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1.
Am J Hum Genet ; 108(10): 1891-1906, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34551312

RESUMO

The success of personalized genomic medicine depends on our ability to assess the pathogenicity of rare human variants, including the important class of missense variation. There are many challenges in training accurate computational systems, e.g., in finding the balance between quantity, quality, and bias in the variant sets used as training examples and avoiding predictive features that can accentuate the effects of bias. Here, we describe VARITY, which judiciously exploits a larger reservoir of training examples with uncertain accuracy and representativity. To limit circularity and bias, VARITY excludes features informed by variant annotation and protein identity. To provide a rationale for each prediction, we quantified the contribution of features and feature combinations to the pathogenicity inference of each variant. VARITY outperformed all previous computational methods evaluated, identifying at least 10% more pathogenic variants at thresholds achieving high (90% precision) stringency.

2.
Am J Hum Genet ; 108(7): 1283-1300, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34214447

RESUMO

Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.


Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Análise Mutacional de DNA , Diploide , Biblioteca Gênica , Genótipo , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Saccharomyces cerevisiae/genética
3.
Bioinformatics ; 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33774657

RESUMO

SUMMARY: Multiplexed assays of variant effect (MAVEs) are capable of experimentally testing all possible single nucleotide or amino acid variants in selected genomic regions, generating 'variant effect maps', which provide biochemical insight and functional evidence to enable more rapid and accurate clinical interpretation of human variation. Because the international community applying MAVE approaches is growing rapidly, we developed the online MaveRegistry platform to catalyze collaboration, reduce redundant efforts, allow stakeholders to nominate targets, and enable tracking and sharing of progress on ongoing MAVE projects. AVAILABILITY AND IMPLEMENTATION: MaveRegistry service: https://registry.varianteffect.org. MaveRegistry source code: https://github.com/kvnkuang/maveregistry-front-end. SUPPLEMENTARY INFORMATION: no Supplementary data.

4.
Bioinformatics ; 36(22-23): 5448-5455, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33300982

RESUMO

MOTIVATION: When rare missense variants are clinically interpreted as to their pathogenicity, most are classified as variants of uncertain significance (VUS). Although functional assays can provide strong evidence for variant classification, such results are generally unavailable. Multiplexed assays of variant effect can generate experimental 'variant effect maps' that score nearly all possible missense variants in selected protein targets for their impact on protein function. However, these efforts have not always prioritized proteins for which variant effect maps would have the greatest impact on clinical variant interpretation. RESULTS: Here, we mined databases of clinically interpreted variants and applied three strategies, each building on the previous, to prioritize genes for systematic functional testing of missense variation. The strategies ranked genes (i) by the number of unique missense VUS that had been reported to ClinVar; (ii) by movability- and reappearance-weighted impact scores, to give extra weight to reappearing, movable VUS and (iii) by difficulty-adjusted impact scores, to account for the more resource-intensive nature of generating variant effect maps for longer genes. Our results could be used to guide systematic functional testing of missense variation toward greater impact on clinical variant interpretation. AVAILABILITY AND IMPLEMENTATION: Source code available at: https://github.com/rothlab/mave-gene-prioritization. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Mutação de Sentido Incorreto , Proteínas
5.
Mol Syst Biol ; 16(9): e9828, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32939983

RESUMO

Essential genes tend to be highly conserved across eukaryotes, but, in some cases, their critical roles can be bypassed through genetic rewiring. From a systematic analysis of 728 different essential yeast genes, we discovered that 124 (17%) were dispensable essential genes. Through whole-genome sequencing and detailed genetic analysis, we investigated the genetic interactions and genome alterations underlying bypass suppression. Dispensable essential genes often had paralogs, were enriched for genes encoding membrane-associated proteins, and were depleted for members of protein complexes. Functionally related genes frequently drove the bypass suppression interactions. These gene properties were predictive of essential gene dispensability and of specific suppressors among hundreds of genes on aneuploid chromosomes. Our findings identify yeast's core essential gene set and reveal that the properties of dispensable essential genes are conserved from yeast to human cells, correlating with human genes that display cell line-specific essentiality in the Cancer Dependency Map (DepMap) project.

