%0 Journal Article %J Clin Microbiol Infect %D 2020 %T Association of a single nucleotide polymorphism in the ubxn6 gene with long-term non-progression phenotype in HIV-positive individuals. %A Díez-Fuertes, F %A De La Torre-Tarazona, H E %A Calonge, E %A Pernas, M %A Bermejo, M %A García-Pérez, J %A Álvarez, A %A Capa, L %A García-García, F %A Saumoy, M %A Riera, M %A Boland-Auge, A %A López-Galíndez, C %A Lathrop, M %A Dopazo, J %A Sakuntabhai, A %A Alcamí, J %K Adaptor Proteins, Vesicular Transport %K Autophagy-Related Proteins %K Caveolin 1 %K Cohort Studies %K Dendritic Cells %K Disease Progression %K Gene Frequency %K Gene Knockdown Techniques %K Genetic Association Studies %K HeLa Cells %K HIV Infections %K HIV Long-Term Survivors %K HIV-1 %K Humans %K Macrophages %K Oligonucleotide Array Sequence Analysis %K Phenotype %K Polymorphism, Single Nucleotide %K whole exome sequencing %X

OBJECTIVES: The long-term non-progressors (LTNPs) are a heterogeneous group of HIV-positive individuals characterized by their ability to maintain high CD4 T-cell counts and partially control viral replication for years in the absence of antiretroviral therapy. The present study aims to identify host single nucleotide polymorphisms (SNPs) associated with non-progression in a cohort of 352 individuals.

METHODS: DNA microarrays and exome sequencing were used for genotyping about 240 000 functional polymorphisms throughout more than 20 000 human genes. The allele frequencies of 85 LTNPs were compared with a control population. SNPs associated with LTNPs were confirmed in a population of typical progressors. Functional analyses in the affected gene were carried out through knockdown experiments in HeLa-P4, macrophages and dendritic cells.

RESULTS: Several SNPs located within the major histocompatibility complex region previously related to LTNPs were confirmed in this new cohort. The SNP rs1127888 (UBXN6) surpassed the statistical significance of these markers after Bonferroni correction (q = 2.11 × 10). An uncommon allelic frequency of rs1127888 among LTNPs was confirmed by comparison with typical progressors and other publicly available populations. UBXN6 knockdown experiments caused an increase in CAV1 expression and its accumulation in the plasma membrane. In vitro infection of different cell types with HIV-1 replication-competent recombinant viruses caused a reduction of the viral replication capacity compared with their corresponding wild-type cells expressing UBXN6.

CONCLUSIONS: A higher prevalence of Ala31Thr in UBXN6 was found among LTNPs within its N-terminal region, which is crucial for UBXN6/VCP protein complex formation. UBXN6 knockdown affected CAV1 turnover and HIV-1 replication capacity.

%B Clin Microbiol Infect %V 26 %P 107-114 %8 2020 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31158522?dopt=Abstract %R 10.1016/j.cmi.2019.05.015 %0 Journal Article %J J Med Genet %D 2020 %T Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies. %A Bogliolo, Massimo %A Pujol, Roser %A Aza-Carmona, Miriam %A Muñoz-Subirana, Núria %A Rodriguez-Santiago, Benjamin %A Casado, José Antonio %A Rio, Paula %A Bauser, Christopher %A Reina-Castillón, Judith %A Lopez-Sanchez, Marcos %A Gonzalez-Quereda, Lidia %A Gallano, Pia %A Catalá, Albert %A Ruiz-Llobet, Ana %A Badell, Isabel %A Diaz-Heredia, Cristina %A Hladun, Raquel %A Senent, Leonort %A Argiles, Bienvenida %A Bergua Burgues, Juan Miguel %A Bañez, Fatima %A Arrizabalaga, Beatriz %A López Almaraz, Ricardo %A Lopez, Monica %A Figuera, Ángela %A Molinés, Antonio %A Pérez de Soto, Inmaculada %A Hernando, Inés %A Muñoz, Juan Antonio %A Del Rosario Marin, Maria %A Balmaña, Judith %A Stjepanovic, Neda %A Carrasco, Estela %A Cuesta, Isabel %A Cosuelo, José Miguel %A Regueiro, Alexandra %A Moraleda Jimenez, José %A Galera-Miñarro, Ana Maria %A Rosiñol, Laura %A Carrió, Anna %A Beléndez-Bieler, Cristina %A Escudero Soto, Antonio %A Cela, Elena %A de la Mata, Gregorio %A Fernández-Delgado, Rafael %A Garcia-Pardos, Maria Carmen %A Sáez-Villaverde, Raquel %A Barragaño, Marta %A Portugal, Raquel %A Lendinez, Francisco %A Hernadez, Ines %A Vagace, José Manue %A Tapia, Maria %A Nieto, José %A Garcia, Marta %A Gonzalez, Macarena %A Vicho, Cristina %A Galvez, Eva %A Valiente, Alberto %A Antelo, Maria Luisa %A Ancliff, Phil %A García, Francisco %A Dopazo, Joaquin %A Sevilla, Julian %A Paprotka, Tobias %A Pérez-Jurado, Luis Alberto %A Bueren, Juan %A Surralles, Jordi %K Cell Line %K DNA Copy Number Variations %K DNA Repair %K DNA-Binding Proteins %K Fanconi Anemia %K Fanconi Anemia Complementation Group A Protein %K Female %K Gene Knockout Techniques %K Genetic Predisposition to Disease %K Humans %K Male %K Mutation, Missense %K Polymorphism, Single Nucleotide %K whole exome sequencing %X

