Publication List

@article{Toll-Riera2012a,
title = {Structure and age jointly influence rates of protein evolution.},
author = {Toll-Riera, Macarena and Bostick, David and Albà, M Mar and Plotkin, Joshua B},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3364943&tool=pmcentrez&rendertype=abstract},
issn = {1553-7358},
year = {2012},
date = {2012-01-01},
journal = {PLoS computational biology},
volume = {8},
number = {5},
pages = {e1002542},
abstract = {What factors determine a protein's rate of evolution are actively debated. Especially unclear is the relative role of intrinsic factors of present-day proteins versus historical factors such as protein age. Here we study the interplay of structural properties and evolutionary age, as determinants of protein evolutionary rate. We use a large set of one-to-one orthologs between human and mouse proteins, with mapped PDB structures. We report that previously observed structural correlations also hold within each age group - including relationships between solvent accessibility, designabililty, and evolutionary rates. However, age also plays a crucial role: age modulates the relationship between solvent accessibility and rate. Additionally, younger proteins, despite being less designable, tend to evolve faster than older proteins. We show that previously reported relationships between age and rate cannot be explained by structural biases among age groups. Finally, we introduce a knowledge-based potential function to study the stability of proteins through large-scale computation. We find that older proteins are more stable for their native structure, and more robust to mutations, than younger ones. Our results underscore that several determinants, both intrinsic and historical, can interact to determine rates of protein evolution.},
keywords = {Animals, Binding Sites, Computational Biology, Eukaryota, Evolution, Humans, Mice, Molecular, Protein Conformation, Protein Stability, Proteins, Proteins: chemistry, Proteins: genetics, Proteins: metabolism, Solvents}
}

@article{Rodilla2009,
title = {Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer.},
author = {Rodilla, Verónica and Villanueva, Alberto and Obrador-Hevia, Antonia and Robert-Moreno, Alex and Fernández-Majada, Vanessa and Grilli, Andrea and López-Bigas, Nuria and Bellora, Nicolás and Albà, M Mar and Torres, Ferran and Duñach, Mireia and Sanjuan, Xavier and Gonzalez, Sara and Gridley, Thomas and Capella, Gabriel and Bigas, Anna and Espinosa, Lluís},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2669348&tool=pmcentrez&rendertype=abstract},
issn = {1091-6490},
year = {2009},
date = {2009-01-01},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {106},
number = {15},
pages = {6315--20},
abstract = {Notch has been linked to beta-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/beta-catenin (down-regulated when blocking Wnt/beta-catenin) that are directly regulated by Notch (repressed by gamma-secretase inhibitors and up-regulated by active Notch1 in the absence of beta-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through beta-catenin-mediated transcriptional activation of the Notch-ligand Jagged1. Consistently, expression of activated Notch1 partially reverts the effects of blocking Wnt/beta-catenin pathway in tumors implanted s.c. in nude mice. Crossing APC(Min/+) with Jagged1(+/Delta) mice is sufficient to significantly reduce the size of the polyps arising in the APC mutant background indicating that Notch is an essential modulator of tumorigenesis induced by nuclear beta-catenin. We show that this mechanism is operating in human tumors from Familial Adenomatous Polyposis patients. We conclude that Notch activation, accomplished by beta-catenin-mediated up-regulation of Jagged1, is required for tumorigenesis in the intestine. The Notch-specific genetic signature is sufficient to block differentiation and promote vasculogenesis in tumors whereas proliferation depends on both pathways.},
keywords = {Alleles, Animals, beta Catenin, beta Catenin: metabolism, Calcium-Binding Proteins, Calcium-Binding Proteins: genetics, Calcium-Binding Proteins: metabolism, Cell Line, Cell Nucleus, Cell Nucleus: metabolism, Colorectal Neoplasms, Colorectal Neoplasms: blood supply, Colorectal Neoplasms: genetics, Colorectal Neoplasms: metabolism, Colorectal Neoplasms: pathology, Gene Expression Profiling, Gene Expression Regulation, Genetic, Genetic: genetics, Humans, Intercellular Signaling Peptides and Proteins, Intercellular Signaling Peptides and Proteins: gen, Intercellular Signaling Peptides and Proteins: met, Membrane Proteins, Membrane Proteins: genetics, Membrane Proteins: metabolism, Mice, Neoplastic, Notch, Notch: metabolism, Receptors, Signal Transduction, TCF Transcription Factors, TCF Transcription Factors: metabolism, Transcription, Transgenic, Wnt Proteins, Wnt Proteins: metabolism}
}