6.
Bioinformatics ; 36(12): 3938-3940, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32251504

RESUMO

SUMMARY: Fully realizing the promise of personalized medicine will require rapid and accurate classification of pathogenic human variation. Multiplexed assays of variant effect (MAVEs) can experimentally test nearly all possible variants in selected gene targets. Planning a MAVE study involves identifying target genes with clinical impact, and identifying scalable functional assays for that target. Here, we describe MaveQuest, a web-based resource enabling systematic variant effect mapping studies by identifying potential functional assays, disease phenotypes and clinical relevance for nearly all human protein-coding genes. AVAILABILITY AND IMPLEMENTATION: MaveQuest service: https://mavequest.varianteffect.org/. MaveQuest source code: https://github.com/kvnkuang/mavequest-front-end/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Software , Humanos , Fenótipo
7.
Genome Med ; 12(1): 13, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000841

RESUMO

BACKGROUND: For the majority of rare clinical missense variants, pathogenicity status cannot currently be classified. Classical homocystinuria, characterized by elevated homocysteine in plasma and urine, is caused by variants in the cystathionine beta-synthase (CBS) gene, most of which are rare. With early detection, existing therapies are highly effective. METHODS: Damaging CBS variants can be detected based on their failure to restore growth in yeast cells lacking the yeast ortholog CYS4. This assay has only been applied reactively, after first observing a variant in patients. Using saturation codon-mutagenesis, en masse growth selection, and sequencing, we generated a comprehensive, proactive map of CBS missense variant function. RESULTS: Our CBS variant effect map far exceeds the performance of computational predictors of disease variants. Map scores correlated strongly with both disease severity (Spearman's ϱ = 0.9) and human clinical response to vitamin B6 (ϱ = 0.93). CONCLUSIONS: We demonstrate that highly multiplexed cell-based assays can yield proactive maps of variant function and patient response to therapy, even for rare variants not previously seen in the clinic.


Assuntos
Cistationina beta-Sintase/genética , Teste de Complementação Genética/métodos , Testes Genéticos/métodos , Homocistinúria/genética , Mutação de Sentido Incorreto , Cistationina beta-Sintase/metabolismo , Genótipo , Humanos , Fenótipo , Saccharomyces cerevisiae , Proteínas de Saccharomyces cerevisiae/genética
8.
Genome Biol ; 20(1): 223, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31679514

RESUMO

Multiplex assays of variant effect (MAVEs), such as deep mutational scans and massively parallel reporter assays, test thousands of sequence variants in a single experiment. Despite the importance of MAVE data for basic and clinical research, there is no standard resource for their discovery and distribution. Here, we present MaveDB ( https://www.mavedb.org ), a public repository for large-scale measurements of sequence variant impact, designed for interoperability with applications to interpret these datasets. We also describe the first such application, MaveVis, which retrieves, visualizes, and contextualizes variant effect maps. Together, the database and applications will empower the community to mine these powerful datasets.


Assuntos
Bases de Dados Genéticas , Variação Genética , Genômica , Software
9.
Hum Mutat ; 40(9): 1463-1473, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31283071

RESUMO

This paper reports the evaluation of predictions for the "CALM1" challenge in the fifth round of the Critical Assessment of Genome Interpretation held in 2018. In the challenge, the participants were asked to predict effects on yeast growth caused by missense variants of human calmodulin, a highly conserved protein in eukaryotic cells sensing calcium concentration. The performance of predictors implementing different algorithms and methods is similar. Most predictors are able to identify the deleterious or tolerated variants with modest accuracy, with a baseline predictor based purely on sequence conservation slightly outperforming the submitted predictions. Nevertheless, we think that the accuracy of predictions remains far from satisfactory, and the field awaits substantial improvements. The most poorly predicted variants in this round surround functional CALM1 sites that bind calcium or peptide, which suggests that better incorporation of structural analysis may help improve predictions.


Assuntos
Calmodulina/química , Calmodulina/genética , Biologia Computacional/métodos , Mutação de Sentido Incorreto , Leveduras/crescimento & desenvolvimento , Algoritmos , Sítios de Ligação , Cálcio/metabolismo , Calmodulina/metabolismo , Evolução Molecular , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Aptidão Genética , Humanos , Modelos Genéticos , Modelos Moleculares , Conformação Proteica , Engenharia de Proteínas , Leveduras/genética
10.
Bioinformatics ; 35(17): 3191-3193, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649215

RESUMO

SUMMARY: The promise of personalized genomic medicine depends on our ability to assess the functional impact of rare sequence variation. Multiplexed assays can experimentally measure the functional impact of missense variants on a massive scale. However, even after such assays, many missense variants remain poorly measured. Here we describe a software pipeline and application to impute missing information in experimentally determined variant effect maps. AVAILABILITY AND IMPLEMENTATION: http://impute.varianteffect.org source code: https://github.com/joewuca/imputation. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Software , Genoma , Genômica , Mutação de Sentido Incorreto
11.
Hum Genet ; 137(9): 665-678, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30073413

