@article {407, title = {The modular network structure of the mutational landscape of Acute Myeloid Leukemia.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0202926}, abstract = {

Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50\% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways.

}, keywords = {Adult, Aged, Cytodiagnosis, Exome Sequencing, Female, Gene Regulatory Networks, Genetic Association Studies, Genetic Heterogeneity, Humans, Karyotype, Leukemia, Myeloid, Acute, Male, Middle Aged, mutation, Neoplasm Proteins, Nucleophosmin, Prognosis}, issn = {1932-6203}, doi = {10.1371/journal.pone.0202926}, author = {Ib{\'a}{\~n}ez, Mariam and Carbonell-Caballero, Jos{\'e} and Such, Esperanza and Garc{\'\i}a-Alonso, Luz and Liquori, Alessandro and L{\'o}pez-Pav{\'\i}a, Mar{\'\i}a and LLop, Marta and Alonso, Carmen and Barrag{\'a}n, Eva and G{\'o}mez-Segu{\'\i}, In{\'e}s and Neef, Alexander and Herv{\'a}s, David and Montesinos, Pau and Sanz, Guillermo and Sanz, Miguel Angel and Dopazo, Joaquin and Cervera, Jos{\'e}} } @article {1184, title = {267 Spanish exomes reveal population-specific differences in disease-related genetic variation.}, journal = {Molecular biology and evolution}, year = {2016}, month = {2016 Jan 13}, abstract = {Recent results from large-scale genomic projects suggest that allele frequencies, which are highly relevant for medical purposes, differ considerably across different populations. The need for a detailed catalogue of local variability motivated the whole exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population. Like in other studies, a considerable number of rare variants were found (almost one third of the described variants). There were also relevant differences in allelic frequencies in polymorphic variants, including about 10,000 polymorphisms private to the Spanish population. The allelic frequencies of variants conferring susceptibility to complex diseases (including cancer, schizophrenia, Alzheimer disease, type 2 diabetes and other pathologies) were overall similar to those of other populations. However, the trend is the opposite for variants linked to Mendelian and rare diseases (including several retinal degenerative dystrophies and cardiomyopathies) that show marked frequency differences between populations. Interestingly, a correspondence between differences in allelic frequencies and disease prevalence was found, highlighting the relevance of frequency differences in disease risk. These differences are also observed in variants that disrupt known drug binding sites, suggesting an important role for local variability in population-specific drug resistances or adverse effects. We have made the Spanish population variant server web page that contains population frequency information for the complete list of 170,888 variant positions we found publicly available (http://spv.babelomics.org/), We show that it if fundamental to determine population-specific variant frequencies in order to distinguish real disease associations from population-specific polymorphisms.}, keywords = {disease, NGS, polymorphisms, Population genomics, prioritization, SNP}, issn = {1537-1719}, doi = {10.1093/molbev/msw005}, url = {https://mbe.oxfordjournals.org/content/early/2016/02/17/molbev.msw005.full}, author = {Joaqu{\'\i}n Dopazo and Amadoz, Alicia and Bleda, Marta and Garc{\'\i}a-Alonso, Luz and Alem{\'a}n, Alejandro and Garcia-Garcia, Francisco and Rodriguez, Juan A and Daub, Josephine T and Muntan{\'e}, Gerard and Antonio Rueda and Vela-Boza, Alicia and L{\'o}pez-Domingo, Francisco J and Florido, Javier P and Arce, Pablo and Ruiz-Ferrer, Macarena and M{\'e}ndez-Vidal, Cristina and Arnold, Todd E and Spleiss, Olivia and Alvarez-Tejado, Miguel and Navarro, Arcadi and Bhattacharya, Shomi S and Borrego, Salud and Santoyo-L{\'o}pez, Javier and Anti{\v n}olo, Guillermo} } @article {453, title = {The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0148346}, abstract = {

Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations.