PURPOSE: Patients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients' characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies.

METHODS: 68 patients with FA were analysed by commercial WES services. Copy number variations were evaluated by sequencing data analysis with RStudio. To test missense variants, wt FANCA cDNA was cloned and variants were introduced by site-directed mutagenesis. Vectors were then tested for their ability to complement DNA repair defects of a FANCA-KO human cell line generated by TALEN technologies.

RESULTS: We identified 93.3% of mutated alleles including large deletions. We determined the pathogenicity of three FANCA missense variants and demonstrated that two variants reported in mutations databases as 'affecting functions' are SNPs. Deep analysis of sequencing data revealed patients' true mutations, highlighting the importance of functional analysis. In one patient, no pathogenic variant could be identified in any of the 22 known FA genes, and in seven patients, only one deleterious variant could be identified (three patients each with FANCA and FANCD2 and one patient with FANCE mutations) CONCLUSION: WES and proper bioinformatics analysis are sufficient to effectively characterise patients with FA regardless of the rarity of their complementation group, type of mutations, mosaic condition and DNA source.

%B J Med Genet %V 57 %P 258-268 %8 2020 04 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/31586946?dopt=Abstract %R 10.1136/jmedgenet-2019-106249 %0 Journal Article %J Sci Rep %D 2016 %T Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa. %A Corton, M %A Avila-Fernández, A %A Campello, L %A Sánchez, M %A Benavides, B %A López-Molina, M I %A Fernández-Sánchez, L %A Sánchez-Alcudia, R %A da Silva, L R J %A Reyes, N %A Martín-Garrido, E %A Zurita, O %A Fernández-San José, P %A Pérez-Carro, R %A García-García, F %A Dopazo, J %A García-Sandoval, B %A Cuenca, N %A Ayuso, C %K Aged %K Animals %K Co-Repressor Proteins %K Codon, Nonsense %K Cohort Studies %K Comparative Genomic Hybridization %K Consanguinity %K DNA Mutational Analysis %K Exome %K Eye Proteins %K Female %K Gene Expression Regulation %K Genes, Recessive %K Homeodomain Proteins %K Homozygote %K Humans %K Male %K Mice %K Middle Aged %K Polymorphism, Single Nucleotide %K Protein Interaction Mapping %K Retina %K Retinal Dystrophies %K Retinal Rod Photoreceptor Cells %K Retinitis pigmentosa %K Spain %K Trans-Activators %K Transcription Factors %X

Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.