@article{Racz2008,
title = {Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain.},
author = {Racz, Ildiko and Nadal, Xavier and Alferink, Judith and Baños, Josep E and Rehnelt, Jennifer and Martín, Miquel and Pintado, Belén and Gutierrez-Adan, Alfonso and Sanguino, Elena and Bellora, Nicolas and Manzanares, Jorge and Zimmer, Andreas and Maldonado, Rafael},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19005078},
issn = {1529-2401},
year = {2008},
date = {2008-01-01},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {28},
number = {46},
pages = {12136--45},
abstract = {Nerve injuries often lead to neuropathic pain syndrome. The mechanisms contributing to this syndrome involve local inflammatory responses, activation of glia cells, and changes in the plasticity of neuronal nociceptive pathways. Cannabinoid CB(2) receptors contribute to the local containment of neuropathic pain by modulating glial activation in response to nerve injury. Thus, neuropathic pain spreads in mice lacking CB(2) receptors beyond the site of nerve injury. To further investigate the mechanisms leading to the enhanced manifestation of neuropathic pain, we have established expression profiles of spinal cord tissues from wild-type and CB(2)-deficient mice after nerve injury. An enhanced interferon-gamma (IFN-gamma) response was revealed in the absence of CB(2) signaling. Immunofluorescence stainings demonstrated an IFN-gamma production by astrocytes and neurons ispilateral to the nerve injury in wild-type animals. In contrast, CB(2)-deficient mice showed neuronal and astrocytic IFN-gamma immunoreactivity also in the contralateral region, thus matching the pattern of nociceptive hypersensitivity in these animals. Experiments in BV-2 microglia cells revealed that transcriptional changes induced by IFN-gamma in two key elements for neuropathic pain development, iNOS (inducible nitric oxide synthase) and CCR2, are modulated by CB(2) receptor signaling. The most direct support for a functional involvement of IFN-gamma as a mediator of CB(2) signaling was obtained with a double knock-out mouse strain deficient in CB(2) receptors and IFN-gamma. These animals no longer show the enhanced manifestations of neuropathic pain observed in CB(2) knock-outs. These data clearly demonstrate that the CB(2) receptor-mediated control of neuropathic pain is IFN-gamma dependent.},
keywords = {Animals, Astrocytes, Astrocytes: immunology, Cannabinoid, CB2, CB2: genetics, CB2: immunology, CB2: metabolism, CCR2, CCR2: immunology, CCR2: metabolism, Cells, Cultured, Gene Knockout Techniques, Gene Knockout Techniques: methods, Hyperalgesia, Hyperalgesia: immunology, Hyperalgesia: physiopathology, Interferon-gamma, Interferon-gamma: genetics, Interferon-gamma: immunology, Interferon-gamma: metabolism, Knockout, Male, Mice, Microglia, Microglia: drug effects, Microglia: immunology, Microglia: metabolism, Neuralgia, Neuralgia: genetics, Neuralgia: immunology, Neuralgia: metabolism, Neurons, Neurons: immunology, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type II: immunology, Nitric Oxide Synthase Type II: metabolism, Peripheral Nerves, Peripheral Nerves: immunology, Peripheral Nerves: injuries, Peripheral Nerves: physiopathology, Peripheral Nervous System Diseases, Peripheral Nervous System Diseases: genetics, Peripheral Nervous System Diseases: immunology, Peripheral Nervous System Diseases: metabolism, Receptor, Receptors, Signal Transduction, Signal Transduction: genetics, Signal Transduction: immunology, Spinal Cord, Spinal Cord: immunology, Spinal Cord: metabolism, Spinal Cord: physiopathology, Up-Regulation, Up-Regulation: immunology}
}