RESUMO

Given the constantly improving cost and speed of genome sequencing, it is reasonable to expect that personal genomes will soon be known for many millions of humans. This stands in stark contrast with our limited ability to interpret the sequence variants which we find. Although it is, perhaps, easiest to interpret variants in coding regions, knowledge of functional impact is unknown for the vast majority of missense variants. While many computational approaches can predict the impact of coding variants, they are given a little weight in the current guidelines for interpreting clinical variants. Laboratory assays produce comparatively more trustworthy results, but until recently did not scale to the space of all possible mutations. The development of deep mutational scanning and other multiplexed assays of variant effect has now brought feasibility of this endeavour within view. Here, we review progress in this field over the last decade, break down the different approaches into their components, and compare methodological differences.


Assuntos
Biologia Computacional/métodos , Estudos de Associação Genética/métodos , Variação Genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Genótipo , Humanos , Fenótipo
12.
Mol Syst Biol ; 14(5): e7985, 2018 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-29807908

RESUMO

Condition-dependent genetic interactions can reveal functional relationships between genes that are not evident under standard culture conditions. State-of-the-art yeast genetic interaction mapping, which relies on robotic manipulation of arrays of double-mutant strains, does not scale readily to multi-condition studies. Here, we describe barcode fusion genetics to map genetic interactions (BFG-GI), by which double-mutant strains generated via en masse "party" mating can also be monitored en masse for growth to detect genetic interactions. By using site-specific recombination to fuse two DNA barcodes, each representing a specific gene deletion, BFG-GI enables multiplexed quantitative tracking of double mutants via next-generation sequencing. We applied BFG-GI to a matrix of DNA repair genes under nine different conditions, including methyl methanesulfonate (MMS), 4-nitroquinoline 1-oxide (4NQO), bleomycin, zeocin, and three other DNA-damaging environments. BFG-GI recapitulated known genetic interactions and yielded new condition-dependent genetic interactions. We validated and further explored a subnetwork of condition-dependent genetic interactions involving MAG1, SLX4, and genes encoding the Shu complex, and inferred that loss of the Shu complex leads to an increase in the activation of the checkpoint protein kinase Rad53.


Assuntos
Mapeamento Cromossômico , Código de Barras de DNA Taxonômico , Dano ao DNA , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Reparo do DNA , Epistasia Genética , Deleção de Genes , Loci Gênicos , Sequenciamento de Nucleotídeos em Larga Escala , Metanossulfonato de Metila , Modelos Teóricos , Regiões Promotoras Genéticas , Reprodutibilidade dos Testes
13.
Mol Syst Biol ; 13(12): 957, 2017 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-29269382

RESUMO

Although we now routinely sequence human genomes, we can confidently identify only a fraction of the sequence variants that have a functional impact. Here, we developed a deep mutational scanning framework that produces exhaustive maps for human missense variants by combining random codon mutagenesis and multiplexed functional variation assays with computational imputation and refinement. We applied this framework to four proteins corresponding to six human genes: UBE2I (encoding SUMO E2 conjugase), SUMO1 (small ubiquitin-like modifier), TPK1 (thiamin pyrophosphokinase), and CALM1/2/3 (three genes encoding the protein calmodulin). The resulting maps recapitulate known protein features and confidently identify pathogenic variation. Assays potentially amenable to deep mutational scanning are already available for 57% of human disease genes, suggesting that DMS could ultimately map functional variation for all human disease genes.


Assuntos
Análise Mutacional de DNA/métodos , Mutação de Sentido Incorreto/genética , Calmodulina/genética , Doença/genética , Humanos , Aprendizado de Máquina , Fenótipo , Filogenia , Reprodutibilidade dos Testes , Proteína SUMO-1/genética , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo
14.
Hum Mutat ; 38(9): 1051-1063, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28817247

RESUMO

The exponential growth of genomic variants uncovered by next-generation sequencing necessitates efficient and accurate computational analyses to predict their functional effects. A number of computational methods have been developed for the task, but few unbiased comparisons of their performance are available. To fill the gap, The Critical Assessment of Genome Interpretation (CAGI) comprehensively assesses phenotypic predictions on newly collected experimental datasets. Here, we present the results of the SUMO conjugase challenge where participants were predicting functional effects of missense mutations in human SUMO-conjugating enzyme UBE2I. The performance of the predictors is similar to each other and is far from perfection. Evolutionary information from sequence alignments dominates the success: deleterious mutations at conserved positions and benign mutations at variable positions are accurately predicted. Prediction accuracy of other mutations remains unsatisfactory, and this fast-growing field of research is yet to learn the use of spatial structure information to improve the predictions significantly.


