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1.
Nucleic Acids Res ; 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31504766

RESUMO

We present Nucleosome Dynamics, a suite of programs integrated into a virtual research environment and created to define nucleosome architecture and dynamics from noisy experimental data. The package allows both the definition of nucleosome architectures and the detection of changes in nucleosomal organization due to changes in cellular conditions. Results are displayed in the context of genomic information thanks to different visualizers and browsers, allowing the user a holistic, multidimensional view of the genome/transcriptome. The package shows good performance for both locating equilibrium nucleosome architecture and nucleosome dynamics and provides abundant useful information in several test cases, where experimental data on nucleosome position (and for some cases expression level) have been collected for cells under different external conditions (cell cycle phase, yeast metabolic cycle progression, changes in nutrients or difference in MNase digestion level). Nucleosome Dynamics is a free software and is provided under several distribution models.

2.
J Mol Biol ; 431(19): 3845-3859, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31325439

RESUMO

The rules governing sequence-specific DNA-protein recognition are under a long-standing debate regarding the prevalence of base versus shape readout mechanisms to explain sequence specificity and of the conformational selection versus induced fit binding paradigms to explain binding-related conformational changes in DNA. Using a combination of atomistic simulations on a subset of representative sequences and mesoscopic simulations at the protein-DNA interactome level, we demonstrate the prevalence of the shape readout model in determining sequence-specificity and of the conformational selection paradigm in defining the general mechanism for binding-related conformational changes in DNA. Our results suggest that the DNA uses a double mechanism to adapt its structure to the protein: it moves along the easiest deformation modes to approach the bioactive conformation, while final adjustments require localized rearrangements at the base-pair step and backbone level. Our study highlights the large impact of B-DNA dynamics in modulating DNA-protein binding.

3.
Stud Health Technol Inform ; 247: 621-625, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29678035

RESUMO

Interoperable metadata is key for the management of genomic information. We propose a flexible approach that we contribute to the standardization by ISO/IEC of a new format for efficient and secure compressed storage and transmission of genomic information.


Assuntos
Genômica , Metadados
4.
Arthritis Res Ther ; 19(1): 138, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28619073

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE. METHODS: A two-stage pathway-based approach was used to identify the genetic variation associated with the main clinical phenotypes in SLE. In the discovery stage, 482 SLE patients were genotyped using Illumina Human Quad610 microarrays. Association between 798 reference genetic pathways from the Molecular Signatures Database and 11 SLE phenotypes was tested using the set-based method implemented in PLINK software. Pathways significantly associated after multiple test correction were subsequently tested for replication in an independent cohort of 425 SLE patients. Using an in silico approach, we analyzed the functional effects of common SLE therapies on the replicated genetic pathways. The association of known SLE risk variants with the development of the clinical phenotypes was also analyzed. RESULTS: In the discovery stage, we found a significant association between the vascular endothelial growth factor (VEGF) pathway and oral ulceration (P value for false discovery rate (P FDR) < 0.05), and between the negative regulation signaling pathway of retinoic acid inducible gene-I/melanoma differentiation associated gene 5 and the production of antinuclear antibodies (P FDR < 0.05). In the replication stage, we validated the association between the VEGF pathway and oral ulceration. Therapies commonly used to treat mucocutaneous phenotypes in SLE were found to strongly influence VEGF pathway gene expression (P = 4.60e-4 to 5.38e-14). Analysis of known SLE risk loci identified a strong association between PTPN22 and the risk of hematologic disorder and with the development of antinuclear antibodies. CONCLUSIONS: The present study has identified VEGF genetic pathway association with the risk of oral ulceration in SLE. New therapies targeting the VEGF pathway could be more effective in reducing the severity of this phenotype. These findings represent a first step towards the understanding of the genetic basis of phenotype heterogeneity in SLE.