@article{Mularoni2007,
title = {Highly constrained proteins contain an unexpectedly large number of amino acid tandem repeats.},
author = {Mularoni, Loris and Veitia, Reiner A and Albà, M Mar},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17196365},
issn = {0888-7543},
year = {2007},
date = {2007-01-01},
journal = {Genomics},
volume = {89},
number = {3},
pages = {316--25},
abstract = {Single-amino-acid tandem repeats are very common in mammalian proteins but their function and evolution are still poorly understood. Here we investigate how the variability and prevalence of amino acid repeats are related to the evolutionary constraints operating on the proteins. We find a significant positive correlation between repeat size difference and protein nonsynonymous substitution rate in human and mouse orthologous genes. This association is observed for all the common amino acid repeat types and indicates that rapid diversification of repeat structures, involving both trinucleotide slippage and nucleotide substitutions, preferentially occurs in proteins subject to low selective constraints. However, strikingly, we also observe a significant negative correlation between the number of repeats in a protein and the gene nonsynonymous substitution rate, particularly for glutamine, glycine, and alanine repeats. This implies that proteins subject to strong selective constraints tend to contain an unexpectedly high number of repeats, which tend to be well conserved between the two species. This is consistent with a role for selection in the maintenance of a significant number of repeats. Analysis of the codon structure of the sequences encoding the repeats shows that codon purity is associated with high repeat size interspecific variability. Interestingly, polyalanine and polyglutamine repeats associated with disease show very distinctive features regarding the degree of repeat conservation and the protein sequence selective constraints.},
keywords = {Amino Acid, Amino Acid Sequence, Animals, Complementary, Conserved Sequence, DNA, Evolution, Genetic, Humans, Mice, Molecular, Point Mutation, Proteins, Proteins: chemistry, Proteins: genetics, Repetitive Sequences, Selection, Trinucleotide Repeats}
}

@article{Farre2007,
title = {Housekeeping genes tend to show reduced upstream sequence conservation.},
author = {Farré, Domènec and Bellora, Nicolás and Mularoni, Loris and Messeguer, Xavier and Albà, M Mar},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2323216&tool=pmcentrez&rendertype=abstract},
issn = {1465-6914},
year = {2007},
date = {2007-01-01},
journal = {Genome biology},
volume = {8},
number = {7},
pages = {R140},
abstract = {Understanding the constraints that operate in mammalian gene promoter sequences is of key importance to understand the evolution of gene regulatory networks. The level of promoter conservation varies greatly across orthologous genes, denoting differences in the strength of the evolutionary constraints. Here we test the hypothesis that the number of tissues in which a gene is expressed is related in a significant manner to the extent of promoter sequence conservation.},
keywords = {Animals, Base Sequence, Conserved Sequence, CpG Islands, Evolution, Gene Expression, Genetic, Genetic Variation, Humans, Mice, Molecular, Molecular Sequence Data, Promoter Regions}
}

@article{Bellora2007,
title = {Positional bias of general and tissue-specific regulatory motifs in mouse gene promoters.},
author = {Bellora, Nicolás and Farré, Domènec and Albà, M Mar},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2249607&tool=pmcentrez&rendertype=abstract},
issn = {1471-2164},
year = {2007},
date = {2007-01-01},
journal = {BMC genomics},
volume = {8},
pages = {459},
abstract = {The arrangement of regulatory motifs in gene promoters, or promoter architecture, is the result of mutation and selection processes that have operated over many millions of years. In mammals, tissue-specific transcriptional regulation is related to the presence of specific protein-interacting DNA motifs in gene promoters. However, little is known about the relative location and spacing of these motifs. To fill this gap, we have performed a systematic search for motifs that show significant bias at specific promoter locations in a large collection of housekeeping and tissue-specific genes.},
keywords = {Animals, Databases, Gene Expression Regulation, Gene Expression Regulation: genetics, Genetic, Genetic: genetics, Mice, Nucleic Acid, Organ Specificity, Organ Specificity: genetics, Promoter Regions, Software, Transcription Factors, Transcription Factors: metabolism}
}

@article{Furney2006,
title = {Differences in the evolutionary history of disease genes affected by dominant or recessive mutations.},
author = {Furney, Simon J and Albà, M Mar and López-Bigas, Núria},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1534034&tool=pmcentrez&rendertype=abstract},
issn = {1471-2164},
year = {2006},
date = {2006-01-01},
journal = {BMC genomics},
volume = {7},
pages = {165},
abstract = {Global analyses of human disease genes by computational methods have yielded important advances in the understanding of human diseases. Generally these studies have treated the group of disease genes uniformly, thus ignoring the type of disease-causing mutations (dominant or recessive). In this report we present a comprehensive study of the evolutionary history of autosomal disease genes separated by mode of inheritance.},
keywords = {Amino Acid, Animals, Caenorhabditis elegans, Caenorhabditis elegans: genetics, Computational Biology, Conserved Sequence, Dominant, Essential, Evolution, Genes, Genetic, Genetic Diseases, Genetic Structures, Humans, Inborn, Inborn: classification, Inborn: genetics, Mice, Molecular, Mutation, Pan troglodytes, Pan troglodytes: genetics, Recessive, Selection, Sequence Homology}
}

