Publications (8)97.89 Total impact
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Article: BlastR--fast and accurate database searches for non-coding RNAs.
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ABSTRACT: We present and validate BlastR, a method for efficiently and accurately searching non-coding RNAs. Our approach relies on the comparison of di-nucleotides using BlosumR, a new log-odd substitution matrix. In order to use BlosumR for comparison, we recoded RNA sequences into protein-like sequences. We then showed that BlosumR can be used along with the BlastP algorithm in order to search non-coding RNA sequences. Using Rfam as a gold standard, we benchmarked this approach and show BlastR to be more sensitive than BlastN. We also show that BlastR is both faster and more sensitive than BlastP used with a single nucleotide log-odd substitution matrix. BlastR, when used in combination with WU-BlastP, is about 5% more accurate than WU-BlastN and about 50 times slower. The approach shown here is equally effective when combined with the NCBI-Blast package. The software is an open source freeware available from www.tcoffee.org/blastr.html.Nucleic Acids Research 05/2011; 39(16):6886-95. · 8.03 Impact Factor -
Article: A more precise characterization of chaperonin substrates.
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ABSTRACT: MOTIVATION: Molecular chaperones prevent the aggregation of their substrate proteins and thereby ensure that they reach their functional native state. The bacterial GroEL/ES chaperonin system is understood in great detail on a structural, mechanistic and functional level; its interactors in Escherichia coli have been identified and characterized. However, a long-standing question in the field is: What makes a protein a chaperone substrate? RESULTS: Here we identify, using a bioinformatics-based approach a simple set of quantities, which characterize the GroEL-substrate proteome. We define three novel parameters differentiating GroEL interactors from other cellular proteins: lower rate of evolution, hydrophobicity and aggregation propensity. Combining them with other known features to a simple Bayesian predictor allows us to identify known homologous and heterologous GroEL substrateproteins. We discuss our findings in relation to established mechanisms of protein folding and evolutionary buffering by chaperones.Bioinformatics 07/2010; 26(14):1685-9. · 5.47 Impact Factor -
Article: Multi-platform next-generation sequencing of the domestic turkey (Meleagris gallopavo): genome assembly and analysis.
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ABSTRACT: A synergistic combination of two next-generation sequencing platforms with a detailed comparative BAC physical contig map provided a cost-effective assembly of the genome sequence of the domestic turkey (Meleagris gallopavo). Heterozygosity of the sequenced source genome allowed discovery of more than 600,000 high quality single nucleotide variants. Despite this heterozygosity, the current genome assembly (∼1.1 Gb) includes 917 Mb of sequence assigned to specific turkey chromosomes. Annotation identified nearly 16,000 genes, with 15,093 recognized as protein coding and 611 as non-coding RNA genes. Comparative analysis of the turkey, chicken, and zebra finch genomes, and comparing avian to mammalian species, supports the characteristic stability of avian genomes and identifies genes unique to the avian lineage. Clear differences are seen in number and variety of genes of the avian immune system where expansions and novel genes are less frequent than examples of gene loss. The turkey genome sequence provides resources to further understand the evolution of vertebrate genomes and genetic variation underlying economically important quantitative traits in poultry. This integrated approach may be a model for providing both gene and chromosome level assemblies of other species with agricultural, ecological, and evolutionary interest.PLoS Biology 01/2010; 8(9). · 11.45 Impact Factor -
Article: Impact of genome reduction on bacterial metabolism and its regulation.
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ABSTRACT: To understand basic principles of bacterial metabolism organization and regulation, but also the impact of genome size, we systematically studied one of the smallest bacteria, Mycoplasma pneumoniae. A manually curated metabolic network of 189 reactions catalyzed by 129 enzymes allowed the design of a defined, minimal medium with 19 essential nutrients. More than 1300 growth curves were recorded in the presence of various nutrient concentrations. Measurements of biomass indicators, metabolites, and 13C-glucose experiments provided information on directionality, fluxes, and energetics; integration with transcription profiling enabled the global analysis of metabolic regulation. Compared with more complex bacteria, the M. pneumoniae metabolic network has a more linear topology and contains a higher fraction of multifunctional enzymes; general features such as metabolite concentrations, cellular energetics, adaptability, and global gene expression responses are similar, however.Science 11/2009; 326(5957):1263-8. · 31.20 Impact Factor -
Article: Faster exact Markovian probability functions for motif occurrences: a DFA-only approach.
