02949nas a2200541 4500008004100000022001400041245008900055210006900144260000900213300001300222490000700235520138200242653001001624653000901634653001801643653001101661653002901672653003201701653002601733653001101759653001401770653002901784653000901813653001601822653001301838653002201851653001801873653001401891653002701905100002101932700003101953700002001984700002402004700002402028700002602052700001602078700001902094700001902113700002502132700002002157700001902177700002002196700002002216700002402236700002002260700001902280856010802299 2018 eng d a1932-620300aThe modular network structure of the mutational landscape of Acute Myeloid Leukemia.0 amodular network structure of the mutational landscape of Acute M c2018 ae02029260 v133 a
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.
10aAdult10aAged10aCytodiagnosis10aFemale10aGene Regulatory Networks10aGenetic Association Studies10aGenetic Heterogeneity10aHumans10aKaryotype10aLeukemia, Myeloid, Acute10aMale10aMiddle Aged10amutation10aNeoplasm Proteins10aNucleophosmin10aPrognosis10awhole exome sequencing1 aIbáñez, Mariam1 aCarbonell-Caballero, José1 aSuch, Esperanza1 aGarcía-Alonso, Luz1 aLiquori, Alessandro1 aLópez-Pavía, María1 aLLop, Marta1 aAlonso, Carmen1 aBarragán, Eva1 aGómez-Seguí, Inés1 aNeef, Alexander1 aHervás, David1 aMontesinos, Pau1 aSanz, Guillermo1 aSanz, Miguel, Angel1 aDopazo, Joaquin1 aCervera, José uhttp://clinbioinfosspa.es/content/modular-network-structure-mutational-landscape-acute-myeloid-leukemia03274nas a2200469 4500008004100000022001400041245010000055210006900155260001600224520184400240653001202084653000802096653001802104653002402122653001902146653000802165100002102173700001902194700001702213700002402230700002302254700002902277700002302306700002302329700002102352700001902373700002202392700003302414700002302447700001602470700002602486700002802512700002002540700002002560700002702580700002002607700002702627700001902654700002702673700002502700856007902725 2016 eng d a1537-171900a267 Spanish exomes reveal population-specific differences in disease-related genetic variation.0 a267 Spanish exomes reveal populationspecific differences in dise c2016 Jan 133 aRecent 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.10adisease10aNGS10apolymorphisms10aPopulation genomics10aprioritization10aSNP1 aDopazo, Joaquín1 aAmadoz, Alicia1 aBleda, Marta1 aGarcía-Alonso, Luz1 aAlemán, Alejandro1 aGarcia-Garcia, Francisco1 aRodriguez, Juan, A1 aDaub, Josephine, T1 aMuntané, Gerard1 aRueda, Antonio1 aVela-Boza, Alicia1 aLópez-Domingo, Francisco, J1 aFlorido, Javier, P1 aArce, Pablo1 aRuiz-Ferrer, Macarena1 aMéndez-Vidal, Cristina1 aArnold, Todd, E1 aSpleiss, Olivia1 aAlvarez-Tejado, Miguel1 aNavarro, Arcadi1 aBhattacharya, Shomi, S1 aBorrego, Salud1 aSantoyo-López, Javier1 aAntiňolo, Guillermo uhttps://mbe.oxfordjournals.org/content/early/2016/02/17/molbev.msw005.full02859nas a2200433 4500008004100000022001400041245013500055210006900190260000900259300001300268490000700281520145800288653001001746653002901756653001801785653001101803653001901814653003501833653001301868653001801881653003601899653003101935100002101966700003101987700002402018700002002042700002902062700001902091700001902110700002602129700001602155700001902171700002502190700002002215700002002235700002002255700001902275856013102294 2016 eng d a1932-620300aThe Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.0 aMutational Landscape of Acute Promyelocytic Leukemia Reveals an c2016 ae01483460 v113 aPreliminary 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.
