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3.
Nat Commun ; 14(1): 4816, 2023 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-37558666

RESUMO

Cholesterol biosynthesis is a highly regulated, oxygen-dependent pathway, vital for cell membrane integrity and growth. In fungi, the dependency on oxygen for sterol production has resulted in a shared transcriptional response, resembling prolyl hydroxylation of Hypoxia Inducible Factors (HIFs) in metazoans. Whether an analogous metazoan pathway exists is unknown. Here, we identify Sterol Regulatory Element Binding Protein 2 (SREBP2), the key transcription factor driving sterol production in mammals, as an oxygen-sensitive regulator of cholesterol synthesis. SREBP2 degradation in hypoxia overrides the normal sterol-sensing response, and is HIF independent. We identify MARCHF6, through its NADPH-mediated activation in hypoxia, as the main ubiquitin ligase controlling SREBP2 stability. Hypoxia-mediated degradation of SREBP2 protects cells from statin-induced cell death by forcing cells to rely on exogenous cholesterol uptake, explaining why many solid organ tumours become auxotrophic for cholesterol. Our findings therefore uncover an oxygen-sensitive pathway for governing cholesterol synthesis through regulated SREBP2-dependent protein degradation.


Assuntos
Oxigênio , Fatores de Transcrição , Animais , Humanos , Oxigênio/metabolismo , Fatores de Transcrição/metabolismo , Hipóxia , Colesterol/metabolismo , Esteróis , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Mamíferos/metabolismo
4.
Nat Metab ; 4(6): 711-723, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35739397

RESUMO

Production of oxidized biomass, which requires regeneration of the cofactor NAD+, can be a proliferation bottleneck that is influenced by environmental conditions. However, a comprehensive quantitative understanding of metabolic processes that may be affected by NAD+ deficiency is currently missing. Here, we show that de novo lipid biosynthesis can impose a substantial NAD+ consumption cost in proliferating cancer cells. When electron acceptors are limited, environmental lipids become crucial for proliferation because NAD+ is required to generate precursors for fatty acid biosynthesis. We find that both oxidative and even net reductive pathways for lipogenic citrate synthesis are gated by reactions that depend on NAD+ availability. We also show that access to acetate can relieve lipid auxotrophy by bypassing the NAD+ consuming reactions. Gene expression analysis demonstrates that lipid biosynthesis strongly anti-correlates with expression of hypoxia markers across tumor types. Overall, our results define a requirement for oxidative metabolism to support biosynthetic reactions and provide a mechanistic explanation for cancer cell dependence on lipid uptake in electron acceptor-limited conditions, such as hypoxia.


Assuntos
NAD , Neoplasias , Proliferação de Células , Elétrons , Humanos , Hipóxia , Lipídeos , NAD/metabolismo
5.
Genome Biol Evol ; 13(2)2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33432359

RESUMO

For more than a decade, the misfolding avoidance hypothesis (MAH) and related theories have dominated evolutionary discussions aimed at explaining the variance of the molecular clock across cellular proteins. In this study, we use various experimental data to further investigate the consistency of the MAH predictions with empirical evidence. We also critically discuss experimental results that motivated the MAH development and that are often viewed as evidence of its major contribution to the variability of protein evolutionary rates. We demonstrate, in Escherichia coli and Homo sapiens, the lack of a substantial negative correlation between protein evolutionary rates and Gibbs free energies of unfolding, a direct measure of protein stability. We then analyze multiple new genome-scale data sets characterizing protein aggregation and interaction propensities, the properties that are likely optimized in evolution to alleviate deleterious effects associated with toxic protein misfolding and misinteractions. Our results demonstrate that the propensity of proteins to aggregate, the fraction of charged amino acids, and protein stickiness do correlate with protein abundances. Nevertheless, across multiple organisms and various data sets we do not observe substantial correlations between proteins' aggregation- and stability-related properties and evolutionary rates. Therefore, diverse empirical data support the conclusion that the MAH and similar hypotheses do not play a major role in mediating a strong negative correlation between protein expression and the molecular clock, and thus in explaining the variability of evolutionary rates across cellular proteins.


