%0 Journal Article %J Nature %D 2023 %T A second update on mapping the human genetic architecture of COVID-19. %K COVID-19 %K Human Genetics %K Humans %B Nature %V 621 %P E7-E26 %8 2023 Sep %G eng %N 7977 %R 10.1038/s41586-023-06355-3 %0 Journal Article %J Biology (Basel) %D 2023 %T SigPrimedNet: A Signaling-Informed Neural Network for scRNA-seq Annotation of Known and Unknown Cell Types. %A Gundogdu, Pelin %A Alamo, Inmaculada %A Nepomuceno-Chamorro, Isabel A %A Dopazo, Joaquin %A Loucera, Carlos %X

Single-cell RNA sequencing is increasing our understanding of the behavior of complex tissues or organs, by providing unprecedented details on the complex cell type landscape at the level of individual cells. Cell type definition and functional annotation are key steps to understanding the molecular processes behind the underlying cellular communication machinery. However, the exponential growth of scRNA-seq data has made the task of manually annotating cells unfeasible, due not only to an unparalleled resolution of the technology but to an ever-increasing heterogeneity of the data. Many supervised and unsupervised methods have been proposed to automatically annotate cells. Supervised approaches for cell-type annotation outperform unsupervised methods except when new (unknown) cell types are present. Here, we introduce SigPrimedNet an artificial neural network approach that leverages (i) efficient training by means of a sparsity-inducing signaling circuits-informed layer, (ii) feature representation learning through supervised training, and (iii) unknown cell-type identification by fitting an anomaly detection method on the learned representation. We show that SigPrimedNet can efficiently annotate known cell types while keeping a low false-positive rate for unseen cells across a set of publicly available datasets. In addition, the learned representation acts as a proxy for signaling circuit activity measurements, which provide useful estimations of the cell functionalities.

%B Biology (Basel) %V 12 %8 2023 Apr 10 %G eng %N 4 %R 10.3390/biology12040579 %0 Journal Article %J Antioxidants (Basel) %D 2022 %T An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in Mice. %A Olivares-González, Lorena %A Velasco, Sheyla %A Gallego, Idoia %A Esteban-Medina, Marina %A Puras, Gustavo %A Loucera, Carlos %A Martínez-Romero, Alicia %A Peña-Chilet, Maria %A Pedraz, José Luis %A Rodrigo, Regina %X

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy causing progressive vision loss. It is accompanied by chronic and sustained inflammation, including M1 microglia activation. This study evaluated the effect of an essential fatty acid (EFA) supplement containing specialized pro-resolving mediators (SPMs), on retinal degeneration and microglia activation in mice, a model of RP, as well as on LPS-stimulated BV2 cells. The EFA supplement was orally administered to mice from postnatal day (P)9 to P18. At P18, the electrical activity of the retina was examined by electroretinography (ERG) and innate behavior in response to light were measured. Retinal degeneration was studied via histology including the TUNEL assay and microglia immunolabeling. Microglia polarization (M1/M2) was assessed by flow cytometry, qPCR, ELISA and histology. Redox status was analyzed by measuring antioxidant enzymes and markers of oxidative damage. Interestingly, the EFA supplement ameliorated retinal dysfunction and degeneration by improving ERG recording and sensitivity to light, and reducing photoreceptor cell loss. The EFA supplement reduced inflammation and microglia activation attenuating M1 markers as well as inducing a shift to the M2 phenotype in mouse retinas and LPS-stimulated BV2 cells. It also reduced oxidative stress markers of lipid peroxidation and carbonylation. These findings could open up new therapeutic opportunities based on resolving inflammation with oral supplementation with SPMs such as the EFA supplement.

%B Antioxidants (Basel) %V 12 %8 2022 Dec 30 %G eng %N 1 %R 10.3390/antiox12010098 %0 Journal Article %J Genes %D 2021 %T Schuurs–Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review %A Tenorio-Castaño, Jair %A Morte, Beatriz %A Nevado, Julián %A Martínez-Glez, Víctor %A Santos-Simarro, Fernando %A García-Miñaur, Sixto %A Palomares-Bralo, María %A Pacio-Míguez, Marta %A Gómez, Beatriz %A Arias, Pedro %A Alcochea, Alba %A Carrión, Juan %A Arias, Patricia %A Almoguera, Berta %A López-Grondona, Fermina %A Lorda-Sanchez, Isabel %A Galán-Gómez, Enrique %A Valenzuela, Irene %A Méndez Perez, María %A Cuscó, Ivón %A Barros, Francisco %A Pié, Juan %A Ramos, Sergio %A Ramos, Feliciano %A Kuechler, Alma %A Tizzano, Eduardo %A Ayuso, Carmen %A Kaiser, Frank %A Pérez-Jurado, Luis %A Carracedo, Ángel %A Lapunzina, Pablo %B Genes %V 12 %P 738 %8 Jan-05-2021 %G eng %U https://www.mdpi.com/2073-4425/12/5/738https://www.mdpi.com/2073-4425/12/5/738/pdf %N 5 %! Genes %R 10.3390/genes12050738 %0 Journal Article %J Hum Mutat %D 2020 %T SMN1 copy-number and sequence variant analysis from next-generation sequencing data. %A López-López, Daniel %A Loucera, Carlos %A Carmona, Rosario %A Aquino, Virginia %A Salgado, Josefa %A Pasalodos, Sara %A Miranda, María %A Alonso, Ángel %A Dopazo, Joaquin %K Base Sequence %K DNA Copy Number Variations %K High-Throughput Nucleotide Sequencing %K Humans %K Reproducibility of Results %K Software %K Survival of Motor Neuron 1 Protein %X

Spinal muscular atrophy (SMA) is a severe neuromuscular autosomal recessive disorder affecting 1/10,000 live births. Most SMA patients present homozygous deletion of SMN1, while the vast majority of SMA carriers present only a single SMN1 copy. The sequence similarity between SMN1 and SMN2, and the complexity of the SMN locus makes the estimation of the SMN1 copy-number by next-generation sequencing (NGS) very difficult. Here, we present SMAca, the first python tool to detect SMA carriers and estimate the absolute SMN1 copy-number using NGS data. Moreover, SMAca takes advantage of the knowledge of certain variants specific to SMN1 duplication to also identify silent carriers. This tool has been validated with a cohort of 326 samples from the Navarra 1000 Genomes Project (NAGEN1000). SMAca was developed with a focus on execution speed and easy installation. This combination makes it especially suitable to be integrated into production NGS pipelines. Source code and documentation are available at https://www.github.com/babelomics/SMAca.

