-the art in experimental methods, including light microscopy and cell/molecular biology, are now able to provide detailed information on the position of genes and their interacting partners. However, such methods by themselves are not able to determine the high-resolution 3D structure of genomes or genomic domains. Here we describe a computational module of the Integrative Modeling Platform (IMP, that uses chromosome conformation capture data to determine the 3D architecture of genomic domains and entire genomes at unprecedented resolutions. This approach, through the visualization of looping interactions between distal regulatory elements, allows characterizing global chromatin features and their relation to gene expression. We illustrate our work by outlining the determination of the 3D architecture of the α-globin domain in the human genome. © 2012 Elsevier Inc.

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