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ABSTRACT: The computation of the statistical properties of motif occurrences has an obviously relevant application: patterns that are significantly over- or under-represented in genomes or proteins are interesting candidates for biological roles. However, the problem is computationally hard; as a result, virtually all the existing motif finders use fast but approximate scoring functions, in spite of the fact that they have been shown to produce systematically incorrect results. A few interesting exact approaches are known, but they are very slow and hence not practical in the case of realistic sequences. We give an exact solution, solely based on deterministic finite-state automata (DFA), to the problem of finding the whole relevant part of the probability distribution function of a simple-word motif in a homogeneous (biological) sequence. Out of that, the z-value can always be computed, while the P-value can be obtained either when it is not too extreme with respect to the number of floating-point digits available in the implementation, or when the number of pattern occurrences is moderately low. In particular, the time complexity of the algorithms for Markov models of moderate order (0 < or = m < or = 2) is far better than that of Nuel, which was the fastest similar exact algorithm known to date; in many cases, even approximate methods are outperformed. DFA are a standard tool of computer science for the study of patterns; previous works in biology propose algorithms involving automata, but there they are used, respectively, as a first step to write a generating function, or to build a finite Markov-chain imbedding (FMCI). In contrast, we directly rely on DFA to perform the calculations; thus we manage to obtain an algorithm which is both easily interpretable and efficient. This approach can be used for exact statistical studies of very long genomes and protein sequences, as we illustrate with some examples on the scale of the human genome.Bioinformatics 10/2008; 24(24):2839-48. · 5.47 Impact Factor -
Article: Evolvability and hierarchy in rewired bacterial gene networks
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ABSTRACT: Sequencing DNA from several organisms has revealed that duplication and drift of existing genes have primarily moulded the contents of a given genome. Though the effect of knocking out or overexpressing a particular gene has been studied in many organisms, no study has systematically explored the effect of adding new links in a biological network. To explore network evolvability, we constructed 598 recombinations of promoters (including regulatory regions) with different transcription or -factor genes in Escherichia coli, added over a wild-type genetic background. Here we show that 95% of new networks are tolerated by the bacteria, that very few alter growth, and that expression level correlates with factor position in the wild-type network hierarchy. Most importantly, we find that certain networks consistently survive over the wild type under various selection pressures. Therefore new links in the network are rarely a barrier for evolution and can even confer a fitness advantage.Nature 04/2008; 452(7189):840-845. · 36.28 Impact Factor -
Article: Novel determinants describe chaperonin substrate proteins
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ABSTRACT: Molecular chaperones ensure that their substrate proteins reach the functional native state and prevent their aggregation. The bacterial GroEL/ES chaperonin system is understood in great detail on a structural, mechanistic and functional level. Its substrate proteins in E. coli have been identified and characterized. However, a long standing and yet unresolved question in the field is: what makes a protein a chaperone substrate? Here we demonstrate with a bioinformatics-based approach that a simple set of criteria is sufficient to describe the GroEL substrate proteome to unprecedented accuracy. We define two novel parameters differentiating GroEL substrates from other cellular proteins: evolutionary rate and hydrophobicity. We demonstrate their conjunct applicability and explain why they are suitable descriptors. Combining them with other specific features of proteins, such as structure and size, we manage to identify the subset of GroEL substrate proteins with high confidence. We verify the applicability of our findings by correctly predicting a number of known heterologous GroEL substrate proteins. Furthermore, our results show that in vivo, the proposed buffering capacity of chaperones does not appear to be a dominant effect. Instead, the observed lower evolutionary rates among substrate proteins could be explained by their energetically unfavorable folding pathways not allowing for additional destabilizing mutations to occur. We show that a combination of simple parameters is sufficient to accurately describe the GroEL substrate proteome and to successfully predict known heterologous substrates. Our approach can potentially be used to predict chaperonin usage for any given polypeptide chain. Observed low evolutionary rates of GroEL substrates suggest that constraints in the folding pathways of the respective proteins do not allow for the accumulation of mutations.Nature Precedings. -
Article: Evolvability of Chaperonin Substrate Proteins
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ABSTRACT: Molecular chaperones ensure that their substrate proteins reach the functional native state, and prevent their aggregation. Recently, an additional function was proposed for molecular chaperones: they serve as buffers (_capacitors_) for evolution by permitting their substrate proteins to mutate and at the same time still allowing them to fold productively. Using pairwise alignments of _E. coli_ genes with genes from other gamma-proteobacteria, we showed that the described buffering effect cannot be observed among substrate proteins of GroEL, an essential chaperone in _E. coli_. Instead, we find that GroEL substrate proteins evolve less than other soluble _E. coli_ proteins. We analyzed several specific structural and biophysical properties of proteins to assess their influence on protein evolution and to find out why specifically GroEL substrates do not show the expected higher divergence from their orthologs. Our results culminate in four main findings: *1.* We find little evidence that GroEL in _E. coli_ acts as a capacitor for evolution _in vivo_. *2.* GroEL substrates evolved less than other _E. coli_ proteins. *3.* Predominantly structural features appear to be a strong determinant of evolutionary rate. *4.* Besides size, hydrophobicity is a criterion for exclusion for a protein as a chaperonin substrate.Nature Precedings.
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Institutions
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2010
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Centro Nacional de Análisis Genómico de Barcelona
Barcelona, Catalonia, Spain
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