Assuntos
Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Úlceras Orais/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Feminino , Predisposição Genética para Doença/genética , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/complicações , Masculino , Fenótipo
5.
Phys Chem Chem Phys ; 19(15): 9849-9861, 2017 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-28352893

RESUMO

Cation-π interactions of aromatic rings and positively charged groups are among the most important interactions in structural biology. The role and energetic characteristics of these interactions are well established. However, the occurrence of cation-π-cation interactions is an unexpected motif, which raises intriguing questions about its functional role in proteins. We present a statistical analysis of the occurrence, composition and geometrical preferences of cation-π-cation interactions identified in a set of non-redundant protein structures taken from the Protein Data Bank. Our results demonstrate that this structural motif is observed at a small, albeit non-negligible frequency in proteins, and suggest a preference to establish cation-π-cation motifs with Trp, followed by Tyr and Phe. Furthermore, we have found that cation-π-cation interactions tend to be highly conserved, which supports their structural or functional role. Finally, we have performed an energetic analysis of a representative subset of cation-π-cation complexes combining quantum-chemical and continuum solvation calculations. Our results point out that the protein environment can strongly screen the cation-cation repulsion, leading to an attractive interaction in 64% of the complexes analyzed. Together with the high degree of conservation observed, these results suggest a potential stabilizing role in the protein fold, as demonstrated recently for a miniature protein (Craven et al., J. Am. Chem. Soc. 2016, 138, 1543). From a computational point of view, the significant contribution of non-additive three-body terms challenges the suitability of standard additive force fields for describing cation-π-cation motifs in molecular simulations.


Assuntos
Proteínas/química , Cátions/química , Humanos , Metais/química , Fenilalanina/química , Estrutura Terciária de Proteína , Proteínas/metabolismo , Teoria Quântica , Receptores da Somatotropina/química , Receptores da Somatotropina/metabolismo , Termodinâmica , Triptofano/química
6.
J Phys Chem B ; 121(15): 3636-3643, 2017 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-28059510

RESUMO

Extensive molecular dynamics (MD) simulations have been used to characterize the multiple roles of water in solvating different types of proteins under different environmental conditions. We analyzed a small set of proteins, representative of the most prevalent meta-folds under native conditions, in the presence of crowding agents, and at high temperature with or without high concentration of urea. We considered also a protein in the unfolded state as characterized by NMR and atomistic MD simulations. Our results outline the main characteristics of the hydration environment of proteins and illustrate the dramatic plasticity of water, and its chameleonic ability to stabilize proteins under a variety of conditions.


Assuntos
Simulação de Dinâmica Molecular , Proteínas/química , Água/química , Espectroscopia de Ressonância Magnética , Estabilidade Proteica , Solubilidade , Temperatura Ambiente , Ureia/química
7.
Nucleic Acids Res ; 44(9): 4052-66, 2016 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-27084952

RESUMO

We present a systematic study of the long-timescale dynamics of the Drew-Dickerson dodecamer (DDD: d(CGCGAATTGCGC)2) a prototypical B-DNA duplex. Using our newly parameterized PARMBSC1 force field, we describe the conformational landscape of DDD in a variety of ionic environments from minimal salt to 2 M Na(+)Cl(-) or K(+)Cl(-) The sensitivity of the simulations to the use of different solvent and ion models is analyzed in detail using multi-microsecond simulations. Finally, an extended (10 µs) simulation is used to characterize slow and infrequent conformational changes in DDD, leading to the identification of previously uncharacterized conformational states of this duplex which can explain biologically relevant conformational transitions. With a total of more than 43 µs of unrestrained molecular dynamics simulation, this study is the most extensive investigation of the dynamics of the most prototypical DNA duplex.


Assuntos
DNA de Forma B/química , DNA de Forma B/ultraestrutura , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico , Modelos Moleculares , Cloreto de Potássio/química , Cloreto de Sódio/química
8.
Rheumatology (Oxford) ; 55(6): 1106-11, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26983453