%B Sci Rep %V 6 %P 35370 %8 2016 10 13 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/27734943?dopt=Abstract %R 10.1038/srep35370 %0 Journal Article %J PLoS One %D 2016 %T The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations. %A Ibáñez, Mariam %A Carbonell-Caballero, José %A García-Alonso, Luz %A Such, Esperanza %A Jiménez-Almazán, Jorge %A Vidal, Enrique %A Barragán, Eva %A López-Pavía, María %A LLop, Marta %A Martín, Iván %A Gómez-Seguí, Inés %A Montesinos, Pau %A Sanz, Miguel A %A Dopazo, Joaquin %A Cervera, José %K Exome %K Gene Regulatory Networks %K Genome, Human %K Humans %K INDEL Mutation %K Leukemia, Promyelocytic, Acute %K mutation %K Mutation Rate %K Polymorphism, Single Nucleotide %K Reproducibility of Results %X

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.

%B PLoS One %V 11 %P e0148346 %8 2016 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/26886259?dopt=Abstract %R 10.1371/journal.pone.0148346 %0 Journal Article %J Drug Metab Pers Ther %D 2016 %T Progress in pharmacogenetics: consortiums and new strategies. %A Maroñas, Olalla %A Latorre, Ana %A Dopazo, Joaquin %A Pirmohamed, Munir %A Rodríguez-Antona, Cristina %A Siest, Gérard %A Carracedo, Ángel %A LLerena, Adrián %K Cooperative Behavior %K Genome-Wide Association Study %K High-Throughput Screening Assays %K Humans %K Patient Care Team %K pharmacogenetics %K Polymorphism, Single Nucleotide %K Precision Medicine %X

Pharmacogenetics (PGx), as a field dedicated to achieving the goal of personalized medicine (PM), is devoted to the study of genes involved in inter-individual response to drugs. Due to its nature, PGx requires access to large samples; therefore, in order to progress, the formation of collaborative consortia seems to be crucial. Some examples of this collective effort are the European Society of Pharmacogenomics and personalized Therapy and the Ibero-American network of Pharmacogenetics. As an emerging field, one of the major challenges that PGx faces is translating their discoveries from research bench to bedside. The development of genomic high-throughput technologies is generating a revolution and offers the possibility of producing vast amounts of genome-wide single nucleotide polymorphisms for each patient. Moreover, there is a need of identifying and replicating associations of new biomarkers, and, in addition, a greater effort must be invested in developing regulatory organizations to accomplish a correct standardization. In this review, we outline the current progress in PGx using examples to highlight both the importance of polymorphisms and the research strategies for their detection. These concepts need to be applied together with a proper dissemination of knowledge to improve clinician and patient understanding, in a multidisciplinary team-based approach.

%B Drug Metab Pers Ther %V 31 %P 17-23 %8 2016 Mar %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/26913460?dopt=Abstract %R 10.1515/dmpt-2015-0039 %0 Journal Article %J PLoS Comput Biol %D 2015 %T A Pan-Cancer Catalogue of Cancer Driver Protein Interaction Interfaces. %A Porta-Pardo, Eduard %A García-Alonso, Luz %A Hrabe, Thomas %A Dopazo, Joaquin %A Godzik, Adam %K Animals %K Base Sequence %K Biomarkers, Tumor %K Catalogs as Topic %K Chromosome Mapping %K Computer Simulation %K DNA Mutational Analysis %K Genetic Predisposition to Disease %K Humans %K Models, Genetic %K Molecular Sequence Data %K mutation %K Neoplasm Proteins %K Neoplasms %K Polymorphism, Single Nucleotide %K Protein Interaction Mapping %K Signal Transduction %X

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.

%B PLoS Comput Biol %V 11 %P e1004518 %8 2015 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/26485003?dopt=Abstract %R 10.1371/journal.pcbi.1004518 %0 Journal Article %J Orphanet J Rare Dis %D 2013 %T Pathways systematically associated to Hirschsprung's disease. %A Fernández, Raquel M %A Bleda, Marta %A Luzón-Toro, Berta %A García-Alonso, Luz %A Arnold, Stacey %A Sribudiani, Yunia %A Besmond, Claude %A Lantieri, Francesca %A Doan, Betty %A Ceccherini, Isabella %A Lyonnet, Stanislas %A Hofstra, Robert Mw %A Chakravarti, Aravinda %A Antiňolo, Guillermo %A Dopazo, Joaquin %A Borrego, Salud %K Female %K Genetic Predisposition to Disease %K Genotype %K Hirschsprung Disease %K Humans %K Male %K Polymorphism, Single Nucleotide %X

Despite 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.