@article{Blanco2006,
title = {ABS: a database of Annotated regulatory Binding Sites from orthologous promoters.},
author = {Blanco, Enrique and Farré, Domènec and Albà, M Mar and Messeguer, Xavier and Guigó, Roderic},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1347478&tool=pmcentrez&rendertype=abstract},
issn = {1362-4962},
year = {2006},
date = {2006-01-01},
journal = {Nucleic acids research},
volume = {34},
number = {Database issue},
pages = {D63--7},
abstract = {Information about the genomic coordinates and the sequence of experimentally identified transcription factor binding sites is found scattered under a variety of diverse formats. The availability of standard collections of such high-quality data is important to design, evaluate and improve novel computational approaches to identify binding motifs on promoter sequences from related genes. ABS (http://genome.imim.es/datasets/abs2005/index.html) is a public database of known binding sites identified in promoters of orthologous vertebrate genes that have been manually curated from bibliography. We have annotated 650 experimental binding sites from 68 transcription factors and 100 orthologous target genes in human, mouse, rat or chicken genome sequences. Computational predictions and promoter alignment information are also provided for each entry. A simple and easy-to-use web interface facilitates data retrieval allowing different views of the information. In addition, the release 1.0 of ABS includes a customizable generator of artificial datasets based on the known sites contained in the collection and an evaluation tool to aid during the training and the assessment of motif-finding programs.},
keywords = {Animals, Binding Sites, Chickens, Chickens: genetics, Databases, Genetic, Genomics, Humans, Internet, Mice, Nucleic Acid, Promoter Regions, Rats, Transcription Factors, Transcription Factors: metabolism, User-Computer Interface}
}

@article{Alba2005,
title = {Inverse relationship between evolutionary rate and age of mammalian genes.},
author = {Albà, M Mar and Castresana, Jose},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15537804},
issn = {0737-4038},
year = {2005},
date = {2005-01-01},
journal = {Molecular biology and evolution},
volume = {22},
number = {3},
pages = {598--606},
abstract = {A large number of genes is shared by all living organisms, whereas many others are unique to some specific lineages, indicating their different times of origin. The availability of a growing number of eukaryotic genomes allows us to estimate which mammalian genes are novel genes and, approximately, when they arose. In this article, we classify human genes into four different age groups and estimate evolutionary rates in human and mouse orthologs. We show that older genes tend to evolve more slowly than newer ones; that is, proteins that arose earlier in evolution currently have a larger proportion of sites subjected to negative selection. Interestingly, this property is maintained when a fraction of the fastest-evolving genes is excluded or when only genes belonging to a given functional class are considered. One way to explain this relationship is by assuming that genes maintain their functional constraints along all their evolutionary history, but the nature of more recent evolutionary innovations is such that the functional constraints operating on them are increasingly weaker. Alternatively, our results would also be consistent with a scenario in which the functional constraints acting on a gene would not need to be constant through evolution. Instead, starting from weak functional constraints near the time of origin of a gene-as supported by mechanisms proposed for the origin of orphan genes-there would be a gradual increase in selective pressures with time, resulting in fewer accepted mutations in older versus more novel genes.},
keywords = {Animals, DNA, Evolution, Genome, human, Humans, Mice, Molecular, Sequence Analysis}
}

@article{Gibbs2004,
title = {Genome sequence of the Brown Norway rat yields insights into mammalian evolution.},
author = {Gibbs, Richard A and Et al.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15057822},
issn = {1476-4687},
year = {2004},
date = {2004-01-01},
journal = {Nature},
volume = {428},
number = {6982},
pages = {493--521},
abstract = {The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.},
keywords = {Animals, Base Composition, Centromere, Centromere: genetics, Chromosomes, CpG Islands, CpG Islands: genetics, DNA, DNA Transposable Elements, DNA Transposable Elements: genetics, Evolution, Gene Duplication, Genome, Genomics, Humans, Inbred BN, Inbred BN: genetics, Introns, Introns: genetics, Male, Mammalian, Mammalian: genetics, Mice, Mitochondrial, Mitochondrial: genetics, Models, Molecular, Mutagenesis, Nucleic Acid, Nucleic Acid: genetics, Polymorphism, Rats, Regulatory Sequences, Retroelements, Retroelements: genetics, RNA, RNA Splice Sites, RNA Splice Sites: genetics, Sequence Analysis, Single Nucleotide, Single Nucleotide: genetics, Telomere, Telomere: genetics, Untranslated, Untranslated: genetics}
}