RESUMO

OBJECTIVE: RA patients with serum ACPA have a strong and specific genetic background. The objective of the study was to identify new susceptibility genes for ACPA-positive RA using a genome-wide association approach. METHODS: A total of 924 ACPA-positive RA patients with joint damage in hands and/or feet, and 1524 healthy controls were genotyped in 582 591 single-nucleotide polymorphisms (SNPs) in the discovery phase. In the validation phase, the most significant SNPs in the genome-wide association study representing new candidate loci for RA were tested in an independent cohort of 863 ACPA-positive patients with joint damage and 1152 healthy controls. All individuals from the discovery and validation cohorts were Caucasian and of Southern European ancestry. RESULTS: In the discovery phase, 60 loci not previously associated with RA risk showed evidence for association at P < 5×10(-4) and were tested for replication in the validation cohort. A total of 12 loci were replicated at the nominal level (P < 0.05, same direction of effect as in the discovery phase). When combining the discovery and validation cohorts, an intronic SNP in the Solute Carrier family 8 gene (SLC8A3) was found to be associated with ACPA-positive RA at a genome-wide level of significance RA [odds ratio (95% CI): 1.42 (1.25, 1.6), Pcombined = 3.19×10(-8)]. CONCLUSIONS: SLC8A3 was identified as a new risk locus for ACPA-positive RA. This study demonstrates the advantage of analysing relevant subsets of RA patients to identify new genetic risk variants.

9.
J Invest Dermatol ; 136(3): 593-602, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26743605

RESUMO

Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the psoriasis heritability is only partially explained. However, there is increasing evidence that the missing heritability in psoriasis could be explained by multiple genetic variants of low effect size from common genetic pathways. The objective of this study was to identify new genetic variation associated with psoriasis risk at the pathway level. We genotyped 598,258 single nucleotide polymorphisms in a discovery cohort of 2,281 case-control individuals from Spain. We performed a genome-wide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (PFDR ≤ 2.55 × 10(-2)) were found to be significantly associated with psoriasis risk. Using an independent validation cohort of 7,353 individuals from the UK, a total of 6 genetic pathways were significantly replicated (PFDR ≤ 3.46 × 10(-2)). We found genetic pathways that had not been previously associated with psoriasis risk such as retinol metabolism (Pcombined = 1.84 × 10(-4)), the transport of inorganic ions and amino acids (Pcombined = 1.57 × 10(-7)), and post-translational protein modification (Pcombined = 1.57 × 10(-7)). In the latter pathway, MGAT5 showed a strong network centrality, and its association with psoriasis risk was further validated in an additional case-control cohort of 3,429 individuals (P < 0.05). These findings provide insights into the biological mechanisms associated with psoriasis susceptibility.


Assuntos
Predisposição Genética para Doença/epidemiologia , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Psoríase/epidemiologia , Psoríase/genética , Adulto , Estudos de Casos e Controles , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Psoríase/fisiopatologia , Valores de Referência , Medição de Risco , Espanha/epidemiologia
10.
Nat Methods ; 13(1): 55-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26569599

RESUMO

We present parmbsc1, a force field for DNA atomistic simulation, which has been parameterized from high-level quantum mechanical data and tested for nearly 100 systems (representing a total simulation time of ∼ 140 µs) covering most of DNA structural space. Parmbsc1 provides high-quality results in diverse systems. Parameters and trajectories are available at http://mmb.irbbarcelona.org/ParmBSC1/.


Assuntos
DNA/química , Teoria Quântica
11.
J Chem Theory Comput ; 11(12): 5929-38, 2015 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-26597989

RESUMO

Molecular dynamics simulations of proteins are usually performed on a single molecule, and coarse-grained protein models are calibrated using single-molecule simulations, therefore ignoring intermolecular interactions. We present here a new coarse-grained force field for the study of many protein systems. The force field, which is implemented in the context of the discrete molecular dynamics algorithm, is able to reproduce the properties of folded and unfolded proteins, in both isolation, complexed forming well-defined quaternary structures, or aggregated, thanks to its proper evaluation of protein-protein interactions. The accuracy and computational efficiency of the method makes it a universal tool for the study of the structure, dynamics, and association/dissociation of proteins.


Assuntos
Simulação de Dinâmica Molecular , Proteínas/química , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Ligações de Hidrogênio , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Domínios e Motivos de Interação entre Proteínas , Estrutura Quaternária de Proteína , Desdobramento de Proteína
12.
Nat Methods ; 12(10): 955-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26322837

RESUMO

Protein tagging is widely used in approaches ranging from affinity purification to fluorescence-based detection in live cells. However, an intrinsic limitation of tagging is that the native function of the protein may be compromised or even abolished by the presence of the tag. Here we describe and characterize a set of small, innocuous protein tags (inntags) that we anticipate will find application in a variety of biological techniques.