10aExome10aGene Regulatory Networks10aGenome, Human10aHumans10aINDEL Mutation10aLeukemia, Promyelocytic, Acute10amutation10aMutation Rate10aPolymorphism, Single Nucleotide10aReproducibility of Results1 aIbáñez, Mariam1 aCarbonell-Caballero, José1 aGarcía-Alonso, Luz1 aSuch, Esperanza1 aJiménez-Almazán, Jorge1 aVidal, Enrique1 aBarragán, Eva1 aLópez-Pavía, María1 aLLop, Marta1 aMartín, Iván1 aGómez-Seguí, Inés1 aMontesinos, Pau1 aSanz, Miguel, A1 aDopazo, Joaquin1 aCervera, José uhttp://clinbioinfosspa.es/content/mutational-landscape-acute-promyelocytic-leukemia-reveals-interacting-network-co-occurrences01573nas a2200253 4500008004100000022001400041245006500055210006300120260001500183300001100198490000700209520080700216653002601023653001301049653001301062100002401075700002401099700002101123700002001144700001701164700002001181700002001201856009801221 2016 eng d a1367-481100aWeb-based network analysis and visualization using CellMaps.0 aWebbased network analysis and visualization using CellMaps c2016 10 01 a3041-30 v323 aUNLABELLED: : 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.
10aBiochemical Phenomena10aInternet10aSoftware1 aSalavert, Francisco1 aGarcía-Alonso, Luz1 aSánchez, Rubén1 aAlonso, Roberto1 aBleda, Marta1 aMedina, Ignacio1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/web-based-network-analysis-and-visualization-using-cellmaps02445nas a2200469 4500008004100000022001400041245008300055210006900138260001600207300001400223490000700237520108700244653001501331653002101346653002201367653001601389653002101405653000801426653001201434653002001446653002001466100002001486700002401506700002901530700003101559700001701590700002401607700002301631700002201654700002401676700002101700700001801721700002201739700001901761700003601780700002301816700002301839700002001862700002001882700002001902856005301922 2015 eng d a1362-496200aBabelomics 5.0: functional interpretation for new generations of genomic data.0 aBabelomics 50 functional interpretation for new generations of g c2015 Apr 20 aW117-W1210 v433 aBabelomics 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.10ababelomics10adata integration10agene set analysis10ainteractome10anetwork analysis10aNGS10aRNA-seq10aSystems biology10atranscriptomics1 aAlonso, Roberto1 aSalavert, Francisco1 aGarcia-Garcia, Francisco1 aCarbonell-Caballero, José1 aBleda, Marta1 aGarcía-Alonso, Luz1 aSanchis-Juan, Alba1 aPerez-Gil, Daniel1 aMarin-Garcia, Pablo1 aSánchez, Rubén1 aCubuk, Cankut1 aHidalgo, Marta, R1 aAmadoz, Alicia1 aHernansaiz-Ballesteros, Rosa, D1 aAlemán, Alejandro1 aTárraga, Joaquín1 aMontaner, David1 aMedina, Ignacio1 aDopazo, Joaquin uhttp://nar.oxfordjournals.org/content/43/W1/W11701498nas a2200289 4500008004100000022001400041245014900055210006900204260000800273300000700281490000600288520057300294100002300867700001700890700001900907700002400926700002600950700002000976700002800996700002701024700002701051700002001078700002501098700002001123700001901143856004601162 2015 eng d a1755-879400aIdentification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas0 aIdentification of epistatic interactions through genomewide asso cDec a830 v83 aThe 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.1 aLuzón-Toro, Berta1 aBleda, Marta1 aNavarro, Elena1 aGarcía-Alonso, Luz1 aRuiz-Ferrer, Macarena1 aMedina, Ignacio1 aMartín-Sánchez, Marta1 aGonzalez, Cristina, Y.1 aFernández, Raquel, M.1 aTorroglosa, Ana1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud uhttps://doi.org/10.1186/s12920-015-0160-702478nas a2200325 