}, keywords = {Exome, Gene Regulatory Networks, Genome, Human, Humans, INDEL Mutation, Leukemia, Promyelocytic, Acute, mutation, Mutation Rate, Polymorphism, Single Nucleotide, Reproducibility of Results}, issn = {1932-6203}, doi = {10.1371/journal.pone.0148346}, author = {Ib{\'a}{\~n}ez, Mariam and Carbonell-Caballero, Jos{\'e} and Garc{\'\i}a-Alonso, Luz and Such, Esperanza and Jim{\'e}nez-Almaz{\'a}n, Jorge and Vidal, Enrique and Barrag{\'a}n, Eva and L{\'o}pez-Pav{\'\i}a, Mar{\'\i}a and LLop, Marta and Mart{\'\i}n, Iv{\'a}n and G{\'o}mez-Segu{\'\i}, In{\'e}s and Montesinos, Pau and Sanz, Miguel A and Dopazo, Joaquin and Cervera, Jos{\'e}} } @article {438, title = {Web-based network analysis and visualization using CellMaps.}, journal = {Bioinformatics}, volume = {32}, year = {2016}, month = {2016 Oct 01}, pages = {3041-3}, abstract = {

UNLABELLED: : CellMaps is an HTML5 open-source web tool that allows displaying, editing, exploring and analyzing biological networks as well as integrating metadata into them. Computations and analyses are remotely executed in high-end servers, and all the functionalities are available through RESTful web services. CellMaps can easily be integrated in any web page by using an available JavaScript API.

AVAILABILITY AND IMPLEMENTATION: The application is available at: http://cellmaps.babelomics.org/ and the code can be found in: https://github.com/opencb/cell-maps The client is implemented in JavaScript and the server in C and Java.