Assuntos
Epitopos/análise , Epitopos/química , Imunofluorescência/métodos , Imunoprecipitação/métodos , Proteínas/análise , Proteínas/imunologia , Animais , Anticorpos Monoclonais , Epitopos/genética , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Conformação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
13.
Ann Rheum Dis ; 74(10): 1875-81, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25990289

RESUMO

OBJECTIVE: Copy number variants (CNVs) have been associated with the risk to develop multiple autoimmune diseases. Our objective was to identify CNVs associated with the risk to develop psoriatic arthritis (PsA) using a genome-wide analysis approach. METHODS: A total of 835 patients with PsA and 1498 healthy controls were genotyped for CNVs using the Illumina HumanHap610 BeadChip genotyping platform. Genomic CNVs were characterised using CNstream analysis software and analysed for association using the χ(2) test. The most significant genomic CNV associations with PsA risk were independently tested in a validation sample of 1133 patients with PsA and 1831 healthy controls. In order to test for the specificity of the variants with PsA aetiology, we also analysed the association to a cohort of 822 patients with purely cutaneous psoriasis (PsC). RESULTS: A total of 165 common CNVs were identified in the genome-wide analysis. We found a highly significant association of an intergenic deletion between ADAMTS9 and MAGI1 genes on chromosome 3p14.1 (p=0.00014). Using the independent patient and control cohort, we validated the association between ADAMTS9-MAGI1 deletion and PsA risk (p=0.032). Using next-generation sequencing, we characterised the 26 kb associated deletion. Finally, analysing the PsC cohort we found a lower frequency of the deletion compared with the PsA cohort (p=0.0088) and a similar frequency to that of healthy controls (p>0.3). CONCLUSIONS: The present genome-wide scan for CNVs associated with PsA risk has identified a new deletion associated with disease risk and which is also differential from PsC risk.


Assuntos
Proteínas ADAM/genética , Artrite Psoriásica/genética , Moléculas de Adesão Celular Neuronais/genética , Deleção de Genes , Proteína ADAMTS9 , Adulto , Idoso , Estudos de Casos e Controles , Variações do Número de Cópias de DNA , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/genética , Fatores de Risco
14.
Gastroenterology ; 148(4): 794-805, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25557950

RESUMO

BACKGROUND & AIMS: Crohn's disease is a highly heterogeneous inflammatory bowel disease comprising multiple clinical phenotypes. Genome-wide association studies (GWASs) have associated a large number of loci with disease risk but have not associated any specific genetic variants with clinical phenotypes. We performed a GWAS of clinical phenotypes in Crohn's disease. METHODS: We genotyped 576,818 single-nucleotide polymorphisms in a well-characterized cohort of 1090 Crohn's disease patients of European ancestry. We assessed their association with 17 phenotypes of Crohn's disease (based on disease location, disease behavior, disease course, age at onset, and extraintestinal manifestations). A total of 57 markers with strong associations to Crohn's disease phenotypes (P < 2 × 10(-4)) were subsequently analyzed in an independent replication cohort of 1296 patients of European ancestry. RESULTS: We replicated the association of 4 loci with different Crohn's disease phenotypes. Variants in MAGI1, CLCA2, 2q24.1, and LY75 loci were associated with a complicated stricturing disease course (Pcombined = 2.01 × 10(-8)), disease location (Pcombined = 1.3 × 10(-6)), mild disease course (Pcombined = 5.94 × 10(-7)), and erythema nodosum (Pcombined = 2.27 × 10(-6)), respectively. CONCLUSIONS: In a GWAS, we associated 4 loci with clinical phenotypes of Crohn's disease. These findings indicate a genetic basis for the clinical heterogeneity observed for this inflammatory bowel disease.