%B Hum Mutat %V 41 %P 2073-2077 %8 2020 12 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/33058415?dopt=Abstract %R 10.1002/humu.24120 %0 Journal Article %J Am J Med Genet A %D 2016 %T Screening of CD96 and ASXL1 in 11 patients with Opitz C or Bohring-Opitz syndromes. %A Urreizti, Roser %A Roca-Ayats, Neus %A Trepat, Judith %A Garcia-Garcia, Francisco %A Alemán, Alejandro %A Orteschi, Daniela %A Marangi, Giuseppe %A Neri, Giovanni %A Opitz, John M %A Dopazo, Joaquin %A Cormand, Bru %A Vilageliu, Lluïsa %A Balcells, Susana %A Grinberg, Daniel %K Adolescent %K Antigens, CD %K Child %K Child, Preschool %K Craniosynostoses %K Exome %K Female %K High-Throughput Nucleotide Sequencing %K Humans %K Infant %K Intellectual Disability %K Male %K mutation %K Pedigree %K Phenotype %K Prognosis %K Repressor Proteins %X

Opitz C trigonocephaly (or Opitz C syndrome, OTCS) and Bohring-Opitz syndrome (BOS or C-like syndrome) are two rare genetic disorders with phenotypic overlap. The genetic causes of these diseases are not understood. However, two genes have been associated with OTCS or BOS with dominantly inherited de novo mutations. Whereas CD96 has been related to OTCS (one case) and to BOS (one case), ASXL1 has been related to BOS only (several cases). In this study we analyze CD96 and ASXL1 in a group of 11 affected individuals, including 2 sibs, 10 of them were diagnosed with OTCS, and one had a BOS phenotype. Exome sequences were available on six patients with OTCS and three parent pairs. Thus, we could analyze the CD96 and ASXL1 sequences in these patients bioinformatically. Sanger sequencing of all exons of CD96 and ASXL1 was carried out in the remaining patients. Detailed scrutiny of the sequences and assessment of variants allowed us to exclude putative pathogenic and private mutations in all but one of the patients. In this patient (with BOS) we identified a de novo mutation in ASXL1 (c.2100dupT). By nature and location within the gene, this mutation resembles those previously described in other BOS patients and we conclude that it may be responsible for the condition. Our results indicate that in 10 of 11, the disease (OTCS or BOS) cannot be explained by small changes in CD96 or ASXL1. However, the cohort is too small to make generalizations about the genetic etiology of these diseases.

%B Am J Med Genet A %V 170A %P 24-31 %8 2016 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/26768331?dopt=Abstract %R 10.1002/ajmg.a.37418 %0 Journal Article %J Oncotarget %D 2016 %T Serum metabolomic profiling facilitates the non-invasive identification of metabolic biomarkers associated with the onset and progression of non-small cell lung cancer. %A Puchades-Carrasco, Leonor %A Jantus-Lewintre, Eloisa %A Pérez-Rambla, Clara %A Garcia-Garcia, Francisco %A Lucas, Rut %A Calabuig, Silvia %A Blasco, Ana %A Dopazo, Joaquin %A Camps, Carlos %A Pineda-Lucena, Antonio %K Adult %K Aged %K Biomarkers, Tumor %K Carcinoma, Non-Small-Cell Lung %K Disease Progression %K Female %K Humans %K Lung Neoplasms %K Male %K metabolomics %K Middle Aged %K Proton Magnetic Resonance Spectroscopy %X

Lung cancer (LC) is responsible for most cancer deaths. One of the main factors contributing to the lethality of this disease is the fact that a large proportion of patients are diagnosed at advanced stages when a clinical intervention is unlikely to succeed. In this study, we evaluated the potential of metabolomics by 1H-NMR to facilitate the identification of accurate and reliable biomarkers to support the early diagnosis and prognosis of non-small cell lung cancer (NSCLC).We found that the metabolic profile of NSCLC patients, compared with healthy individuals, is characterized by statistically significant changes in the concentration of 18 metabolites representing different amino acids, organic acids and alcohols, as well as different lipids and molecules involved in lipid metabolism. Furthermore, the analysis of the differences between the metabolic profiles of NSCLC patients at different stages of the disease revealed the existence of 17 metabolites involved in metabolic changes associated with disease progression.Our results underscore the potential of metabolomics profiling to uncover pathophysiological mechanisms that could be useful to objectively discriminate NSCLC patients from healthy individuals, as well as between different stages of the disease.

%B Oncotarget %V 7 %P 12904-16 %8 2016 Mar 15 %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/26883203?dopt=Abstract %R 10.18632/oncotarget.7354 %0 Journal Article %J Mol Metab %D 2016 %T Stress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis. %A Razzoli, Maria %A Frontini, Andrea %A Gurney, Allison %A Mondini, Eleonora %A Cubuk, Cankut %A Katz, Liora S %A Cero, Cheryl %A Bolan, Patrick J %A Dopazo, Joaquin %A Vidal-Puig, Antonio %A Cinti, Saverio %A Bartolomucci, Alessandro %X

BACKGROUND: Stress-associated conditions such as psychoemotional reactivity and depression have been paradoxically linked to either weight gain or weight loss. This bi-directional effect of stress is not understood at the functional level. Here we tested the hypothesis that pre-stress level of adaptive thermogenesis and brown adipose tissue (BAT) functions explain the vulnerability or resilience to stress-induced obesity.

METHODS: We used wt and triple β1,β2,β3-Adrenergic Receptors knockout (β-less) mice exposed to a model of chronic subordination stress (CSS) at either room temperature (22 °C) or murine thermoneutrality (30 °C). A combined behavioral, physiological, molecular, and immunohistochemical analysis was conducted to determine stress-induced modulation of energy balance and BAT structure and function. Immortalized brown adipocytes were used for in vitro assays.