CONTACT: jdopazo@cipf.es

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

}, keywords = {Biochemical Phenomena, Internet, Software}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btw332}, author = {Salavert, Francisco and Garc{\'\i}a-Alonso, Luz and S{\'a}nchez, Rub{\'e}n and Alonso, Roberto and Bleda, Marta and Medina, Ignacio and Dopazo, Joaquin} } @article {1129, title = {Babelomics 5.0: functional interpretation for new generations of genomic data.}, journal = {Nucleic acids research}, volume = {43}, number = {W1}, year = {2015}, month = {2015 Apr 20}, pages = {W117-W121}, abstract = {Babelomics has been running for more than one decade offering a user-friendly interface for the functional analysis of gene expression and genomic data. Here we present its fifth release, which includes support for Next Generation Sequencing data including gene expression (RNA-seq), exome or genome resequencing. Babelomics has simplified its interface, being now more intuitive. Improved visualization options, such as a genome viewer as well as an interactive network viewer, have been implemented. New technical enhancements at both, client and server sides, makes the user experience faster and more dynamic. Babelomics offers user-friendly access to a full range of methods that cover: (i) primary data analysis, (ii) a variety of tests for different experimental designs and (iii) different enrichment and network analysis algorithms for the interpretation of the results of such tests in the proper functional context. In addition to the public server, local copies of Babelomics can be downloaded and installed. Babelomics is freely available at: http://www.babelomics.org.}, keywords = {babelomics, data integration, gene set analysis, interactome, network analysis, NGS, RNA-seq, Systems biology, transcriptomics}, issn = {1362-4962}, doi = {10.1093/nar/gkv384}, url = {http://nar.oxfordjournals.org/content/43/W1/W117}, author = {Alonso, Roberto and Salavert, Francisco and Garcia-Garcia, Francisco and Carbonell-Caballero, Jos{\'e} and Bleda, Marta and Garc{\'\i}a-Alonso, Luz and Sanchis-Juan, Alba and Perez-Gil, Daniel and Marin-Garcia, Pablo and S{\'a}nchez, Rub{\'e}n and Cubuk, Cankut and Hidalgo, Marta R and Amadoz, Alicia and Hernansaiz-Ballesteros, Rosa D and Alem{\'a}n, Alejandro and T{\'a}rraga, Joaqu{\'\i}n and Montaner, David and Medina, Ignacio and Dopazo, Joaquin} } @article {562, title = {Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas}, journal = {BMC Medical Genomics}, volume = {8}, year = {2015}, month = {Dec}, pages = {83}, abstract = {The molecular mechanisms leading to sporadic medullary thyroid carcinoma (sMTC) and juvenile papillary thyroid carcinoma (PTC), two rare tumours of the thyroid gland, remain poorly understood. Genetic studies on thyroid carcinomas have been conducted, although just a few loci have been systematically associated. Given the difficulties to obtain single-loci associations, this work expands its scope to the study of epistatic interactions that could help to understand the genetic architecture of complex diseases and explain new heritable components of genetic risk.}, issn = {1755-8794}, doi = {10.1186/s12920-015-0160-7}, url = {https://doi.org/10.1186/s12920-015-0160-7}, author = {Luz{\'o}n-Toro, Berta and Bleda, Marta and Navarro, Elena and Garc{\'\i}a-Alonso, Luz and Ruiz-Ferrer, Macarena and Medina, Ignacio and Mart{\'\i}n-S{\'a}nchez, Marta and Gonzalez, Cristina Y. and Fern{\'a}ndez, Raquel M. and Torroglosa, Ana and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} } @article {1179, title = {Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas.}, journal = {BMC medical genomics}, volume = {8}, year = {2015}, month = {2015}, pages = {83}, abstract = {BACKGROUND: The molecular mechanisms leading to sporadic medullary thyroid carcinoma (sMTC) and juvenile papillary thyroid carcinoma (PTC), two rare tumours of the thyroid gland, remain poorly understood. Genetic studies on thyroid carcinomas have been conducted, although just a few loci have been systematically associated. Given the difficulties to obtain single-loci associations, this work expands its scope to the study of epistatic interactions that could help to understand the genetic architecture of complex diseases and explain new heritable components of genetic risk. METHODS: We carried out the first screening for epistasis by Multifactor-Dimensionality Reduction (MDR) in genome-wide association study (GWAS) on sMTC and juvenile PTC, to identify the potential simultaneous involvement of pairs of variants in the disease. RESULTS: We have identified two significant epistatic gene interactions in sMTC (CHFR-AC016582.2 and C8orf37-RNU1-55P) and three in juvenile PTC (RP11-648k4.2-DIO1, RP11-648k4.2-DMGDH and RP11-648k4.2-LOXL1). Interestingly, each interacting gene pair included a non-coding RNA, providing thus support to the relevance that these elements are increasingly gaining to explain carcinoma development and progression. CONCLUSIONS: Overall, this study contributes to the understanding of the genetic basis of thyroid carcinoma susceptibility in two different case scenarios such as sMTC and juvenile PTC.}, keywords = {epistasis, GWAS, Thyroid cancer}, issn = {1755-8794}, doi = {10.1186/s12920-015-0160-7}, url = {http://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-015-0160-7}, author = {Luz{\'o}n-Toro, Berta and Bleda, Marta and Navarro, Elena and Garc{\'\i}a-Alonso, Luz and Ruiz-Ferrer, Macarena and Medina, Ignacio and Mart{\'\i}n-S{\'a}nchez, Marta and Gonzalez, Cristina Y and Fern{\'a}ndez, Raquel M and Torroglosa, Ana and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} } @article {460, title = {A Pan-Cancer Catalogue of Cancer Driver Protein Interaction Interfaces.}, journal = {PLoS Comput Biol}, volume = {11}, year = {2015}, month = {2015 Oct}, pages = {e1004518}, abstract = {

Despite their importance in maintaining the integrity of all cellular pathways, the role of mutations on protein-protein interaction (PPI) interfaces as cancer drivers has not been systematically studied. Here we analyzed the mutation patterns of the PPI interfaces from 10,028 proteins in a pan-cancer cohort of 5,989 tumors from 23 projects of The Cancer Genome Atlas (TCGA) to find interfaces enriched in somatic missense mutations. To that end we use e-Driver, an algorithm to analyze the mutation distribution of specific protein functional regions. We identified 103 PPI interfaces enriched in somatic cancer mutations. 32 of these interfaces are found in proteins coded by known cancer driver genes. The remaining 71 interfaces are found in proteins that have not been previously identified as cancer drivers even that, in most cases, there is an extensive literature suggesting they play an important role in cancer. Finally, we integrate these findings with clinical information to show how tumors apparently driven by the same gene have different behaviors, including patient outcomes, depending on which specific interfaces are mutated.