Assuntos
Antígenos CD/genética , Moléculas de Adesão Celular Neuronais/genética , Canais de Cloreto/genética , Cromossomos Humanos Par 2/genética , Doença de Crohn/genética , Lectinas Tipo C/genética , Receptores de Superfície Celular/genética , Adulto , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor , Fenótipo , Polimorfismo de Nucleotídeo Único
15.
PLoS One ; 9(1): e80018, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24489641

RESUMO

The effects of pre-incubation with mercury (Hg(2+)) and cadmium (Cd(2+)) on the activities of individual glycolytic enzymes, on the flux and on internal metabolite concentrations of the upper part of glycolysis were investigated in mouse muscle extracts. In the range of metal concentrations analysed we found that only hexokinase and phosphofructokinase, the enzymes that shared the control of the flux, were inhibited by Hg(2+) and Cd(2+). The concentrations of the internal metabolites glucose-6-phosphate and fructose-6-phosphate did not change significantly when Hg(2+) and Cd(2+) were added. A mathematical model was constructed to explore the mechanisms of inhibition of Hg(2+) and Cd(2+) on hexokinase and phosphofructokinase. Equations derived from detailed mechanistic models for each inhibition were fitted to the experimental data. In a concentration-dependent manner these equations describe the observed inhibition of enzyme activity. Under the conditions analysed, the integral model showed that the simultaneous inhibition of hexokinase and phosphofructokinase explains the observation that the concentrations of glucose-6-phosphate and fructose-6-phosphate did not change as the heavy metals decreased the glycolytic flux.


Assuntos
Cádmio/toxicidade , Glicólise/efeitos dos fármacos , Mercúrio/toxicidade , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Animais , Frutosefosfatos/metabolismo , Glucose/metabolismo , Glucose-6-Fosfato/metabolismo , Hexoquinase/metabolismo , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Fosfofrutoquinase-1/metabolismo , Fosfofrutoquinases/metabolismo
16.
PLoS Comput Biol ; 9(12): e1003393, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24348236

RESUMO

After decades of using urea as denaturant, the kinetic role of this molecule in the unfolding process is still undefined: does urea actively induce protein unfolding or passively stabilize the unfolded state? By analyzing a set of 30 proteins (representative of all native folds) through extensive molecular dynamics simulations in denaturant (using a range of force-fields), we derived robust rules for urea unfolding that are valid at the proteome level. Irrespective of the protein fold, presence or absence of disulphide bridges, and secondary structure composition, urea concentrates in the first solvation shell of quasi-native proteins, but with a density lower than that of the fully unfolded state. The presence of urea does not alter the spontaneous vibration pattern of proteins. In fact, it reduces the magnitude of such vibrations, leading to a counterintuitive slow down of the atomic-motions that opposes unfolding. Urea stickiness and slow diffusion is, however, crucial for unfolding. Long residence urea molecules placed around the hydrophobic core are crucial to stabilize partially open structures generated by thermal fluctuations. Our simulations indicate that although urea does not favor the formation of partially open microstates, it is not a mere spectator of unfolding that simply displaces to the right of the folded ←→ unfolded equilibrium. On the contrary, urea actively favors unfolding: it selects and stabilizes partially unfolded microstates, slowly driving the protein conformational ensemble far from the native one and also from the conformations sampled during thermal unfolding.


Assuntos
Desdobramento de Proteína , Proteoma
17.
Nucleic Acids Res ; 41(Web Server issue): W47-55, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23685436

RESUMO

We present NAFlex, a new web tool to study the flexibility of nucleic acids, either isolated or bound to other molecules. The server allows the user to incorporate structures from protein data banks, completing gaps and removing structural inconsistencies. It is also possible to define canonical (average or sequence-adapted) nucleic acid structures using a variety of predefined internal libraries, as well to create specific nucleic acid conformations from the sequence. The server offers a variety of methods to explore nucleic acid flexibility, such as a colorless wormlike-chain model, a base-pair resolution mesoscopic model and atomistic molecular dynamics simulations with a wide variety of protocols and force fields. The trajectories obtained by simulations, or imported externally, can be visualized and analyzed using a large number of tools, including standard Cartesian analysis, essential dynamics, helical analysis, local and global stiffness, energy decomposition, principal components and in silico NMR spectra. The server is accessible free of charge from the mmb.irbbarcelona.org/NAFlex webpage.