RESULTS: Departing from our initial observation that βARs are dispensable for cold-induced BAT browning, we demonstrated that under physiological conditions promoting low adaptive thermogenesis and BAT activity (e.g. thermoneutrality or genetic deletion of the βARs), exposure to CSS acted as a stimulus for BAT activation and thermogenesis, resulting in resistance to diet-induced obesity despite the presence of hyperphagia. Conversely, in wt mice acclimatized to room temperature, and therefore characterized by sustained BAT function, exposure to CSS increased vulnerability to obesity. Exposure to CSS enhanced the sympathetic innervation of BAT in wt acclimatized to thermoneutrality and in β-less mice. Despite increased sympathetic innervation suggesting adrenergic-mediated browning, norepinephrine did not promote browning in βARs knockout brown adipocytes, which led us to identify an alternative sympathetic/brown adipocytes purinergic pathway in the BAT. This pathway is downregulated under conditions of low adaptive thermogenesis requirements, is induced by stress, and elicits activation of UCP1 in wt and β-less brown adipocytes. Importantly, this purinergic pathway is conserved in human BAT.

CONCLUSION: Our findings demonstrate that thermogenesis and BAT function are determinant of the resilience or vulnerability to stress-induced obesity. Our data support a model in which adrenergic and purinergic pathways exert complementary/synergistic functions in BAT, thus suggesting an alternative to βARs agonists for the activation of human BAT.

%B Mol Metab %V 5 %P 19-33 %8 2016 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/26844204?dopt=Abstract %R 10.1016/j.molmet.2015.10.005 %0 Journal Article %J Fungal Genet Biol %D 2014 %T Sequencing and functional analysis of the genome of a nematode egg-parasitic fungus, Pochonia chlamydosporia. %A Larriba, Eduardo %A Jaime, María D L A %A Carbonell-Caballero, José %A Conesa, Ana %A Dopazo, Joaquin %A Nislow, Corey %A Martín-Nieto, José %A Lopez-Llorca, Luis Vicente %K Animals %K Ascomycota %K Female %K Gene Expression Regulation, Fungal %K Gene ontology %K Genome, Fungal %K Hordeum %K Host-Pathogen Interactions %K Nematoda %K Ovum %K Phylogeny %K Plant Roots %K Sequence Analysis, DNA %K Signal Transduction %K Transcriptome %X

Pochonia chlamydosporia is a worldwide-distributed soil fungus with a great capacity to infect and destroy the eggs and kill females of plant-parasitic nematodes. Additionally, it has the ability to colonize endophytically roots of economically-important crop plants, thereby promoting their growth and eliciting plant defenses. This multitrophic behavior makes P. chlamydosporia a potentially useful tool for sustainable agriculture approaches. We sequenced and assembled ∼41 Mb of P. chlamydosporia genomic DNA and predicted 12,122 gene models, of which many were homologous to genes of fungal pathogens of invertebrates and fungal plant pathogens. Predicted genes (65%) were functionally annotated according to Gene Ontology, and 16% of them found to share homology with genes in the Pathogen Host Interactions (PHI) database. The genome of this fungus is highly enriched in genes encoding hydrolytic enzymes, such as proteases, glycoside hydrolases and carbohydrate esterases. We used RNA-Seq technology in order to identify the genes expressed during endophytic behavior of P. chlamydosporia when colonizing barley roots. Functional annotation of these genes showed that hydrolytic enzymes and transporters are expressed during endophytism. This structural and functional analysis of the P. chlamydosporia genome provides a starting point for understanding the molecular mechanisms involved in the multitrophic lifestyle of this fungus. The genomic information provided here should also prove useful for enhancing the capabilities of this fungus as a biocontrol agent of plant-parasitic nematodes and as a plant growth-promoting organism.

%B Fungal Genet Biol %V 65 %P 69-80 %8 2014 Apr %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/24530791?dopt=Abstract %R 10.1016/j.fgb.2014.02.002 %0 Journal Article %J International journal of data mining and bioinformatics %D 2012 %T Select your SNPs (SYSNPs): a web tool for automatic and massive selection of SNPs. %A Lorente-Galdos, Belén %A Medina, Ignacio %A Morcillo-Suarez, Carlos %A Heredia, Txema %A Carreño-Torres, Angel %A Sangrós, Ricardo %A Alegre, Josep %A Pita, Guillermo %A Vellalta, Gemma %A Malats, Nuria %A Pisano, David G %A Joaquín Dopazo %A Navarro, Arcadi %X Association studies are the choice approach in the discovery of the genomic basis of complex traits. To carry out such analysis, researchers frequently need to (1) select optimally informative sets of Single Nucleotide Polymorphisms (SNPs) in candidate regions and (2) annotate the results of associations found by means of genome-wide SNP arrays. These are complex tasks, since many criteria have to be considered, including the SNPs’ functional properties, technological information and haplotype frequencies in given populations. SYSNPs implements algorithms that allow for efficient and simultaneous consideration of all the relevant criteria to obtain sets of SNPs that properly cover arbitrarily large lists of genes or genomic regions. Complementarily, SYSNPs allows for comprehensive functional annotation of SNPs linked to any given marker SNP. SYSNPs dramatically reduces the effort needed for SNP selection from days of searching various databases to a few minutes using a simple browser. %B International journal of data mining and bioinformatics %V 6 %P 324-34 %8 2012 %G eng %U http://inderscience.metapress.com/content/f76740x8071u513n/ %0 Journal Article %J Nucleic Acids Res %D 2012 %T SNPeffect 4.0: on-line prediction of molecular and structural effects of protein-coding variants. %A De Baets, Greet %A Van Durme, Joost %A Reumers, Joke %A Maurer-Stroh, Sebastian %A Vanhee, Peter %A Dopazo, Joaquin %A Schymkowitz, Joost %A Rousseau, Frederic %K Databases, Protein %K Humans %K Internet %K Meta-Analysis as Topic %K Phenotype %K Polymorphism, Single Nucleotide %K Protein Conformation %K Proteins %X

Single nucleotide variants (SNVs) are, together with copy number variation, the primary source of variation in the human genome and are associated with phenotypic variation such as altered response to drug treatment and susceptibility to disease. Linking structural effects of non-synonymous SNVs to functional outcomes is a major issue in structural bioinformatics. The SNPeffect database (http://snpeffect.switchlab.org) uses sequence- and structure-based bioinformatics tools to predict the effect of protein-coding SNVs on the structural phenotype of proteins. It integrates aggregation prediction (TANGO), amyloid prediction (WALTZ), chaperone-binding prediction (LIMBO) and protein stability analysis (FoldX) for structural phenotyping. Additionally, SNPeffect holds information on affected catalytic sites and a number of post-translational modifications. The database contains all known human protein variants from UniProt, but users can now also submit custom protein variants for a SNPeffect analysis, including automated structure modeling. The new meta-analysis application allows plotting correlations between phenotypic features for a user-selected set of variants.