}, keywords = {Animals, Base Sequence, Biomarkers, Tumor, Catalogs as Topic, Chromosome Mapping, Computer Simulation, DNA Mutational Analysis, Genetic Predisposition to Disease, Humans, Models, Genetic, Molecular Sequence Data, mutation, Neoplasm Proteins, Neoplasms, Polymorphism, Single Nucleotide, Protein Interaction Mapping, Signal Transduction}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1004518}, author = {Porta-Pardo, Eduard and Garc{\'\i}a-Alonso, Luz and Hrabe, Thomas and Dopazo, Joaquin and Godzik, Adam} } @article {468, title = {PTMcode v2: a resource for functional associations of post-translational modifications within and between proteins.}, journal = {Nucleic Acids Res}, volume = {43}, year = {2015}, month = {2015 Jan}, pages = {D494-502}, abstract = {

The post-translational regulation of proteins is mainly driven by two molecular events, their modification by several types of moieties and their interaction with other proteins. These two processes are interdependent and together are responsible for the function of the protein in a particular cell state. Several databases focus on the prediction and compilation of protein-protein interactions (PPIs) and no less on the collection and analysis of protein post-translational modifications (PTMs), however, there are no resources that concentrate on describing the regulatory role of PTMs in PPIs. We developed several methods based on residue co-evolution and proximity to predict the functional associations of pairs of PTMs that we apply to modifications in the same protein and between two interacting proteins. In order to make data available for understudied organisms, PTMcode v2 (http://ptmcode.embl.de) includes a new strategy to propagate PTMs from validated modified sites through orthologous proteins. The second release of PTMcode covers 19 eukaryotic species from which we collected more than 300,000 experimentally verified PTMs (>1,300,000 propagated) of 69 types extracting the post-translational regulation of >100,000 proteins and >100,000 interactions. In total, we report 8 million associations of PTMs regulating single proteins and over 9.4 million interplays tuning PPIs.

}, keywords = {Databases, Protein, Internet, Protein Interaction Mapping, Protein Processing, Post-Translational}, issn = {1362-4962}, doi = {10.1093/nar/gku1081}, author = {Minguez, Pablo and Letunic, Ivica and Parca, Luca and Garc{\'\i}a-Alonso, Luz and Dopazo, Joaquin and Huerta-Cepas, Jaime and Bork, Peer} } @article {486, title = {Deciphering intrafamilial phenotypic variability by exome sequencing in a Bardet-Biedl family.}, journal = {Mol Genet Genomic Med}, volume = {2}, year = {2014}, month = {2014 Mar}, pages = {124-33}, abstract = {

Bardet-Biedl syndrome (BBS) is a model ciliopathy characterized by a wide range of clinical variability. The heterogeneity of this condition is reflected in the number of underlying gene defects and the epistatic interactions between the proteins encoded. BBS is generally inherited in an autosomal recessive trait. However, in some families, mutations across different loci interact to modulate the expressivity of the phenotype. In order to investigate the magnitude of epistasis in one BBS family with remarkable intrafamilial phenotypic variability, we designed an exome sequencing-based approach using SOLID 5500xl platform. This strategy allowed the reliable detection of the primary causal mutations in our family consisting of two novel compound heterozygous mutations in McKusick-Kaufman syndrome (MKKS) gene (p.D90G and p.V396F). Additionally, exome sequencing enabled the detection of one novel heterozygous NPHP4 variant which is predicted to activate a cryptic acceptor splice site and is only present in the most severely affected patient. Here, we provide an exome sequencing analysis of a BBS family and show the potential utility of this tool, in combination with network analysis, to detect disease-causing mutations and second-site modifiers. Our data demonstrate how next-generation sequencing (NGS) can facilitate the dissection of epistatic phenomena, and shed light on the genetic basis of phenotypic variability.