%B Orphanet J Rare Dis %V 8 %P 187 %8 2013 Dec 02 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/24289864?dopt=Abstract %R 10.1186/1750-1172-8-187 %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 Nucleic Acids Res %D 2012 %T VARIANT: Command Line, Web service and Web interface for fast and accurate functional characterization of variants found by Next-Generation Sequencing. %A Medina, Ignacio %A De Maria, Alejandro %A Bleda, Marta %A Salavert, Francisco %A Alonso, Roberto %A Gonzalez, Cristina Y %A Dopazo, Joaquin %K Databases, Nucleic Acid %K Genetic Variation %K High-Throughput Nucleotide Sequencing %K Internet %K Molecular Sequence Annotation %K mutation %K Polymorphism, Single Nucleotide %K Software %K User-Computer Interface %X

The massive use of Next-Generation Sequencing (NGS) technologies is uncovering an unexpected amount of variability. The functional characterization of such variability, particularly in the most common form of variation found, the Single Nucleotide Variants (SNVs), has become a priority that needs to be addressed in a systematic way. VARIANT (VARIant ANalyis Tool) reports information on the variants found that include consequence type and annotations taken from different databases and repositories (SNPs and variants from dbSNP and 1000 genomes, and disease-related variants from the Genome-Wide Association Study (GWAS) catalog, Online Mendelian Inheritance in Man (OMIM), Catalog of Somatic Mutations in Cancer (COSMIC) mutations, etc). VARIANT also produces a rich variety of annotations that include information on the regulatory (transcription factor or miRNA-binding sites, etc.) or structural roles, or on the selective pressures on the sites affected by the variation. This information allows extending the conventional reports beyond the coding regions and expands the knowledge on the contribution of non-coding or synonymous variants to the phenotype studied. Contrarily to other tools, VARIANT uses a remote database and operates through efficient RESTful Web Services that optimize search and transaction operations. In this way, local problems of installation, update or disk size limitations are overcome without the need of sacrifice speed (thousands of variants are processed per minute). VARIANT is available at: http://variant.bioinfo.cipf.es.

%B Nucleic Acids Res %V 40 %P W54-8 %8 2012 Jul %G eng %N Web Server issue %1 https://www.ncbi.nlm.nih.gov/pubmed/22693211?dopt=Abstract %R 10.1093/nar/gks572 %0 Journal Article %J PLoS One %D 2010 %T Exploring the link between germline and somatic genetic alterations in breast carcinogenesis. %A Bonifaci, Núria %A Górski, Bohdan %A Masojć, Bartlomiej %A Wokołorczyk, Dominika %A Jakubowska, Anna %A Dębniak, Tadeusz %A Berenguer, Antoni %A Serra Musach, Jordi %A Brunet, Joan %A Dopazo, Joaquin %A Narod, Steven A %A Lubiński, Jan %A Lázaro, Conxi %A Cybulski, Cezary %A Pujana, Miguel Angel %K Adult %K Bone Morphogenetic Protein Receptors, Type I %K Breast %K Breast Neoplasms %K Calcium-Calmodulin-Dependent Protein Kinases %K Case-Control Studies %K Cyclin-Dependent Kinases %K Disease Progression %K Estrogen Receptor alpha %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Germ-Line Mutation %K Humans %K Odds Ratio %K Poland %K Polymorphism, Single Nucleotide %K Protein Serine-Threonine Kinases %K Protein-Tyrosine Kinases %K Receptor Protein-Tyrosine Kinases %K Receptor, EphA3 %K Receptor, EphA7 %K Receptor, EphB1 %K Risk Factors %X