%B Nucleic Acids Res %V 40 %P D935-9 %8 2012 Jan %G eng %N Database issue %1 https://www.ncbi.nlm.nih.gov/pubmed/22075996?dopt=Abstract %R 10.1093/nar/gkr996 %0 Journal Article %J PloS one %D 2011 %T Sexual selection halts the relaxation of protamine 2 among rodents. %A Lüke, Lena %A Vicens, Alberto %A Serra, François %A Luque-Larena, Juan Jose %A Dopazo, Hernán %A Roldan, Eduardo R S %A Gomendio, Montserrat %X Sexual selection has been proposed as the driving force promoting the rapid evolutionary changes observed in some reproductive genes including protamines. We test this hypothesis in a group of rodents which show marked differences in the intensity of sexual selection. Levels of sperm competition were not associated with the evolutionary rates of protamine 1 but, contrary to expectations, were negatively related to the evolutionary rate of cleaved- and mature-protamine 2. Since both domains were found to be under relaxation, our findings reveal an unforeseen role of sexual selection: to halt the degree of degeneration that proteins within families may experience due to functional redundancy. The degree of relaxation of protamine 2 in this group of rodents is such that in some species it has become dysfunctional and it is not expressed in mature spermatozoa. In contrast, protamine 1 is functionally conserved but shows directed positive selection on specific sites which are functionally relevant such as DNA-anchoring domains and phosphorylation sites. We conclude that in rodents protamine 2 is under relaxation and that sexual selection removes deleterious mutations among species with high levels of sperm competition to maintain the protein functional and the spermatozoa competitive. %B PloS one %V 6 %P e29247 %8 2011 %G eng %U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0029247 %R 10.1371/journal.pone.0029247 %0 Journal Article %J Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology %D 2011 %T Structure determination of genomic domains by satisfaction of spatial restraints. %A Baù, Davide %A Marti-Renom, Marc A %X

The three-dimensional (3D) architecture of a genome is non-random and known to facilitate the spatial colocalization of regulatory elements with the genes they regulate. Determining the 3D structure of a genome may therefore probe an essential step in characterizing how genes are regulated. Currently, there are several experimental and theoretical approaches that aim at determining the 3D structure of genomes and genomic domains; however, approaches integrating experiments and computation to identify the most likely 3D folding of a genome at medium to high resolutions have not been widely explored. Here, we review existing methodologies and propose that the integrative modeling platform ( http://www.integrativemodeling.org ), a computational package developed for structurally characterizing protein assemblies, could be used for integrating diverse experimental data towards the determination of the 3D architecture of genomic domains and entire genomes at unprecedented resolution. Our approach, through the visualization of looping interactions between distal regulatory elements, will allow for the characterization of global chromatin features and their relation to gene expression. We illustrate our work by outlining the recent determination of the 3D architecture of the α-globin domain in the human genome.

%B Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology %V 19 %P 25-35 %8 2011 Jan %G eng %0 Journal Article %J Nucleic acids research %D 2011 %T SUS1 introns are required for efficient mRNA nuclear export in yeast. %A Cuenca-Bono, Bernardo %A García-Molinero, Varinia %A Pascual-García, Pau %A Dopazo, Hernán %A Llopis, Ana %A Vilardell, Josep %A Rodríguez-Navarro, Susana %X

Efficient coupling between mRNA synthesis and export is essential for gene expression. Sus1/ENY2, a component of the SAGA and TREX-2 complexes, is involved in both transcription and mRNA export. While most yeast genes lack introns, we previously reported that yeast SUS1 bears two. Here we show that this feature is evolutionarily conserved and critical for Sus1 function. We determine that while SUS1 splicing is inefficient, it responds to cellular conditions, and intronic mutations either promoting or blocking splicing lead to defects in mRNA export and cell growth. Consistent with this, we find that an intron-less SUS1 only partially rescues sus1Δ phenotypes. Remarkably, splicing of each SUS1 intron is also affected by the presence of the other and by SUS1 exonic sequences. Moreover, by following SUS1 RNA and protein levels we establish that nonsense-mediated decay (NMD) pathway and the splicing factor Mud2 both play a role in SUS1 expression. Our data (and those of the accompanying work by Hossain et al.) provide evidence of the involvement of splicing, translation, and decay in the regulation of early events in mRNP biogenesis; and imply the additional requirement for a balance in splicing isoforms from a single gene.

%B Nucleic acids research %V 39 %P 8599-611 %8 2011 Oct 1 %G eng %0 Journal Article %J PLoS Comput. Biol. %D 2010 %T Selection upon Genome Architecture: Conservation of Functional Neighborhoods with Changing Genes %A Al-Shahrour, Fátima %A Minguez, Pablo %A Marqués-Bonet, Tomás %A Gazave, Elodie %A Navarro, Arcadi %A Dopazo, Joaquin %B PLoS Comput. Biol. %V 6 %P e1000953 %G eng %U http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000953 %R doi:10.1371/journal.pcbi.1000953 %0 Journal Article %J Nucleic Acids Res %D 2010 %T Serial Expression Analysis: a web tool for the analysis of serial gene expression data. %A Nueda, Maria José %A Carbonell, José %A Medina, Ignacio %A Dopazo, Joaquin %A Conesa, Ana %K Algorithms %K Gene Expression Profiling %K Internet %K Kinetics %K Linear Models %K Oligonucleotide Array Sequence Analysis %K Software %X

Serial transcriptomics experiments investigate the dynamics of gene expression changes associated with a quantitative variable such as time or dosage. The statistical analysis of these data implies the study of global and gene-specific expression trends, the identification of significant serial changes, the comparison of expression profiles and the assessment of transcriptional changes in terms of cellular processes. We have created the SEA (Serial Expression Analysis) suite to provide a complete web-based resource for the analysis of serial transcriptomics data. SEA offers five different algorithms based on univariate, multivariate and functional profiling strategies framed within a user-friendly interface and a project-oriented architecture to facilitate the analysis of serial gene expression data sets from different perspectives. SEA is available at sea.bioinfo.cipf.es.