}, issn = {2324-9269}, doi = {10.1002/mgg3.50}, author = {Gonz{\'a}lez-del Pozo, Mar{\'\i}a and M{\'e}ndez-Vidal, Cristina and Santoyo-L{\'o}pez, Javier and Vela-Boza, Alicia and Bravo-Gil, Nereida and Rueda, Antonio and Garc{\'\i}a-Alonso, Luz and V{\'a}zquez-Marouschek, Carmen and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {1035, title = {Deciphering intrafamilial phenotypic variability by exome sequencing in a Bardet{\textendash}Biedl family}, journal = {Molecular Genetics \& Genomic Medicine}, volume = {2}, number = {2}, year = {2014}, pages = {124-133}, abstract = {Bardet{\textendash}Biedl syndrome (BBS) is a model ciliopathy characterized by a wide range of clinical variability. The heterogeneity of this condition is reflected in the number of underlying gene defects and the epistatic interactions between the proteins encoded. BBS is generally inherited in an autosomal recessive trait. However, in some families, mutations across different loci interact to modulate the expressivity of the phenotype. In order to investigate the magnitude of epistasis in one BBS family with remarkable intrafamilial phenotypic variability, we designed an exome sequencing{\textendash}based approach using SOLID 5500xl platform. This strategy allowed the reliable detection of the primary causal mutations in our family consisting of two novel compound heterozygous mutations in McKusick{\textendash}Kaufman syndrome (MKKS) gene (p.D90G and p.V396F). Additionally, exome sequencing enabled the detection of one novel heterozygous NPHP4 variant which is predicted to activate a cryptic acceptor splice site and is only present in the most severely affected patient. Here, we provide an exome sequencing analysis of a BBS family and show the potential utility of this tool, in combination with network analysis, to detect disease-causing mutations and second-site modifiers. Our data demonstrate how next-generation sequencing (NGS) can facilitate the dissection of epistatic phenomena, and shed light on the genetic basis of phenotypic variability.}, doi = {10.1002/mgg3.50}, url = {http://onlinelibrary.wiley.com/doi/10.1002/mgg3.50/full}, author = {Gonz{\'a}lez-del Pozo, Mar{\'\i}a and M{\'e}ndez-Vidal, Cristina and Santoyo-L{\'o}pez, Javier and Vela-Boza, Alicia and Nereida Bravo-Gil and Antonio Rueda and Garc{\'\i}a-Alonso, Luz and V{\'a}zquez-Marouschek, Carmen and Joaqu{\'\i}n Dopazo and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {494, title = {The role of the interactome in the maintenance of deleterious variability in human populations.}, journal = {Mol Syst Biol}, volume = {10}, year = {2014}, month = {2014 Sep 26}, pages = {752}, abstract = {

Recent genomic projects have revealed the existence of an unexpectedly large amount of deleterious variability in the human genome. Several hypotheses have been proposed to explain such an apparently high mutational load. However, the mechanisms by which deleterious mutations in some genes cause a pathological effect but are apparently innocuous in other genes remain largely unknown. This study searched for deleterious variants in the 1,000 genomes populations, as well as in a newly sequenced population of 252 healthy Spanish individuals. In addition, variants causative of monogenic diseases and somatic variants from 41 chronic lymphocytic leukaemia patients were analysed. The deleterious variants found were analysed in the context of the interactome to understand the role of network topology in the maintenance of the observed mutational load. Our results suggest that one of the mechanisms whereby the effect of these deleterious variants on the phenotype is suppressed could be related to the configuration of the protein interaction network. Most of the deleterious variants observed in healthy individuals are concentrated in peripheral regions of the interactome, in combinations that preserve their connectivity, and have a marginal effect on interactome integrity. On the contrary, likely pathogenic cancer somatic deleterious variants tend to occur in internal regions of the interactome, often with associated structural consequences. Finally, variants causative of monogenic diseases seem to occupy an intermediate position. Our observations suggest that the real pathological potential of a variant might be more a systems property rather than an intrinsic property of individual proteins.