Assuntos
Evolução Molecular , Proteínas/genética , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Humanos , Dobramento de Proteína , Estabilidade Proteica , Proteínas/química , Proteínas/metabolismo , RNA Mensageiro/metabolismo
6.
Mol Psychiatry ; 26(5): 1685-1695, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33110259

RESUMO

Autism spectrum disorders (ASD) are a group of related neurodevelopmental diseases displaying significant genetic and phenotypic heterogeneity. Despite recent progress in understanding ASD genetics, the nature of phenotypic heterogeneity across probands remains unclear. Notably, likely gene-disrupting (LGD) de novo mutations affecting the same gene often result in substantially different ASD phenotypes. Nevertheless, we find that truncating mutations affecting the same exon frequently lead to strikingly similar intellectual phenotypes in unrelated ASD probands. Analogous patterns are observed for two independent proband cohorts and several other important ASD-associated phenotypes. We find that exons biased toward prenatal and postnatal expression preferentially contribute to ASD cases with lower and higher IQ phenotypes, respectively. These results suggest that exons, rather than genes, often represent a unit of effective phenotypic impact for truncating mutations in autism. The observed phenotypic patterns are likely mediated by nonsense-mediated decay (NMD) of splicing isoforms, with autism phenotypes usually triggered by relatively mild (15-30%) decreases in overall gene dosage. We find that each ASD gene with recurrent mutations can be characterized by a parameter, phenotype dosage sensitivity (PDS), which quantifies the relationship between changes in a gene's dosage and changes in a given disease phenotype. We further demonstrate analogous relationships between exon LGDs and gene expression changes in multiple human tissues. Therefore, similar phenotypic patterns may be also observed in other human genetic disorders.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Éxons/genética , Humanos , Mutação/genética , Fenótipo
7.
Nat Microbiol ; 5(5): 768-775, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32284567

RESUMO

The gut microbiota is now widely recognized as a dynamic ecosystem that plays an important role in health and disease. Although current sequencing technologies make it possible to explore how relative abundances of host-associated bacteria change over time, the biological processes governing microbial dynamics remain poorly understood. Therefore, as in other ecological systems, it is important to identify quantitative relationships describing various aspects of gut microbiota dynamics. In the present study, we use multiple high-resolution time series data obtained from humans and mice to demonstrate that, despite their inherent complexity, gut microbiota dynamics can be characterized by several robust scaling relationships. Interestingly, the observed patterns are highly similar to those previously identified across diverse ecological communities and economic systems, including the temporal fluctuations of animal and plant populations and the performance of publicly traded companies. Specifically, we find power-law relationships describing short- and long-term changes in gut microbiota abundances, species residence and return times, and the correlation between the mean and the temporal variance of species abundances. The observed scaling laws are altered in mice receiving different diets and are affected by context-specific perturbations in humans. We use the macroecological relationships to reveal specific bacterial taxa, the dynamics of which are substantially perturbed by dietary and environmental changes. Overall, our results suggest that a quantitative macroecological framework will be important for characterizing and understanding the complex dynamics of diverse microbial communities.


Assuntos
Bactérias/classificação , Microbioma Gastrointestinal/fisiologia , Trato Gastrointestinal/microbiologia , Animais , Bactérias/genética , Biodiversidade , Simulação por Computador , Dieta , Microbioma Gastrointestinal/genética , Humanos , Camundongos , Microbiota , Modelos Teóricos , RNA Ribossômico 16S
8.
Elife ; 92020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31961323