%B Nucleic Acids Res %V 38 %P W239-45 %8 2010 Jul %G eng %N Web Server issue %1 https://www.ncbi.nlm.nih.gov/pubmed/20525784?dopt=Abstract %R 10.1093/nar/gkq488 %0 Journal Article %J Nucleic acids research %D 2010 %T SIMAP–a comprehensive database of pre-calculated protein sequence similarities, domains, annotations and clusters. %A Rattei, Thomas %A Tischler, Patrick %A Götz, Stefan %A Jehl, Marc-André %A Hoser, Jonathan %A Arnold, Roland %A Ana Conesa %A Mewes, Hans-Werner %X

The prediction of protein function as well as the reconstruction of evolutionary genesis employing sequence comparison at large is still the most powerful tool in sequence analysis. Due to the exponential growth of the number of known protein sequences and the subsequent quadratic growth of the similarity matrix, the computation of the Similarity Matrix of Proteins (SIMAP) becomes a computational intensive task. The SIMAP database provides a comprehensive and up-to-date pre-calculation of the protein sequence similarity matrix, sequence-based features and sequence clusters. As of September 2009, SIMAP covers 48 million proteins and more than 23 million non-redundant sequences. Novel features of SIMAP include the expansion of the sequence space by including databases such as ENSEMBL as well as the integration of metagenomes based on their consistent processing and annotation. Furthermore, protein function predictions by Blast2GO are pre-calculated for all sequences in SIMAP and the data access and query functions have been improved. SIMAP assists biologists to query the up-to-date sequence space systematically and facilitates large-scale downstream projects in computational biology. Access to SIMAP is freely provided through the web portal for individuals (http://mips.gsf.de/simap/) and for programmatic access through DAS (http://webclu.bio.wzw.tum.de/das/) and Web-Service (http://mips.gsf.de/webservices/services/SimapService2.0?wsdl).

%B Nucleic acids research %V 38 %P D223-6 %8 2010 Jan %G eng %0 Journal Article %J Nucl. Acids Res. %D 2009 %T SARA: a server for function annotation of RNA structures %A Capriotti, Emidio %A M. A. Marti-Renom %K RNA %K RNA structure %X

Recent interest in non-coding RNA transcripts has resulted in a rapid increase of deposited RNA structures in the Protein Data Bank. However, a characterization and functional classification of the RNA structure and function space have only been partially addressed. Here, we introduce the SARA program for pair-wise alignment of RNA structures as a web server for structure-based RNA function assignment. The SARA server relies on the SARA program, which aligns two RNA structures based on a unit-vector root-mean-square approach. The likely accuracy of the SARA alignments is assessed by three different P-values estimating the statistical significance of the sequence, secondary structure and tertiary structure identity scores, respectively. Our benchmarks, which relied on a set of 419 RNA structures with known SCOR structural class, indicate that at a negative logarithm of mean P-value higher or equal than 2.5, SARA can assign the correct or a similar SCOR class to 81.4% and 95.3% of the benchmark set, respectively. The SARA server is freely accessible via the World Wide Web at http://sgu.bioinfo.cipf.es/services/SARA/.

%B Nucl. Acids Res. %P gkp433 %G eng %U http://nar.oxfordjournals.org/cgi/content/abstract/gkp433v1 %R 10.1093/nar/gkp433 %0 Journal Article %J Proc Biol Sci %D 2009 %T Sexual selection drives weak positive selection in protamine genes and high promoter divergence, enhancing sperm competitiveness %A Martin-Coello, J. %A H. Dopazo %A Arbiza, L. %A Ausio, J. %A Roldan, E. R. %A Gomendio, M. %K Adaptation %K positive selection %K sperm competition %X

Phenotypic adaptations may be the result of changes in gene structure or gene regulation, but little is known about the evolution of gene expression. In addition, it is unclear whether the same selective forces may operate at both levels simultaneously. Reproductive proteins evolve rapidly, but the underlying selective forces promoting such rapid changes are still a matter of debate. In particular, the role of sexual selection in driving positive selection among reproductive proteins remains controversial, whereas its potential influence on changes in promoter regions has not been explored. Protamines are responsible for maintaining DNA in a compacted form in chromosomes in sperm and the available evidence suggests that they evolve rapidly. Because protamines condense DNA within the sperm nucleus, they influence sperm head shape. Here, we examine the influence of sperm competition upon protamine 1 and protamine 2 genes and their promoters, by comparing closely related species of Mus that differ in relative testes size, a reliable indicator of levels of sperm competition. We find evidence of positive selection in the protamine 2 gene in the species with the highest inferred levels of sperm competition. In addition, sperm competition levels across all species are strongly associated with high divergence in protamine 2 promoters that, in turn, are associated with sperm swimming speed. We suggest that changes in protamine 2 promoters are likely to enhance sperm swimming speed by making sperm heads more hydrodynamic. Such phenotypic changes are adaptive because sperm swimming speed may be a major determinant of fertilization success under sperm competition. Thus, when species have diverged recently, few changes in gene-coding sequences are found, while high divergence in promoters seems to be associated with the intensity of sexual selection.

%B Proc Biol Sci %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19364735 %0 Journal Article %J Nucleic Acids Res %D 2009 %T SNOW, a web-based tool for the statistical analysis of protein-protein interaction networks. %A Minguez, Pablo %A Götz, Stefan %A Montaner, David %A Al-Shahrour, Fátima %A Dopazo, Joaquin %K Computer Graphics %K Data Interpretation, Statistical %K Databases, Protein %K Humans %K Internet %K Protein Interaction Mapping %K Software %X

Understanding the structure and the dynamics of the complex intercellular network of interactions that contributes to the structure and function of a living cell is one of the main challenges of today's biology. SNOW inputs a collection of protein (or gene) identifiers and, by using the interactome as scaffold, draws the connections among them, calculates several relevant network parameters and, as a novelty among the rest of tools of its class, it estimates their statistical significance. The parameters calculated for each node are: connectivity, betweenness and clustering coefficient. It also calculates the number of components, number of bicomponents and articulation points. An interactive network viewer is also available to explore the resulting network. SNOW is available at http://snow.bioinfo.cipf.es.