Assuntos
Biologia Computacional/métodos , Mutação de Sentido Incorreto , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Bases de Dados Genéticas , Evolução Molecular , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Moleculares , Ligação Proteica , Seleção Genética , Alinhamento de Sequência , Enzimas de Conjugação de Ubiquitina/química
15.
Mol Syst Biol ; 12(4): 863, 2016 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-27107012

RESUMO

High-throughput binary protein interaction mapping is continuing to extend our understanding of cellular function and disease mechanisms. However, we remain one or two orders of magnitude away from a complete interaction map for humans and other major model organisms. Completion will require screening at substantially larger scales with many complementary assays, requiring further efficiency gains in proteome-scale interaction mapping. Here, we report Barcode Fusion Genetics-Yeast Two-Hybrid (BFG-Y2H), by which a full matrix of protein pairs can be screened in a single multiplexed strain pool. BFG-Y2H uses Cre recombination to fuse DNA barcodes from distinct plasmids, generating chimeric protein-pair barcodes that can be quantified via next-generation sequencing. We applied BFG-Y2H to four different matrices ranging in scale from ~25 K to 2.5 M protein pairs. The results show that BFG-Y2H increases the efficiency of protein matrix screening, with quality that is on par with state-of-the-art Y2H methods.


Assuntos
Centrossomo/metabolismo , Mapeamento de Interação de Proteínas/métodos , Proteoma/metabolismo , Saccharomyces cerevisiae/genética , Cromossomos Humanos/metabolismo , Biblioteca Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Ligação Proteica , Técnicas do Sistema de Duplo-Híbrido
16.
Cell ; 161(3): 647-660, 2015 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-25910212

RESUMO

How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability. While common variants from healthy individuals rarely affect interactions, two-thirds of disease-associated alleles perturb protein-protein interactions, with half corresponding to "edgetic" alleles affecting only a subset of interactions while leaving most other interactions unperturbed. With transcription factors, many alleles that leave protein-protein interactions intact affect DNA binding. Different mutations in the same gene leading to different interaction profiles often result in distinct disease phenotypes. Thus disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread.


Assuntos
Doença/genética , Mutação de Sentido Incorreto , Mapas de Interação de Proteínas , Proteínas/genética , Proteínas/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Fases de Leitura Aberta , Dobramento de Proteína , Estabilidade Proteica
17.
BMC Cardiovasc Disord ; 13: 4, 2013 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-23324130

RESUMO

BACKGROUND: Atherosclerosis (AT) is a chronic inflammatory disease characterized by the accumulation of inflammatory cells, lipoproteins and fibrous tissue in the walls of arteries. AT is the primary cause of heart attacks and stroke and is the leading cause of death in Western countries. To date, the pathogenesis of AT is not well-defined. Studies have shown that the dedifferentiation of contractile and quiescent vascular smooth muscle cells (SMC) to the proliferative, migratory and synthetic phenotype in the intima is pivotal for the onset and progression of AT. To further delineate the mechanisms underlying the pathogenesis of AT, we analyzed the early molecular pathways and networks involved in the SMC phenotype transformation. METHODS: Quiescent human coronary artery SMCs were treated with minimally-oxidized LDL (moxLDL), for 3 hours and 21 hours, respectively. Transcriptomic data was generated for both time-points using microarrays and was subjected to pathway analysis using Gene Set Enrichment Analysis, GeneMANIA and Ingenuity software tools. Gene expression heat maps and pathways enriched in differentially expressed genes were compared to identify functional biological themes to elucidate early and late molecular mechanisms of moxLDL-induced SMC dedifferentiation. RESULTS: Differentially expressed genes were found to be enriched in cholesterol biosynthesis, inflammatory cytokines, chemokines, growth factors, cell cycle control and myogenic contraction themes. These pathways are consistent with inflammatory responses, cell proliferation, migration and ECM production, which are characteristic of SMC dedifferentiation. Furthermore, up-regulation of cholesterol synthesis and dysregulation of cholesterol metabolism was observed in moxLDL-induced SMC. These observations are consistent with the accumulation of cholesterol and oxidized cholesterol esters, which induce proinflammatory reactions during atherogenesis. Our data implicate for the first time IL12, IFN-α, HGF, CSF3, and VEGF signaling in SMC phenotype transformation. GPCR signaling, HBP1 (repressor of cyclin D1 and CDKN1B), and ID2 and ZEB1 transcriptional regulators were also found to have important roles in SMC dedifferentiation. Several microRNAs were observed to regulate the SMC phenotype transformation via an interaction with IFN-γ pathway. Also, several "nexus" genes in complex networks, including components of the multi-subunit enzyme complex involved in the terminal stages of cholesterol synthesis, microRNAs (miR-203, miR-511, miR-590-3p, miR-346*/miR- 1207-5p/miR-4763-3p), GPCR proteins (GPR1, GPR64, GPRC5A, GPR171, GPR176, GPR32, GPR25, GPR124) and signal transduction pathways, were found to be regulated. CONCLUSIONS: The systems biology analysis of the in vitro model of moxLDL-induced VSMC phenotype transformation was associated with the regulation of several genes not previously implicated in SMC phenotype transformation. The identification of these potential candidate genes enable hypothesis generation and in vivo functional experimentation (such as gain and loss-of-function studies) to establish causality with the process of SMC phenotype transformation and atherogenesis.