Recent genome-wide association studies (GWASs) have identified candidate genes contributing to cancer risk through low-penetrance mutations. Many of these genes were unexpected and, intriguingly, included well-known players in carcinogenesis at the somatic level. To assess the hypothesis of a germline-somatic link in carcinogenesis, we evaluated the distribution of somatic gene labels within the ordered results of a breast cancer risk GWAS. This analysis suggested frequent influence on risk of genetic variation in loci encoding for "driver kinases" (i.e., kinases encoded by genes that showed higher somatic mutation rates than expected by chance and, therefore, whose deregulation may contribute to cancer development and/or progression). Assessment of these predictions using a population-based case-control study in Poland replicated the association for rs3732568 in EPHB1 (odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.63-0.98; P(trend) = 0.031). Analyses by early age at diagnosis and by estrogen receptor α (ERα) tumor status indicated potential associations for rs6852678 in CDKL2 (OR = 0.32, 95% CI: 0.10-1.00; P(recessive) = 0.044) and rs10878640 in DYRK2 (OR = 2.39, 95% CI: 1.32-4.30; P(dominant) = 0.003), and for rs12765929, rs9836340, rs4707795 in BMPR1A, EPHA3 and EPHA7, respectively (ERα tumor status P(interaction)<0.05). The identification of three novel candidates as EPH receptor genes might indicate a link between perturbed compartmentalization of early neoplastic lesions and breast cancer risk and progression. Together, these data may lay the foundations for replication in additional populations and could potentially increase our knowledge of the underlying molecular mechanisms of breast carcinogenesis.

%B PLoS One %V 5 %P e14078 %8 2010 Nov 22 %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/21124932?dopt=Abstract %R 10.1371/journal.pone.0014078 %0 Journal Article %J Hum Mutat %D 2010 %T Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa. %A Barragán, Isabel %A Borrego, Salud %A Pieras, Juan Ignacio %A González-del Pozo, María %A Santoyo, Javier %A Ayuso, Carmen %A Baiget, Montserrat %A Millán, José M %A Mena, Marcela %A Abd El-Aziz, Mai M %A Audo, Isabelle %A Zeitz, Christina %A Littink, Karin W %A Dopazo, Joaquin %A Bhattacharya, Shomi S %A Antiňolo, Guillermo %K Amino Acid Sequence %K Animals %K Case-Control Studies %K DNA Mutational Analysis %K Drosophila Proteins %K Evolution, Molecular %K Eye Proteins %K Female %K Genes, Recessive %K Genetic Variation %K Humans %K Male %K Molecular Sequence Data %K mutation %K Pedigree %K Polymorphism, Single Nucleotide %K Protein Structure, Tertiary %K Retinitis pigmentosa %K Spain %K Structural Homology, Protein %X

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene(EYS) encoding an ortholog of Drosophila space maker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9% (12/28) are very likely pathogenic, 17.9% (5/28)are possibly pathogenic, whereas 39.3% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain.Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study.

%B Hum Mutat %V 31 %P E1772-800 %8 2010 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/21069908?dopt=Abstract %R 10.1002/humu.21334 %0 Journal Article %J Nucleic Acids Res %D 2009 %T Gene set-based analysis of polymorphisms: finding pathways or biological processes associated to traits in genome-wide association studies. %A Medina, Ignacio %A Montaner, David %A Bonifaci, Núria %A Pujana, Miguel Angel %A Carbonell, José %A Tárraga, Joaquín %A Al-Shahrour, Fátima %A Dopazo, Joaquin %K Biological Phenomena %K Breast Neoplasms %K Female %K Genes %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Software %K User-Computer Interface %X

Genome-wide association studies have become a popular strategy to find associations of genes to traits of interest. Despite the high-resolution available today to carry out genotyping studies, the success of its application in real studies has been limited by the testing strategy used. As an alternative to brute force solutions involving the use of very large cohorts, we propose the use of the Gene Set Analysis (GSA), a different analysis strategy based on testing the association of modules of functionally related genes. We show here how the Gene Set-based Analysis of Polymorphisms (GeSBAP), which is a simple implementation of the GSA strategy for the analysis of genome-wide association studies, provides a significant increase in the power testing for this type of studies. GeSBAP is freely available at http://bioinfo.cipf.es/gesbap/.

%B Nucleic Acids Res %V 37 %P W340-4 %8 2009 Jul %G eng %N Web Server issue %1 https://www.ncbi.nlm.nih.gov/pubmed/19502494?dopt=Abstract %R 10.1093/nar/gkp481 %0 Journal Article %J Nucleic Acids Res %D 2008 %T Joint annotation of coding and non-coding single nucleotide polymorphisms and mutations in the SNPeffect and PupaSuite databases. %A Reumers, Joke %A Conde, Lucia %A Medina, Ignacio %A Maurer-Stroh, Sebastian %A Van Durme, Joost %A Dopazo, Joaquin %A Rousseau, Frederic %A Schymkowitz, Joost %K Amino Acid Substitution %K Animals %K Databases, Genetic %K Genetic Diseases, Inborn %K HSP70 Heat-Shock Proteins %K Humans %K Internet %K Mice %K MicroRNAs %K mutation %K Polymorphism, Single Nucleotide %K Proteins %K Rats %K RNA Splice Sites %K Transcription Factors %X