%B Nucleic Acids Res %V 37 %P W109-14 %8 2009 Jul %G eng %N Web Server issue %1 https://www.ncbi.nlm.nih.gov/pubmed/19454602?dopt=Abstract %R 10.1093/nar/gkp402 %0 Journal Article %J Nucl. Acids Res. %D 2009 %T SNOW, a web-based tool for the statistical analysis of protein-protein interaction networks %A Minguez, Pablo %A Gotz, S. %A Montaner, David %A Fatima Al-Shahrour %A Dopazo, Joaquin %K interactome %K network %K snow %X

Understanding the structure and the dynamics of the complex intercellular network of interactions that contributes to the structure and function of a living cell is one of the main challenges of today’s biology. SNOW inputs a collection of protein (or gene) identifiers and, by using the interactome as scaffold, draws the connections among them, calculates several relevant network parameters and, as a novelty among the rest of tools of its class, it estimates their statistical significance. The parameters calculated for each node are: connectivity, betweenness and clustering coefficient. It also calculates the number of components, number of bicomponents and articulation points. An interactive network viewer is also available to explore the resulting network. SNOW is available at http://snow.bioinfo.cipf.es.

%B Nucl. Acids Res. %V 37 %P W109-114 %G eng %U http://nar.oxfordjournals.org/content/early/2009/05/19/nar.gkp402.full %R 10.1093/nar/gkp402 %0 Journal Article %J Nature Methods %D 2009 %T Statistical methods for analysis of high-throughput RNA interference screens %A Birmingham, Amanda %A Selfors, Laura M %A Forster, Thorsten %A Wrobel, David %A Kennedy, Caleb J %A Shanks, Emma %A Santoyo-López, Javier %A Dunican, Dara J %A Long, Aideen %A Kelleher, Dermot %A Smith, Queta %A Beijersbergen, Roderick L %A Ghazal, Peter %A Shamu, Caroline E %K gene silencing %K regulation %K siRNA %B Nature Methods %I Nature Publishing Group %V 6 %P 569 - 575 %8 2009/08//print %@ 1548-7091 %G eng %U http://dx.doi.org/10.1038/nmeth.1351 %0 Book Section %B Structural Bioinformatics %D 2009 %T Structural Comparison and Alignment %A M. A. Marti-Renom %A E. Capriotti %A Shindyalov, I. %A Bourne, P. %K Structural Bioinformatics %B Structural Bioinformatics %7 2nd %I Wiley-Blackwell %C New Jersey. USA %G eng %U http://www.amazon.com/gp/product/0470181052/ %0 Book Section %B Encyclopedia of Life Science %D 2008 %T Selective Constraints and Human Disease Genes: Evolutionary and Bioinformatic Approaches %A H. Dopazo %B Encyclopedia of Life Science %I John Wiley & Sons, Ltd. %C UK %G eng %R 10.1002/9780470015902.a0020762 %0 Book Section %B Handbook of Human Molecular Evolution %D 2008 %T Selective Constraints on Human Disease Mutations and Polymorphisms %A H. Dopazo %B Handbook of Human Molecular Evolution %I Hildegard Kehrer-Sawatzki & David N. Cooper. John Wiley & Sons, Ltd %C UK %G eng %U http://eu.wiley.com/WileyCDA/WileyTitle/productCd-0470517468,descCd-description.html %0 Journal Article %J Nat Genet %D 2008 %T SNP and haplotype mapping for genetic analysis in the rat %A K. Saar %A A. Beck %A M. T. Bihoreau %A E. Birney %A D. Brocklebank %A Y. Chen %A E. Cuppen %A S. Demonchy %A Dopazo, J. %A P. Flicek %A M. Foglio %A A. Fujiyama %A I. G. Gut %A D. Gauguier %A R. Guigo %A V. Guryev %A M. Heinig %A O. Hummel %A N. Jahn %A S. Klages %A V. Kren %A M. Kube %A H. Kuhl %A Kuramoto, T. %A Kuroki, Y. %A Lechner, D. %A Lee, Y. A. %A Lopez-Bigas, N. %A Lathrop, G. M. %A Mashimo, T. %A Medina, Ignacio %A Mott, R. %A Patone, G. %A Perrier-Cornet, J. A. %A Platzer, M. %A Pravenec, M. %A Reinhardt, R. %A Sakaki, Y. %A Schilhabel, M. %A Schulz, H. %A Serikawa, T. %A Shikhagaie, M. %A Tatsumoto, S. %A Taudien, S. %A Toyoda, A. %A Voigt, B. %A Zelenika, D. %A Zimdahl, H. %A Hubner, N. %K Animals Chromosome Mapping *Databases %K Genetic %K Genetic Genome *Haplotypes Linkage Disequilibrium Phylogeny *Polymorphism %K Inbred Strains/*genetics Recombination %K Single Nucleotide *Quantitative Trait Loci Rats/*genetics Rats %X

The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies.

%B Nat Genet %V 40 %P 560-6 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18443594 %0 Journal Article %J Nat Genet %D 2008 %T SNP and haplotype mapping for genetic analysis in the rat. %A Saar, Kathrin %A Beck, Alfred %A Bihoreau, Marie-Thérèse %A Birney, Ewan %A Brocklebank, Denise %A Chen, Yuan %A Cuppen, Edwin %A Demonchy, Stephanie %A Dopazo, Joaquin %A Flicek, Paul %A Foglio, Mario %A Fujiyama, Asao %A Gut, Ivo G %A Gauguier, Dominique %A Guigó, Roderic %A Guryev, Victor %A Heinig, Matthias %A Hummel, Oliver %A Jahn, Niels %A Klages, Sven %A Kren, Vladimir %A Kube, Michael %A Kuhl, Heiner %A Kuramoto, Takashi %A Kuroki, Yoko %A Lechner, Doris %A Lee, Young-Ae %A Lopez-Bigas, Nuria %A Lathrop, G Mark %A Mashimo, Tomoji %A Medina, Ignacio %A Mott, Richard %A Patone, Giannino %A Perrier-Cornet, Jeanne-Antide %A Platzer, Matthias %A Pravenec, Michal %A Reinhardt, Richard %A Sakaki, Yoshiyuki %A Schilhabel, Markus %A Schulz, Herbert %A Serikawa, Tadao %A Shikhagaie, Medya %A Tatsumoto, Shouji %A Taudien, Stefan %A Toyoda, Atsushi %A Voigt, Birger %A Zelenika, Diana %A Zimdahl, Heike %A Hubner, Norbert %K Animals %K Chromosome Mapping %K Databases, Genetic %K Genome %K Haplotypes %K Linkage Disequilibrium %K Phylogeny %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Rats %K Rats, Inbred Strains %K Recombination, Genetic %X

The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies.