RESUMO

Detecting relative rather than absolute changes in extracellular signals enables cells to make decisions in constantly fluctuating environments. It is currently not well understood how mammalian signaling networks store the memories of past stimuli and subsequently use them to compute relative signals, that is perform fold change detection. Using the growth factor-activated PI3K-Akt signaling pathway, we develop here computational and analytical models, and experimentally validate a novel non-transcriptional mechanism of relative sensing in mammalian cells. This mechanism relies on a new form of cellular memory, where cells effectively encode past stimulation levels in the abundance of cognate receptors on the cell surface. The surface receptor abundance is regulated by background signal-dependent receptor endocytosis and down-regulation. We show the robustness and specificity of relative sensing for two physiologically important ligands, epidermal growth factor (EGF) and hepatocyte growth factor (HGF), and across wide ranges of background stimuli. Our results suggest that similar mechanisms of cell memory and fold change detection may be important in diverse signaling cascades and multiple biological contexts.


Assuntos
Fenômenos Fisiológicos Celulares/fisiologia , Espaço Extracelular/metabolismo , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/fisiologia , Linhagem Celular , Membrana Celular/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Endocitose/fisiologia , Fator de Crescimento Epidérmico/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Modelos Biológicos , Proteínas Proto-Oncogênicas c-akt/metabolismo
9.
Cell Syst ; 10(2): 204-212.e8, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-31864963

RESUMO

Predictive models of signaling networks are essential for understanding cell population heterogeneity and designing rational interventions in disease. However, using computational models to predict heterogeneity of signaling dynamics is often challenging because of the extensive variability of biochemical parameters across cell populations. Here, we describe a maximum entropy-based framework for inference of heterogeneity in dynamics of signaling networks (MERIDIAN). MERIDIAN estimates the joint probability distribution over signaling network parameters that is consistent with experimentally measured cell-to-cell variability of biochemical species. We apply the developed approach to investigate the response heterogeneity in the EGFR/Akt signaling network. Our analysis demonstrates that a significant fraction of cells exhibits high phosphorylated Akt (pAkt) levels hours after EGF stimulation. Our findings also suggest that cells with high EGFR levels predominantly contribute to the subpopulation of cells with high pAkt activity. We also discuss how MERIDIAN can be extended to accommodate various experimental measurements.


Assuntos
Células/metabolismo , Entropia , Heterogeneidade Genética , Humanos , Transdução de Sinais
10.
Elife ; 82019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31532392

RESUMO

Functional conservation is known to constrain protein evolution. Nevertheless, the long-term divergence patterns of proteins maintaining the same molecular function and the possible limits of this divergence have not been explored in detail. We investigate these fundamental questions by characterizing the divergence between ancient protein orthologs with conserved molecular function. Our results demonstrate that the decline of sequence and structural similarities between such orthologs significantly slows down after ~1-2 billion years of independent evolution. As a result, the sequence and structural similarities between ancient orthologs have not substantially decreased for the past billion years. The effective divergence limit (>25% sequence identity) is not primarily due to protein sites universally conserved in all linages. Instead, less than four amino acid types are accepted, on average, per site across orthologous protein sequences. Our analysis also reveals different divergence patterns for protein sites with experimentally determined small and large fitness effects of mutations. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).


Assuntos
Enzimas/genética , Enzimas/metabolismo , Evolução Molecular , Redes e Vias Metabólicas/genética , Biologia Computacional , Enzimas/química , Conformação Proteica
11.
Nat Methods ; 16(8): 731-736, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31308552

RESUMO

Metagenomic sequencing has enabled detailed investigation of diverse microbial communities, but understanding their spatiotemporal variability remains an important challenge. Here, we present decomposition of variance using replicate sampling (DIVERS), a method based on replicate sampling and spike-in sequencing. The method quantifies the contributions of temporal dynamics, spatial sampling variability, and technical noise to the variances and covariances of absolute bacterial abundances. We applied DIVERS to investigate a high-resolution time series of the human gut microbiome and a spatial survey of a soil bacterial community in Manhattan's Central Park. Our analysis showed that in the gut, technical noise dominated the abundance variability for nearly half of the detected taxa. DIVERS also revealed substantial spatial heterogeneity of gut microbiota, and high temporal covariances of taxa within the Bacteroidetes phylum. In the soil community, spatial variability primarily contributed to abundance fluctuations at short time scales (weeks), while temporal variability dominated at longer time scales (several months).