Single nucleotide polymorphisms (SNPs) are, together with copy number variation, the primary source of variation in the human genome. SNPs are associated with altered response to drug treatment, susceptibility to disease and other phenotypic variation. Furthermore, during genetic screens for disease-associated mutations in groups of patients and control individuals, the distinction between disease causing mutation and polymorphism is often unclear. Annotation of the functional and structural implications of single nucleotide changes thus provides valuable information to interpret and guide experiments. The SNPeffect and PupaSuite databases are now synchronized to deliver annotations for both non-coding and coding SNP, as well as annotations for the SwissProt set of human disease mutations. In addition, SNPeffect now contains predictions of Tango2: an improved aggregation detector, and Waltz: a novel predictor of amyloid-forming sequences, as well as improved predictors for regions that are recognized by the Hsp70 family of chaperones. The new PupaSuite version incorporates predictions for SNPs in silencers and miRNAs including their targets, as well as additional methods for predicting SNPs in TFBSs and splice sites. Also predictions for mouse and rat genomes have been added. In addition, a PupaSuite web service has been developed to enable data access, programmatically. The combined database holds annotations for 4,965,073 regulatory as well as 133,505 coding human SNPs and 14,935 disease mutations, and phenotypic descriptions of 43,797 human proteins and is accessible via http://snpeffect.vib.be and http://pupasuite.bioinfo.cipf.es/.

%B Nucleic Acids Res %V 36 %P D825-9 %8 2008 Jan %G eng %N Database issue %1 https://www.ncbi.nlm.nih.gov/pubmed/18086700?dopt=Abstract %R 10.1093/nar/gkm979 %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 Hum Mutat %D 2008 %T Use of estimated evolutionary strength at the codon level improves the prediction of disease-related protein mutations in humans. %A Capriotti, Emidio %A Arbiza, Leonardo %A Casadio, Rita %A Dopazo, Joaquin %A Dopazo, Hernán %A Marti-Renom, Marc A %K Algorithms %K Codon %K Computational Biology %K Databases, Protein %K DNA Mutational Analysis %K Evolution, Molecular %K Genetic Predisposition to Disease %K Genetic Variation %K Genome, Human %K Humans %K Iduronic Acid %K Point Mutation %K Polymorphism, Single Nucleotide %K Proteins %K Tumor Suppressor Protein p53 %X

Predicting the functional impact of protein variation is one of the most challenging problems in bioinformatics. A rapidly growing number of genome-scale studies provide large amounts of experimental data, allowing the application of rigorous statistical approaches for predicting whether a given single point mutation has an impact on human health. Up until now, existing methods have limited their source data to either protein or gene information. Novel in this work, we take advantage of both and focus on protein evolutionary information by using estimated selective pressures at the codon level. Here we introduce a new method (SeqProfCod) to predict the likelihood that a given protein variant is associated with human disease or not. Our method relies on a support vector machine (SVM) classifier trained using three sources of information: protein sequence, multiple protein sequence alignments, and the estimation of selective pressure at the codon level. SeqProfCod has been benchmarked with a large dataset of 8,987 single point mutations from 1,434 human proteins from SWISS-PROT. It achieves 82% overall accuracy and a correlation coefficient of 0.59, indicating that the estimation of the selective pressure helps in predicting the functional impact of single-point mutations. Moreover, this study demonstrates the synergic effect of combining two sources of information for predicting the functional effects of protein variants: protein sequence/profile-based information and the evolutionary estimation of the selective pressures at the codon level. The results of large-scale application of SeqProfCod over all annotated point mutations in SWISS-PROT (available for download at http://sgu.bioinfo.cipf.es/services/Omidios/; last accessed: 24 August 2007), could be used to support clinical studies.

%B Hum Mutat %V 29 %P 198-204 %8 2008 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/17935148?dopt=Abstract %R 10.1002/humu.20628