%B Nat Genet %V 40 %P 560-6 %8 2008 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/18443594?dopt=Abstract %R 10.1038/ng.124 %0 Journal Article %J Eukaryot Cell %D 2007 %T Spatial differentiation in the vegetative mycelium of Aspergillus niger %A Levin, A. M. %A de Vries, R. P. %A A. Conesa %A de Bekker, C. %A Talon, M. %A Menke, H. H. %A van Peij, N. N. %A Wosten, H. A. %K Aspergillus niger/*metabolism Cell Wall/metabolism Fungal Proteins/metabolism *Gene Expression Regulation %K Biological Mycelium/*metabolism Oligonucleotide Array Sequence Analysis RNA %K Fungal Genes %K Fungal Genome %K Fungal Glucans/chemistry Maltose/chemistry Models %K Fungal Time Factors Trans-Activators/metabolism Xylose/chemistry %X Fungal mycelia are exposed to heterogenic substrates. The substrate in the central part of the colony has been (partly) degraded, whereas it is still unexplored at the periphery of the mycelium. We here assessed whether substrate heterogeneity is a main determinant of spatial gene expression in colonies of Aspergillus niger. This question was addressed by analyzing whole-genome gene expression in five concentric zones of 7-day-old maltose- and xylose-grown colonies. Expression profiles at the periphery and the center were clearly different. More than 25% of the active genes showed twofold differences in expression between the inner and outermost zones of the colony. Moreover, 9% of the genes were expressed in only one of the five concentric zones, showing that a considerable part of the genome is active in a restricted part of the colony only. Statistical analysis of expression profiles of colonies that had either been or not been transferred to fresh xylose-containing medium showed that differential expression in a colony is due to the heterogeneity of the medium (e.g., genes involved in secretion, genes encoding proteases, and genes involved in xylose metabolism) as well as to medium-independent mechanisms (e.g., genes involved in nitrate metabolism and genes involved in cell wall synthesis and modification). Thus, we conclude that the mycelia of 7-day-old colonies of A. niger are highly differentiated. This conclusion is also indicated by the fact that distinct zones of the colony grow and secrete proteins, even after transfer to fresh medium. %B Eukaryot Cell %V 6 %P 2311-22 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17951513 %0 Journal Article %J Philos Trans R Soc Lond B Biol Sci %D 2007 %T Structural analyses of a hypothetical minimal metabolism %A Gabaldón, T. %A Peretó, J. %A Montero, F. %A Gil, R. %A Latorre, A. %A Moya, A. %K *Cell Physiological Phenomena Cells/*metabolism Cluster Analysis *Computer Simulation *Metabolic Networks and Pathways *Models %K Biological Models %K Statistical %X By integrating data from comparative genomics and large-scale deletion studies, we previously proposed a minimal gene set comprising 206 protein-coding genes. To evaluate the consistency of the metabolism encoded by such a minimal genome, we have carried out a series of computational analyses. Firstly, the topology of the minimal metabolism was compared with that of the reconstructed networks from natural bacterial genomes. Secondly, the robustness of the metabolic network was evaluated by simulated mutagenesis and, finally, the stoichiometric consistency was assessed by automatically deriving the steady-state solutions from the reaction set. The results indicated that the proposed minimal metabolism presents stoichiometric consistency and that it is organized as a complex power-law network with topological parameters falling within the expected range for a natural metabolism of its size. The robustness analyses revealed that most random mutations do not alter the topology of the network significantly, but do cause significant damage by preventing the synthesis of several compounds or compromising the stoichiometric consistency of the metabolism. The implications that these results have on the origins of metabolic complexity and the theoretical design of an artificial minimal cell are discussed. %B Philos Trans R Soc Lond B Biol Sci %V 362 %P 1751-62 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17510022 %0 Journal Article %J J Mol Biol %D 2006 %T Selective pressures at a codon-level predict deleterious mutations in human disease genes %A Arbiza, L. %A Duchi, S. %A Montaner, D. %A Burguet, J. %A Pantoja-Uceda, D. %A Pineda-Lucena, A. %A Dopazo, J. %A H. Dopazo %K Amino Acid Sequence Amino Acid Substitution Codon/*genetics Databases %K Genetic Evolution %K Genetic Models %K Human Humans Models %K Inborn/*genetics Genome %K Molecular Genes %K Molecular Molecular Sequence Data *Mutation Neoplasms/genetics Proteins/genetics *Selection (Genetics) Tumor Suppressor Protein p53/chemistry/genetics %K p53 Genetic Diseases %X Deleterious mutations affecting biological function of proteins are constantly being rejected by purifying selection from the gene pool. The non-synonymous/synonymous substitution rate ratio (omega) is a measure of selective pressure on amino acid replacement mutations for protein-coding genes. Different methods have been developed in order to predict non-synonymous changes affecting gene function. However, none has considered the estimation of selective constraints acting on protein residues. Here, we have used codon-based maximum likelihood models in order to estimate the selective pressures on the individual amino acid residues of a well-known model protein: p53. We demonstrate that the number of residues under strong purifying selection in p53 is much higher than those that are strictly conserved during the evolution of the species. In agreement with theoretical expectations, residues that have been noted to be of structural relevance, or in direct association with DNA, were among those showing the highest signals of purifying selection. Conversely, those changing according to a neutral, or nearly neutral mode of evolution, were observed to be irrelevant for protein function. Finally, using more than 40 human disease genes, we demonstrate that residues evolving under strong selective pressures (omega<0.1) are significantly associated (p<0.01) with human disease. We hypothesize that non-synonymous change on amino acids showing omega<0.1 will most likely affect protein function. The application of this evolutionary prediction at a genomic scale will provide an a priori hypothesis of the phenotypic effect of non-synonymous coding single nucleotide polymorphisms (SNPs) in the human genome. %B J Mol Biol %V 358 %P 1390-404 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16584746 %0 Book Section %B Adaptation to life in high salt concentrations in Archaea, Bacteria and Eukarya %D 2005 %T Salinibacter ruber: genomics and biogeography %A Antón, J %A Peña, A %A Valens, M %A Santos, F %A Glöckner, F.O %A Bauer, M %A Dopazo, J. %A Herrero, J. %A Rosselló-Mora, R %A Amann, R %B Adaptation to life in high salt concentrations in Archaea, Bacteria and Eukarya %I Nina Gunde-Cimerman, Ana Plemenitas, and Aharon Oren. Kluwer Academic Publishers %C Dordrecht, Netherlands %V 9 %P 257-266 %G eng %0 Journal Article %J Biochim Biophys Acta %D 2004 %T Shaping the mitochondrial proteome %A Gabaldón, T. %A M. A. Huynen %K Animals Biological Transport Energy Metabolism Eukaryotic Cells/physiology *Evolution Humans Mitochondria/*physiology Phylogeny