4500008004100000022001400041245015000055210006900205260000900274300000700283490000600290520144200296653001401738653000901752653001901761100002301780700001701803700001901820700002401839700002601863700002001889700002801909700002601937700002601963700002001989700002502009700002002034700001902054856007902073 2015 eng d a1755-879400aIdentification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas.0 aIdentification of epistatic interactions through genomewide asso c2015 a830 v83 aBACKGROUND: 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.10aepistasis10aGWAS10aThyroid cancer1 aLuzón-Toro, Berta1 aBleda, Marta1 aNavarro, Elena1 aGarcía-Alonso, Luz1 aRuiz-Ferrer, Macarena1 aMedina, Ignacio1 aMartín-Sánchez, Marta1 aGonzalez, Cristina, Y1 aFernández, Raquel, M1 aTorroglosa, Ana1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud uhttp://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-015-0160-702385nas a2200397 4500008004100000022001400041245007600055210006900131260001300200300001300213490000700226520116000233653001201393653001801405653002201423653002201445653002301467653002401490653002801514653003801542653001101580653002001591653002801611653001301639653002201652653001401674653003601688653003201724653002401756100002401780700002401804700001801828700002001846700001701866856010401883 2015 eng d a1553-735800aA Pan-Cancer Catalogue of Cancer Driver Protein Interaction Interfaces.0 aPanCancer Catalogue of Cancer Driver Protein Interaction Interfa c2015 Oct ae10045180 v113 aDespite 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.
10aAnimals10aBase Sequence10aBiomarkers, Tumor10aCatalogs as Topic10aChromosome Mapping10aComputer Simulation10aDNA Mutational Analysis10aGenetic Predisposition to Disease10aHumans10aModels, Genetic10aMolecular Sequence Data10amutation10aNeoplasm Proteins10aNeoplasms10aPolymorphism, Single Nucleotide10aProtein Interaction Mapping10aSignal Transduction1 aPorta-Pardo, Eduard1 aGarcía-Alonso, Luz1 aHrabe, Thomas1 aDopazo, Joaquin1 aGodzik, Adam uhttp://clinbioinfosspa.es/content/pan-cancer-catalogue-cancer-driver-protein-interaction-interfaces02325nas a2200265 4500008004100000022001400041245012000055210006900175260001300244300001300257490000700270520140800277653002301685653001301708653003201721653004301753100001901796700001901815700001601834700002401850700002001874700002401894700001501918856012601933 2015 eng d a1362-496200aPTMcode v2: a resource for functional associations of post-translational modifications within and between proteins.0 aPTMcode v2 a resource for functional associations of posttransla c2015 Jan aD494-5020 v433 aThe 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.
10aDatabases, Protein10aInternet10aProtein Interaction Mapping10aProtein Processing, Post-Translational1 aMinguez, Pablo1 aLetunic, Ivica1 aParca, Luca1 aGarcía-Alonso, Luz1 aDopazo, Joaquin1 aHuerta-Cepas, Jaime1 aBork, Peer uhttp://clinbioinfosspa.es/content/ptmcode-v2-resource-functional-associations-post-translational-modifications-within-and02364nas a2200265 4500008004100000022001400041245009900055210006900154260001300223300001100236490000600247520144900253100003301702700002801735700002701763700002201790700002301812700001901835700002401854700003201878700002001910700001901930700002501949856012401974 2014 eng d a2324-926900aDeciphering intrafamilial phenotypic variability by exome sequencing in a Bardet-Biedl family.0 aDeciphering intrafamilial phenotypic variability by exome sequen c2014 Mar a124-330 v23 aBardet-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.