Assuntos
Conformação de Ácido Nucleico , Software , DNA/química , Proteínas de Ligação a DNA/química , Humanos , Internet , Proteínas Mitocondriais/química , Simulação de Dinâmica Molecular , Análise de Sequência de DNA , Análise de Sequência de RNA , Fatores de Transcrição/química
18.
J Chem Theory Comput ; 9(2): 1222-9, 2013 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-26588765

RESUMO

Protein-protein interactions are responsible for the transfer of information inside the cell and represent one of the most interesting research fields in structural biology. Unfortunately, after decades of intense research, experimental approaches still have difficulties in providing 3D structures for the hundreds of thousands of interactions formed between the different proteins in a living organism. The use of theoretical approaches like docking aims to complement experimental efforts to represent the structure of the protein interactome. However, we cannot ignore that current methods have limitations due to problems of sampling of the protein-protein conformational space and the lack of accuracy of available force fields. Cases that are especially difficult for prediction are those in which complex formation implies a non-negligible change in the conformation of the interacting proteins, i.e., those cases where protein flexibility plays a key role in protein-protein docking. In this work, we present a new approach to treat flexibility in docking by global structural relaxation based on ultrafast discrete molecular dynamics. On a standard benchmark of protein complexes, the method provides a general improvement over the results obtained by rigid docking. The method is especially efficient in cases with large conformational changes upon binding, in which structure relaxation with discrete molecular dynamics leads to a predictive success rate double that obtained with state-of-the-art rigid-body docking.

19.
Gut ; 62(10): 1440-5, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22936669

RESUMO

OBJECTIVE: Genome-wide association studies (GWAS) have identified multiple risk loci for Crohn's disease (CD). However, the cumulative risk exerted by these loci is low, and the likelihood that additional, as-yet undiscovered loci contribute to the risk of CD is very high. We performed a GWAS on a southern European population to identify new CD risk loci. DESIGN: We genotyped 620 901 genome markers on 1341 CD patients and 1518 controls from Spain. The top association signals representing new candidate risk loci were subsequently analysed in an independent replication cohort of 1365 CD patients and 1396 controls. RESULTS: We identified a genome-wide significant association on chromosome 22q13.2 in the intergenic region between the RBX1 and EP300 genes (single nucleotide polymorphism rs4820425, OR 1.27, 95% CI 1.17 to 1.38, p=3.42E-8). We also found suggestive evidence for the association of the IFNGR2 (21q22.11), FOXP2 (7q31), MACROD2 (20p12.1) and AIF1 (6p21.3) loci with CD risk. CONCLUSIONS: In this GWAS performed on a southern European cohort, we have identified a new risk locus for CD between RBX1 and EP300. This study demonstrates that using populations of different ancestry is a useful strategy to identify new risk loci for CD.


Assuntos
Proteínas de Transporte/genética , Doença de Crohn/genética , Proteína p300 Associada a E1A/genética , Adulto , Estudos de Casos e Controles , Cromossomos Humanos Par 22/genética , Doença de Crohn/epidemiologia , DNA Intergênico/genética , Feminino , Loci Gênicos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Espanha/epidemiologia
20.
Genet Epidemiol ; 36(7): 710-6, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22886951

RESUMO

The detection of gene-gene interactions (i.e., epistasis) in the human genome is becoming decisive for the complete characterization of the genetic factors associated with complex binary traits. Despite the fact that many methods have been developed to address this challenging issue, their performance still remains insufficient. We will show how case and control groups store complementary information regarding interactions, and the use of this fundamental property in the design of a new, rapid, and highly powerful epistasis analysis method. Unlike previous approaches where statistical methods are tested over a very limited range of situations, we have performed an exhaustive evaluation of the power of our new method. To this end, we also propose a more comprehensive interpretation of epistasis in which genotype interactions may be of risk, protective, or neutral. In this extended view of genetic interactions, we demonstrate that our method has superior performance than existing approaches, thus, providing a highly powerful tool for the identification of gene-gene interactions associated with binary traits.


Assuntos
Estudos de Casos e Controles , Interpretação Estatística de Dados , Epistasia Genética , Modelos Genéticos , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial , Software
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