Assuntos
Aterosclerose/genética , Aterosclerose/metabolismo , Desdiferenciação Celular/genética , Lipoproteínas LDL/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Aterosclerose/patologia , Células Cultivadas , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Genótipo , Humanos , Músculo Liso Vascular/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Biologia de Sistemas , Fatores de Tempo
18.
Bioinformatics ; 28(11): 1495-500, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22492647

RESUMO

MOTIVATION: Biological experiments give insight into networks of processes inside a cell, but are subject to error and uncertainty. However, due to the overlap between the large number of experiments reported in public databases it is possible to assess the chances of individual observations being correct. In order to do so, existing methods rely on high-quality 'gold standard' reference networks, but such reference networks are not always available. RESULTS: We present a novel algorithm for computing the probability of network interactions that operates without gold standard reference data. We show that our algorithm outperforms existing gold standard-based methods. Finally, we apply the new algorithm to a large collection of genetic interaction and protein-protein interaction experiments. AVAILABILITY: The integrated dataset and a reference implementation of the algorithm as a plug-in for the Ondex data integration framework are available for download at http://bio-nexus.ncl.ac.uk/projects/nogold/


Assuntos
Algoritmos , Teorema de Bayes , Epistasia Genética , Mapeamento de Interação de Proteínas/normas , Funções Verossimilhança , Mapeamento de Interação de Proteínas/métodos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
19.
Bioinformatics ; 27(9): 1299-306, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21414991

RESUMO

MOTIVATION: The rise of high-throughput technologies in the post-genomic era has led to the production of large amounts of biological data. Many of these datasets are freely available on the Internet. Making optimal use of these data is a significant challenge for bioinformaticians. Various strategies for integrating data have been proposed to address this challenge. One of the most promising approaches is the development of semantically rich integrated datasets. Although well suited to computational manipulation, such integrated datasets are typically too large and complex for easy visualization and interactive exploration. RESULTS: We have created an integrated dataset for Saccharomyces cerevisiae using the semantic data integration tool Ondex, and have developed a view-based visualization technique that allows for concise graphical representations of the integrated data. The technique was implemented in a plug-in for Cytoscape, called OndexView. We used OndexView to investigate telomere maintenance in S. cerevisiae. AVAILABILITY: The Ondex yeast dataset and the OndexView plug-in for Cytoscape are accessible at http://bsu.ncl.ac.uk/ondexview.


Assuntos
Biologia Computacional/métodos , Bases de Dados Genéticas , Armazenamento e Recuperação da Informação/métodos , Biologia de Sistemas/métodos , Internet , Saccharomyces cerevisiae/genética , Telômero/genética
20.
J Integr Bioinform ; 7(3)2010 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-20375448

RESUMO

Drug development is expensive and prone to failure. It is potentially much less risky and expensive to reuse a drug developed for one condition for treating a second disease, than it is to develop an entirely new compound. Systematic approaches to drug repositioning are needed to increase throughput and find candidates more reliably. Here we address this need with an integrated systems biology dataset, developed using the Ondex data integration platform, for the in silico discovery of new drug repositioning candidates. We demonstrate that the information in this dataset allows known repositioning examples to be discovered. We also propose a means of automating the search for new treatment indications of existing compounds.


Assuntos
Biologia Computacional , Bases de Dados como Assunto , Descoberta de Drogas , Clorpromazina/análise , Semântica
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