1 adel Pozo, María, González-1 aMéndez-Vidal, Cristina1 aSantoyo-López, Javier1 aVela-Boza, Alicia1 aBravo-Gil, Nereida1 aRueda, Antonio1 aGarcía-Alonso, Luz1 aVázquez-Marouschek, Carmen1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo uhttp://clinbioinfosspa.es/content/deciphering-intrafamilial-phenotypic-variability-exome-sequencing-bardet-biedl-family02250nas a2200241 4500008004100000245010000041210006900141300001200210490000600222520144700228100003301675700002801708700002701736700002201763700002301785700001901808700002401827700003201851700002101883700001901904700002501923856006001948 2014 eng d00aDeciphering intrafamilial phenotypic variability by exome sequencing in a Bardet–Biedl family0 aDeciphering intrafamilial phenotypic variability by exome sequen a124-1330 v23 aBardet–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.1 adel Pozo, María, González-1 aMéndez-Vidal, Cristina1 aSantoyo-López, Javier1 aVela-Boza, Alicia1 aBravo-Gil, Nereida1 aRueda, Antonio1 aGarcía-Alonso, Luz1 aVázquez-Marouschek, Carmen1 aDopazo, Joaquín1 aBorrego, Salud1 aAntiňolo, Guillermo uhttp://onlinelibrary.wiley.com/doi/10.1002/mgg3.50/full02932nas a2200397 4500008004100000022001400041245010000055210006900155260001600224300000800240490000700248520172500255653001201980653001001992653001702002653002202019653002502041653001802066653001302084653001102097653002002108653001302128653001402141653002502155653002902180653002702209653001102236100002402247700002902271700003102300700002202331700002702353700002502380700002002405856010902425 2014 eng d a1744-429200aThe role of the interactome in the maintenance of deleterious variability in human populations.0 arole of the interactome in the maintenance of deleterious variab c2014 Sep 26 a7520 v103 aRecent 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.
10aAlleles10aExome10aGene Library10aGenetic Variation10aGenetics, Population10aGenome, Human10aGenomics10aHumans10aModels, Genetic10amutation10aPhenotype10aProtein Conformation10aProtein Interaction Maps10aSequence Analysis, DNA10aWhites1 aGarcía-Alonso, Luz1 aJiménez-Almazán, Jorge1 aCarbonell-Caballero, José1 aVela-Boza, Alicia1 aSantoyo-López, Javier1 aAntiňolo, Guillermo1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/role-interactome-maintenance-deleterious-variability-human-populations02519nas a2200373 4500008004100000022001400041245006800055210006500123260001500188300000800203490000600211520145200217653000901669653001601678653002101694653002701715100002601742700001701768700002301785700002401808700001901832700002201851700002001873700002401893700001601917700002501933700002301958700002401981700002602005700002502031700002102056700001902077856004902096 2013 eng d a1750-117200aPathways systematically associated to Hirschsprung’s disease.0 aPathways systematically associated to Hirschsprung s disease c2013 Dec 2 a1870 v83 aDespite it has been reported that several loci are involved in Hirschsprung’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’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.10aGWAS10aHirschprung10anetwork analysis10aPathway Based Analysis1 aFernández, Raquel, M1 aBleda, Marta1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aArnold, Stacey1 aSribudiani, Yunia1 aBesmond, Claude1 aLantieri, Francesca1 aDoan, Betty1 aCeccherini, Isabella1 aLyonnet, Stanislas1 aHofstra, Robert, Mw1 aChakravarti, Aravinda1 aAntiňolo, Guillermo1 aDopazo, Joaquín1 aBorrego, Salud uhttp://www.ojrd.com/content/8/1/187/abstract02672nas a2200409 4500008004100000022001400041245006600055210006400121260001600185300000800201490000600209520145600215653001101671653003801682653001301720653002501733653001101758653000901769653003601778100002601814700001701840700002301857700002401880700001901904700002201923700002001945700002401965700001601989700002502005700002302030700002402053700002602077700002502103700002002128700001902148856009502167 2013 eng d a1750-117200aPathways systematically associated to Hirschsprung's disease.0 aPathways systematically associated to Hirschsprungs disease c2013 Dec 02 a1870 v83 aDespite it has been reported that several loci are involved in Hirschsprung'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'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.