Assuntos
Algoritmos , Bactérias/genética , Fezes/microbiologia , Microbioma Gastrointestinal , Metagenômica/métodos , Microbiologia do Solo , Análise Espaço-Temporal , Bactérias/classificação , Humanos , RNA Ribossômico 16S , Análise de Sequência de DNA , Manejo de Espécimes
12.
Mol Biol Evol ; 35(3): 700-703, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29309671

RESUMO

The avoidance of cytotoxic effects associated with protein misfolding has been proposed as a dominant constraint on the sequence evolution and molecular clock of highly expressed proteins. Recently, Leuenberger et al. developed an elegant experimental approach to measure protein thermal stability at the proteome scale. The collected data allow us to rigorously test the predictions of the misfolding avoidance hypothesis that highly expressed proteins have evolved to be more stable, and that maintaining thermodynamic stability significantly constrains their evolution. Notably, reanalysis of the Leuenberger et al. data across four different organisms reveals no substantial correlation between protein stability and protein abundance. Therefore, the key predictions of the misfolding toxicity and related hypotheses are not supported by available empirical data. The data also suggest that, regardless of protein expression, protein stability does not substantially affect the protein molecular clock across organisms.

13.
Science ; 353(6304): 1161-5, 2016 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-27609895

RESUMO

Tumor genetics guides patient selection for many new therapies, and cell culture studies have demonstrated that specific mutations can promote metabolic phenotypes. However, whether tissue context defines cancer dependence on specific metabolic pathways is unknown. Kras activation and Trp53 deletion in the pancreas or the lung result in pancreatic ductal adenocarinoma (PDAC) or non-small cell lung carcinoma (NSCLC), respectively, but despite the same initiating events, these tumors use branched-chain amino acids (BCAAs) differently. NSCLC tumors incorporate free BCAAs into tissue protein and use BCAAs as a nitrogen source, whereas PDAC tumors have decreased BCAA uptake. These differences are reflected in expression levels of BCAA catabolic enzymes in both mice and humans. Loss of Bcat1 and Bcat2, the enzymes responsible for BCAA use, impairs NSCLC tumor formation, but these enzymes are not required for PDAC tumor formation, arguing that tissue of origin is an important determinant of how cancers satisfy their metabolic requirements.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , Antígenos de Histocompatibilidade Menor/genética , Mutação , Nitrogênio/metabolismo , Especificidade de Órgãos , Proteínas da Gravidez/genética , Transaminases/genética
14.
Nature ; 517(7534): 369-72, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25363780

RESUMO

For many decades comparative analyses of protein sequences and structures have been used to investigate fundamental principles of molecular evolution. In contrast, relatively little is known about the long-term evolution of species' phenotypic and genetic properties. This represents an important gap in our understanding of evolution, as exactly these proprieties play key roles in natural selection and adaptation to diverse environments. Here we perform a comparative analysis of bacterial growth and gene deletion phenotypes using hundreds of genome-scale metabolic models. Overall, bacterial phenotypic evolution can be described by a two-stage process with a rapid initial phenotypic diversification followed by a slow long-term exponential divergence. The observed average divergence trend, with approximately similar fractions of phenotypic properties changing per unit time, continues for billions of years. We experimentally confirm the predicted divergence trend using the phenotypic profiles of 40 diverse bacterial species across more than 60 growth conditions. Our analysis suggests that, at long evolutionary distances, gene essentiality is significantly more conserved than the ability to utilize different nutrients, while synthetic lethality is significantly less conserved. We also find that although a rapid phenotypic evolution is sometimes observed within the same species, a transition from high to low phenotypic similarity occurs primarily at the genus level.