@article{Huang2004,
title = {Evolutionary conservation and selection of human disease gene orthologs in the rat and mouse genomes.},
author = {Huang, Hui and Winter, Eitan E and Wang, Huajun and Weinstock, Keith G and Xing, Heming and Goodstadt, Leo and Stenson, Peter D and Cooper, David N and Smith, Douglas and Albà, M Mar and Ponting, Chris P and Fechtel, Kim},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=463309&tool=pmcentrez&rendertype=abstract},
issn = {1465-6914},
year = {2004},
date = {2004-01-01},
journal = {Genome biology},
volume = {5},
number = {7},
pages = {R47},
abstract = {Model organisms have contributed substantially to our understanding of the etiology of human disease as well as having assisted with the development of new treatment modalities. The availability of the human, mouse and, most recently, the rat genome sequences now permit the comprehensive investigation of the rodent orthologs of genes associated with human disease. Here, we investigate whether human disease genes differ significantly from their rodent orthologs with respect to their overall levels of conservation and their rates of evolutionary change.},
keywords = {Amino Acid, Amino Acid: genetics, Animal, Animals, Chromosome Mapping, Chromosome Mapping: methods, Conserved Sequence, Conserved Sequence: genetics, Disease Models, Evolution, Fishes, Fishes: genetics, Fungal, Fungal: genetics, Genes, Genes: genetics, Genes: physiology, Genetic, Genetic Diseases, Genome, Helminth, Helminth: genetics, human, Humans, Inborn, Inborn: genetics, Inborn: physiopathology, Insect, Insect: genetics, Mice, Molecular, Mutagenesis, Mutagenesis: genetics, Nucleic Acid, Nucleotides, Nucleotides: genetics, Point Mutation, Point Mutation: genetics, Rats, Repetitive Sequences, Selection, Sequence Homology, Trinucleotide Repeat Expansion, Trinucleotide Repeat Expansion: genetics}
}

@article{Alba2004,
title = {Comparative analysis of amino acid repeats in rodents and humans.},
author = {Albà, M Mar and Guigó, Roderic},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=383298&tool=pmcentrez&rendertype=abstract},
issn = {1088-9051},
year = {2004},
date = {2004-01-01},
journal = {Genome research},
volume = {14},
number = {4},
pages = {549--54},
abstract = {Amino acid tandem repeats, also called homopolymeric tracts, are extremely abundant in eukaryotic proteins. To gain insight into the genome-wide evolution of these regions in mammals, we analyzed the repeat content in a large data set of rat-mouse-human orthologs. Our results show that human proteins contain more amino acid repeats than rodent proteins and that trinucleotide repeats are also more abundant in human coding sequences. Using the human species as an outgroup, we were able to address differences in repeat loss and repeat gain in the rat and mouse lineages. In this data set, mouse proteins contain substantially more repeats than rat proteins, which can be at least partly attributed to a higher repeat loss in the rat lineage. The data are consistent with a role for trinucleotide slippage in the generation of novel amino acid repeats. We confirm the previously observed functional bias of proteins with repeats, with overrepresentation of transcription factors and DNA-binding proteins. We show that genes encoding amino acid repeats tend to have an unusually high GC content, and that differences in coding GC content among orthologs are directly related to the presence/absence of repeats. We propose that the different GC content isochore structure in rodents and humans may result in an increased amino acid repeat prevalence in the human lineage.},
keywords = {Amino Acid, Amino Acid: genetics, Amino Acid: physiology, Animals, Chromosome Mapping, Chromosome Mapping: methods, Chromosome Mapping: statistics & numerical data, Computational Biology, Computational Biology: methods, Computational Biology: statistics & numerical data, GC Rich Sequence, GC Rich Sequence: genetics, Humans, Mice, Proteins, Proteins: chemistry, Proteins: genetics, Proteins: physiology, Rats, Repetitive Sequences, Trinucleotide Repeats, Trinucleotide Repeats: genetics}
}