10aFemale10aGenetic Predisposition to Disease10aGenotype10aHirschsprung Disease10aHumans10aMale10aPolymorphism, Single Nucleotide1 aFernández, Raquel, M1 aBleda, Marta1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aArnold, Stacey1 aSribudiani, Yunia1 aBesmond, Claude1 aLantieri, Francesca1 aDoan, Betty1 aCeccherini, Isabella1 aLyonnet, Stanislas1 aHofstra, Robert, Mw1 aChakravarti, Aravinda1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud uhttp://clinbioinfosspa.es/content/pathways-systematically-associated-hirschsprungs-disease02076nas a2200241 4500008004100000022001400041245014000055210006900195260001300264300001200277490000700289520129000296100001701586700002301603700002401626700002401650700002401674700001901698700001901717700002001736700002001756856005801776 2012 eng d a1362-496200aCellBase, a comprehensive collection of RESTful web services for retrieving relevant biological information from heterogeneous sources.0 aCellBase a comprehensive collection of RESTful web services for c2012 Jul aW609-140 v403 aDuring 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.1 aBleda, Marta1 aTárraga, Joaquín1 aDe Maria, Alejandro1 aSalavert, Francisco1 aGarcía-Alonso, Luz1 aCelma, Matilde1 aMartin, Ainoha1 aDopazo, Joaquin1 aMedina, Ignacio uhttp://nar.oxfordjournals.org/content/40/W1/W609.long02616nas a2200325 4500008004100000022001400041245012100055210006900176260001600245300000900261490000700270520154400277653002101821653001901842653002901861653002001890653003401910653001301944653001101957653003201968100002402000700002002024700001902044700001902063700002402082700001902106700002002125700002002145856012502165 2012 eng d a1362-496200aDiscovering the hidden sub-network component in a ranked list of genes or proteins derived from genomic experiments.0 aDiscovering the hidden subnetwork component in a ranked list of c2012 Nov 01 ae1580 v403 aGenomic 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.
10aBipolar Disorder10aFanconi Anemia10aGene Regulatory Networks10aGenes, Neoplasm10aGenome-Wide Association Study10aGenomics10aHumans10aProtein Interaction Mapping1 aGarcía-Alonso, Luz1 aAlonso, Roberto1 aVidal, Enrique1 aAmadoz, Alicia1 aDe Maria, Alejandro1 aMinguez, Pablo1 aMedina, Ignacio1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/discovering-hidden-sub-network-component-ranked-list-genes-or-proteins-derived-genomic02193nas a2200289 4500008004100000022001400041245014800055210006900203260001600272300000800288490000600296520126100302100002701563700001701590700002701607700002001634700002301654700002401677700002001701700002001721700002801741700002001769700002501789700002101814700001901835856004901854 2012 eng d a1750-117200aFour new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung’s disease.0 aFour new loci associations discovered by pathwaybased and networ c2012 Dec 28 a1030 v73 aABSTRACT: 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’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.1 aFernández, Raquel, Ma1 aBleda, Marta1 aNúñez-Torres, Rocío1 aMedina, Ignacio1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aTorroglosa, Ana1 aMarbà, Martina1 aEnguix-Riego, Ma, Valle1 aMontaner, David1 aAntiňolo, Guillermo1 aDopazo, Joaquín1 aBorrego, Salud uhttp://www.ojrd.com/content/7/1/103/abstract02486nas a2200373 4500008004100000022001400041245014600055210006900201260001600270300000800286490000600294520125600300653001101556653003801567653003401605653001301639653002501652653001101677653000901688100002701697700001701724700002701741700002001768700002301788700002401811700002001835700002001855700002801875700002001903700002501923700002001948700001901968856012501987 2012 eng d a1750-117200aFour new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung's disease.0 aFour new loci associations discovered by pathwaybased and networ c2012 Dec 28 a1030 v73 aFinding 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'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.
10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHirschsprung Disease10aHumans10aMale1 aFernández, Raquel, Ma1 aBleda, Marta1 aNúñez-Torres, Rocío1 aMedina, Ignacio1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aTorroglosa, Ana1 aMarbà, Martina1 aEnguix-Riego, Ma, Valle1 aMontaner, David1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud uhttp://clinbioinfosspa.es/content/four-new-loci-associations-discovered-pathway-based-and-network-analyses-genome-wide-0