Assuntos
Bactérias/classificação , Bactérias/metabolismo , Evolução Biológica , Fenótipo , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Deleção de Genes , Genoma Bacteriano/genética , Seleção Genética
15.
Nat Neurosci ; 18(2): 191-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25531569

RESUMO

Autism spectrum disorders (ASDs) are characterized by phenotypic and genetic heterogeneity. Our analysis of functional networks perturbed in ASD suggests that both truncating and nontruncating de novo mutations contribute to autism, with a bias against truncating mutations in early embryonic development. We find that functional mutations are preferentially observed in genes likely to be haploinsufficient. Multiple cell types and brain areas are affected, but the impact of ASD mutations appears to be strongest in cortical interneurons, pyramidal neurons and the medium spiny neurons of the striatum, implicating cortical and corticostriatal brain circuits. In females, truncating ASD mutations on average affect genes with 50-100% higher brain expression than in males. Our results also suggest that truncating de novo mutations play a smaller role in the etiology of high-functioning ASD cases. Overall, we find that stronger functional insults usually lead to more severe intellectual, social and behavioral ASD phenotypes.


Assuntos
Encéfalo/metabolismo , Transtornos Globais do Desenvolvimento Infantil/genética , Estudos de Associação Genética/métodos , Genótipo , Mutação/genética , Fenótipo , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Transtornos Globais do Desenvolvimento Infantil/fisiopatologia , Feminino , Humanos , Masculino
16.
Nucleic Acids Res ; 42(4): 2405-14, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24288370

RESUMO

Gene duplications are a major source of evolutionary innovations. Understanding the functional divergence of duplicates and their role in genetic robustness is an important challenge in biology. Previously, analyses of genetic robustness were primarily focused on duplicates essentiality and epistasis in several laboratory conditions. In this study, we use several quantitative data sets to understand compensatory interactions between Saccharomyces cerevisiae duplicates that are likely to be relevant in natural biological populations. We find that, owing to their high functional load, close duplicates are unlikely to provide substantial backup in the context of large natural populations. Interestingly, as duplicates diverge from each other, their overall functional load is reduced. At intermediate divergence distances the quantitative decrease in fitness due to removal of one duplicate becomes smaller. At these distances, yeast duplicates display more balanced functional loads and their transcriptional control becomes significantly more complex. As yeast duplicates diverge beyond 70% sequence identity, their ability to compensate for each other becomes similar to that of random pairs of singletons.


Assuntos
Evolução Molecular , Duplicação Gênica , Genes Fúngicos , Fenótipo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento
17.
Nat Biotechnol ; 31(6): 522-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23604282

RESUMO

Reprogramming of cellular metabolism is an emerging hallmark of neoplastic transformation. However, it is not known how the expression of metabolic genes in tumors differs from that in normal tissues, or whether different tumor types exhibit similar metabolic changes. Here we compare expression patterns of metabolic genes across 22 diverse types of human tumors. Overall, the metabolic gene expression program in tumors is similar to that in the corresponding normal tissues. Although expression changes of some metabolic pathways (e.g., upregulation of nucleotide biosynthesis and glycolysis) are frequently observed across tumors, expression changes of other pathways (e.g., oxidative phosphorylation) are very heterogeneous. Our analysis also suggests that the expression changes of some metabolic genes (e.g., isocitrate dehydrogenase and fumarate hydratase) may enhance or mimic the effects of recurrent mutations in tumors. On the level of individual biochemical reactions, many hundreds of metabolic isoenzymes show significant and tumor-specific expression changes. These isoenzymes are potential targets for anticancer therapy.