}, keywords = {Alleles, Exome, Gene Library, Genetic Variation, Genetics, Population, Genome, Human, Genomics, Humans, Models, Genetic, mutation, Phenotype, Protein Conformation, Protein Interaction Maps, Sequence Analysis, DNA, Whites}, issn = {1744-4292}, doi = {10.15252/msb.20145222}, author = {Garc{\'\i}a-Alonso, Luz and Jim{\'e}nez-Almaz{\'a}n, Jorge and Carbonell-Caballero, Jos{\'e} and Vela-Boza, Alicia and Santoyo-L{\'o}pez, Javier and Anti{\v n}olo, Guillermo and Dopazo, Joaquin} } @article {1033, title = {Pathways systematically associated to Hirschsprung{\textquoteright}s disease.}, journal = {Orphanet journal of rare diseases}, volume = {8}, year = {2013}, month = {2013 Dec 2}, pages = {187}, abstract = {Despite it has been reported that several loci are involved in Hirschsprung{\textquoteright}s disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung{\textquoteright}s disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations.}, keywords = {GWAS, Hirschprung, network analysis, Pathway Based Analysis}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-187}, url = {http://www.ojrd.com/content/8/1/187/abstract}, author = {Fern{\'a}ndez, Raquel M and Bleda, Marta and Luz{\'o}n-Toro, Berta and Garc{\'\i}a-Alonso, Luz and Arnold, Stacey and Sribudiani, Yunia and Besmond, Claude and Lantieri, Francesca and Doan, Betty and Ceccherini, Isabella and Lyonnet, Stanislas and Hofstra, Robert Mw and Chakravarti, Aravinda and Anti{\v n}olo, Guillermo and Joaqu{\'\i}n Dopazo and Borrego, Salud} } @article {495, title = {Pathways systematically associated to Hirschsprung{\textquoteright}s disease.}, journal = {Orphanet J Rare Dis}, volume = {8}, year = {2013}, month = {2013 Dec 02}, pages = {187}, abstract = {

Despite it has been reported that several loci are involved in Hirschsprung{\textquoteright}s disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung{\textquoteright}s disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations.

}, keywords = {Female, Genetic Predisposition to Disease, Genotype, Hirschsprung Disease, Humans, Male, Polymorphism, Single Nucleotide}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-187}, author = {Fern{\'a}ndez, Raquel M and Bleda, Marta and Luz{\'o}n-Toro, Berta and Garc{\'\i}a-Alonso, Luz and Arnold, Stacey and Sribudiani, Yunia and Besmond, Claude and Lantieri, Francesca and Doan, Betty and Ceccherini, Isabella and Lyonnet, Stanislas and Hofstra, Robert Mw and Chakravarti, Aravinda and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} } @article {916, title = {CellBase, a comprehensive collection of RESTful web services for retrieving relevant biological information from heterogeneous sources.}, journal = {Nucleic acids research}, volume = {40}, year = {2012}, month = {2012 Jul}, pages = {W609-14}, abstract = {During the past years, the advances in high-throughput technologies have produced an unprecedented growth in the number and size of repositories and databases storing relevant biological data. Today, there is more biological information than ever but, unfortunately, the current status of many of these repositories is far from being optimal. Some of the most common problems are that the information is spread out in many small databases; frequently there are different standards among repositories and some databases are no longer supported or they contain too specific and unconnected information. In addition, data size is increasingly becoming an obstacle when accessing or storing biological data. All these issues make very difficult to extract and integrate information from different sources, to analyze experiments or to access and query this information in a programmatic way. CellBase provides a solution to the growing necessity of integration by easing the access to biological data. CellBase implements a set of RESTful web services that query a centralized database containing the most relevant biological data sources. The database is hosted in our servers and is regularly updated. CellBase documentation can be found at http://docs.bioinfo.cipf.es/projects/cellbase.}, issn = {1362-4962}, doi = {10.1093/nar/gks575}, url = {http://nar.oxfordjournals.org/content/40/W1/W609.long}, author = {Bleda, Marta and T{\'a}rraga, Joaqu{\'\i}n and De Maria, Alejandro and Salavert, Francisco and Garc{\'\i}a-Alonso, Luz and Celma, Matilde and Martin, Ainoha and Dopazo, Joaquin and Medina, Ignacio} } @article {512, title = {Discovering the hidden sub-network component in a ranked list of genes or proteins derived from genomic experiments.}, journal = {Nucleic Acids Res}, volume = {40}, year = {2012}, month = {2012 Nov 01}, pages = {e158}, abstract = {