Proteome/*physiology %X Mitochondria are eukaryotic organelles that originated from a single bacterial endosymbiosis some 2 billion years ago. The transition from the ancestral endosymbiont to the modern mitochondrion has been accompanied by major changes in its protein content, the so-called proteome. These changes included complete loss of some bacterial pathways, amelioration of others and gain of completely new complexes of eukaryotic origin such as the ATP/ADP translocase and most of the mitochondrial protein import machinery. This renewal of proteins has been so extensive that only 14-16% of modern mitochondrial proteome has an origin that can be traced back to the bacterial endosymbiont. The rest consists of proteins of diverse origin that were eventually recruited to function in the organelle. This shaping of the proteome content reflects the transformation of mitochondria into a highly specialized organelle that, besides ATP production, comprises a variety of functions within the eukaryotic metabolism. Here we review recent advances in the fields of comparative genomics and proteomics that are throwing light on the origin and evolution of the mitochondrial proteome. %B Biochim Biophys Acta %V 1659 %P 212-20 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15576054 %0 Journal Article %J Cancer Res %D 2004 %T Structure-based assessment of missense mutations in human BRCA1: implications for breast and ovarian cancer predisposition %A Mirkovic, N. %A M. A. Marti-Renom %A Weber, B. L. %A Sali, A. %A Monteiro, A. N. %K BRCA1 Genetic Predisposition to Disease Humans *Mutation %K BRCA1 Protein/*chemistry/genetics Breast Neoplasms/*genetics Female *Genes %K Missense Ovarian Neoplasms/*genetics Pedigree Protein Conformation Structure-Activity Relationship Transcriptional Activation %X The BRCA1 gene from individuals at risk of breast and ovarian cancers can be screened for the presence of mutations. However, the cancer association of most alleles carrying missense mutations is unknown, thus creating significant problems for genetic counseling. To increase our ability to identify cancer-associated mutations in BRCA1, we set out to use the principles of protein three-dimensional structure as well as the correlation between the cancer-associated mutations and those that abolish transcriptional activation. Thirty-one of 37 missense mutations of known impact on the transcriptional activation function of BRCA1 are readily rationalized in structural terms. Loss-of-function mutations involve nonconservative changes in the core of the BRCA1 C-terminus (BRCT) fold or are localized in a groove that presumably forms a binding site involved in the transcriptional activation by BRCA1; mutations that do not abolish transcriptional activation are either conservative changes in the core or are on the surface outside of the putative binding site. Next, structure-based rules for predicting functional consequences of a given missense mutation were applied to 57 germ-line BRCA1 variants of unknown cancer association. Such a structure-based approach may be helpful in an integrated effort to identify mutations that predispose individuals to cancer. %B Cancer Res %V 64 %P 3790-7 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15172985 %0 Book Section %B Microarray data analysis II %D 2002 %T Supervised Neural Networks For Clustering Conditions In DNA Array Data After Reducing Noise By Clustering Gene Expression Profiles %A A. Mateos %A Herrero, J. %A J. Tamames %A Dopazo, J. %B Microarray data analysis II %I Kluwer Academic %P 91-103 %G eng %0 Journal Article %J Genome Res %D 2002 %T Systematic learning of gene functional classes from DNA array expression data by using multilayer perceptrons %A A. Mateos %A Dopazo, J. %A Jansen, R. %A Tu, Y. %A Gerstein, M. %A Stolovitzky, G. %K Algorithms Artificial Intelligence Citric Acid Cycle/genetics Cluster Analysis Computational Biology/methods Gene Expression Profiling/*methods/statistics & numerical data Genes/*physiology Genetic Heterogeneity Neural Networks (Computer) Oligonucleotide %X Recent advances in microarray technology have opened new ways for functional annotation of previously uncharacterised genes on a genomic scale. This has been demonstrated by unsupervised clustering of co-expressed genes and, more importantly, by supervised learning algorithms. Using prior knowledge, these algorithms can assign functional annotations based on more complex expression signatures found in existing functional classes. Previously, support vector machines (SVMs) and other machine-learning methods have been applied to a limited number of functional classes for this purpose. Here we present, for the first time, the comprehensive application of supervised neural networks (SNNs) for functional annotation. Our study is novel in that we report systematic results for 100 classes in the Munich Information Center for Protein Sequences (MIPS) functional catalog. We found that only 10% of these are learnable (based on the rate of false negatives). A closer analysis reveals that false positives (and negatives) in a machine-learning context are not necessarily "false" in a biological sense. We show that the high degree of interconnections among functional classes confounds the signatures that ought to be learned for a unique class. We term this the "Borges effect" and introduce two new numerical indices for its quantification. Our analysis indicates that classification systems with a lower Borges effect are better suitable for machine learning. Furthermore, we introduce a learning procedure for combining false positives with the original class. We show that in a few iterations this process converges to a gene set that is learnable with considerably low rates of false positives and negatives and contains genes that are biologically related to the original class, allowing for a coarse reconstruction of the interactions between associated biological pathways. We exemplify this methodology using the well-studied tricarboxylic acid cycle. %B Genome Res %V 12 %P 1703-15 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12421757 %0 Journal Article %J Fungal Genet Biol %D 2001 %T The secretion pathway in filamentous fungi: a biotechnological view %A A. Conesa %A Punt, P. J. %A van Luijk, N. %A van den Hondel, C. A. %K Animals Biotechnology/*methods Fungal Proteins/*genetics/*metabolism Fungi/*genetics/*metabolism Humans Recombinant Proteins/metabolism %X The high capacity of the secretion machinery of filamentous fungi has been widely exploited for the production of homologous and heterologous proteins; however, our knowledge of the fungal secretion pathway is still at an early stage. Most of the knowledge comes from models developed in yeast and higher eukaryotes, which have served as reference for the studies on fungal species. In this review we compile the data accumulated in recent years on the molecular basis of fungal secretion, emphasizing the relevance of these data for the biotechnological use of the fungal cell and indicating how this information has been applied in attempts to create improved production strains. We also present recent emerging approaches that promise to provide answers to fundamental questions on the molecular genetics of the fungal secretory pathway. %B Fungal Genet Biol %V 33 %P 155-71 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11495573