Assuntos
Transformação Celular Neoplásica/metabolismo , Isocitrato Desidrogenase/genética , Redes e Vias Metabólicas/genética , Neoplasias/metabolismo , Transformação Celular Neoplásica/genética , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Glicólise/genética , Humanos , Isocitrato Desidrogenase/metabolismo , Isoenzimas , Terapia de Alvo Molecular , Mutação , Neoplasias/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação Oxidativa
18.
Mol Syst Biol ; 9: 644, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23385484

RESUMO

Using models to simulate and analyze biological networks requires principled approaches to parameter estimation and model discrimination. We use Bayesian and Monte Carlo methods to recover the full probability distributions of free parameters (initial protein concentrations and rate constants) for mass-action models of receptor-mediated cell death. The width of the individual parameter distributions is largely determined by non-identifiability but covariation among parameters, even those that are poorly determined, encodes essential information. Knowledge of joint parameter distributions makes it possible to compute the uncertainty of model-based predictions whereas ignoring it (e.g., by treating parameters as a simple list of values and variances) yields nonsensical predictions. Computing the Bayes factor from joint distributions yields the odds ratio (∼20-fold) for competing 'direct' and 'indirect' apoptosis models having different numbers of parameters. Our results illustrate how Bayesian approaches to model calibration and discrimination combined with single-cell data represent a generally useful and rigorous approach to discriminate between competing hypotheses in the face of parametric and topological uncertainty.


Assuntos
Teorema de Bayes , Morte Celular , Modelos Biológicos , Calibragem , Simulação por Computador , Modelos Teóricos , Método de Monte Carlo , Razão de Chances , Receptores Citoplasmáticos e Nucleares/metabolismo
19.
Nat Neurosci ; 15(12): 1723-8, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23143521

RESUMO

Despite the successful identification of several relevant genomic loci, the underlying molecular mechanisms of schizophrenia remain largely unclear. We developed a computational approach (NETBAG+) that allows an integrated analysis of diverse disease-related genetic data using a unified statistical framework. The application of this approach to schizophrenia-associated genetic variations, obtained using unbiased whole-genome methods, allowed us to identify several cohesive gene networks related to axon guidance, neuronal cell mobility, synaptic function and chromosomal remodeling. The genes forming the networks are highly expressed in the brain, with higher brain expression during prenatal development. The identified networks are functionally related to genes previously implicated in schizophrenia, autism and intellectual disability. A comparative analysis of copy number variants associated with autism and schizophrenia suggests that although the molecular networks implicated in these distinct disorders may be related, the mutations associated with each disease are likely to lead, at least on average, to different functional consequences.


Assuntos
Redes Reguladoras de Genes/genética , Variação Genética/genética , Família Multigênica/genética , Fenótipo , Esquizofrenia/genética , Transtorno Autístico/diagnóstico , Transtorno Autístico/epidemiologia , Transtorno Autístico/genética , Análise por Conglomerados , Regulação da Expressão Gênica no Desenvolvimento , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Domínios e Motivos de Interação entre Proteínas/genética , Esquizofrenia/diagnóstico , Esquizofrenia/epidemiologia
20.
Nat Chem Biol ; 8(10): 848-54, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22960854

RESUMO

Annotation of organism-specific metabolic networks is one of the main challenges of systems biology. Importantly, owing to inherent uncertainty of computational annotations, predictions of biochemical function need to be treated probabilistically. We present a global probabilistic approach to annotate genome-scale metabolic networks that integrates sequence homology and context-based correlations under a single principled framework. The developed method for global biochemical reconstruction using sampling (GLOBUS) not only provides annotation probabilities for each functional assignment but also suggests likely alternative functions. GLOBUS is based on statistical Gibbs sampling of probable metabolic annotations and is able to make accurate functional assignments even in cases of remote sequence identity to known enzymes. We apply GLOBUS to genomes of Bacillus subtilis and Staphylococcus aureus and validate the method predictions by experimentally demonstrating the 6-phosphogluconolactonase activity of YkgB and the role of the Sps pathway for rhamnose biosynthesis in B. subtilis.


Assuntos
Enzimas/metabolismo , Redes e Vias Metabólicas , Probabilidade , Bacillus subtilis/enzimologia , Bacillus subtilis/metabolismo , Genoma Bacteriano , Staphylococcus aureus/enzimologia , Staphylococcus aureus/metabolismo
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