Genomic experiments (e.g. differential gene expression, single-nucleotide polymorphism association) typically produce ranked list of genes. We present a simple but powerful approach which uses protein-protein interaction data to detect sub-networks within such ranked lists of genes or proteins. We performed an exhaustive study of network parameters that allowed us concluding that the average number of components and the average number of nodes per component are the parameters that best discriminate between real and random networks. A novel aspect that increases the efficiency of this strategy in finding sub-networks is that, in addition to direct connections, also connections mediated by intermediate nodes are considered to build up the sub-networks. The possibility of using of such intermediate nodes makes this approach more robust to noise. It also overcomes some limitations intrinsic to experimental designs based on differential expression, in which some nodes are invariant across conditions. The proposed approach can also be used for candidate disease-gene prioritization. Here, we demonstrate the usefulness of the approach by means of several case examples that include a differential expression analysis in Fanconi Anemia, a genome-wide association study of bipolar disorder and a genome-scale study of essentiality in cancer genes. An efficient and easy-to-use web interface (available at http://www.babelomics.org) based on HTML5 technologies is also provided to run the algorithm and represent the network.

}, keywords = {Bipolar Disorder, Fanconi Anemia, Gene Regulatory Networks, Genes, Neoplasm, Genome-Wide Association Study, Genomics, Humans, Protein Interaction Mapping}, issn = {1362-4962}, doi = {10.1093/nar/gks699}, author = {Garc{\'\i}a-Alonso, Luz and Alonso, Roberto and Vidal, Enrique and Amadoz, Alicia and De Maria, Alejandro and Minguez, Pablo and Medina, Ignacio and Dopazo, Joaquin} } @article {944, title = {Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung{\textquoteright}s disease.}, journal = {Orphanet journal of rare diseases}, volume = {7}, year = {2012}, month = {2012 Dec 28}, pages = {103}, abstract = {ABSTRACT: Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung{\textquoteright}s disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.}, issn = {1750-1172}, doi = {10.1186/1750-1172-7-103}, url = {http://www.ojrd.com/content/7/1/103/abstract}, author = {Fern{\'a}ndez, Raquel Ma and Bleda, Marta and N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Medina, Ignacio and Luz{\'o}n-Toro, Berta and Garc{\'\i}a-Alonso, Luz and Torroglosa, Ana and Marb{\`a}, Martina and Enguix-Riego, Ma Valle and Montaner, David and Anti{\v n}olo, Guillermo and Joaqu{\'\i}n Dopazo and Borrego, Salud} } @article {515, title = {Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung{\textquoteright}s disease.}, journal = {Orphanet J Rare Dis}, volume = {7}, year = {2012}, month = {2012 Dec 28}, pages = {103}, abstract = {

Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung{\textquoteright}s disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.

}, keywords = {Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Hirschsprung Disease, Humans, Male}, issn = {1750-1172}, doi = {10.1186/1750-1172-7-103}, author = {Fern{\'a}ndez, Raquel Ma and Bleda, Marta and N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Medina, Ignacio and Luz{\'o}n-Toro, Berta and Garc{\'\i}a-Alonso, Luz and Torroglosa, Ana and Marb{\`a}, Martina and Enguix-Riego, Ma Valle and Montaner, David and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} }