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1.
Transl Psychiatry ; 12(1): 389, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114174

RESUMO

Observations of comorbidity in heart diseases, including cardiac dysfunction (CD) are increasing, including and cognitive impairment, such as Alzheimer's disease and dementia (AD/D). This comorbidity might be due to a pleiotropic effect of genetic variants shared between CD and AD/D. Here, we validated comorbidity of CD and AD/D based on diagnostic records from millions of patients in Korea and the University of California, San Francisco Medical Center (odds ratio 11.5 [8.5-15.5, 95% Confidence Interval (CI)]). By integrating a comprehensive human disease-SNP association database (VARIMED, VARiants Informing MEDicine) and whole-exome sequencing of 50 brains from individuals with and without Alzheimer's disease (AD), we identified missense variants in coding regions including APOB, a known risk factor for CD and AD/D, which potentially have a pleiotropic role in both diseases. Of the identified variants, site-directed mutation of ADIPOQ (268 G > A; Gly90Ser) in neurons produced abnormal aggregation of tau proteins (p = 0.02), suggesting a functional impact for AD/D. The association of CD and ADIPOQ variants was confirmed based on domain deletion in cardiac cells. Using the UK Biobank including data from over 500000 individuals, we examined a pleiotropic effect of the ADIPOQ variant by comparing CD- and AD/D-associated phenotypic evidence, including cardiac hypertrophy and cognitive degeneration. These results indicate that convergence of health care records and genetic evidences may help to dissect the molecular underpinnings of heart disease and associated cognitive impairment, and could potentially serve a prognostic function. Validation of disease-disease associations through health care records and genomic evidence can determine whether health conditions share risk factors based on pleiotropy.


Assuntos
Adiponectina , Doença de Alzheimer , Cardiopatias , Adiponectina/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteínas B , Atenção à Saúde , Registros de Saúde Pessoal , Cardiopatias/genética , Cardiopatias/metabolismo , Humanos , Proteínas tau
2.
Cell Rep ; 28(3): 712-722.e3, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31315049

RESUMO

The homeodomain is found in hundreds of transcription factors that play roles in fate determination via cell-autonomous regulation of gene expression. However, some homeodomain-containing proteins (HPs) are thought to be secreted and penetrate neighboring cells to affect the recipient cell fate. To determine whether this is a general characteristic of HPs, we carried out a large-scale validation for intercellular transfer of HPs. Our screening reveals that intercellular transfer is a general feature of HPs, but it occurs in a cell-context-sensitive manner. We also found the secretion is not solely a function of the homeodomain, but it is supported by external motifs containing hydrophobic residues. Thus, mutations of hydrophobic residues of HPs abrogate secretion and consequently interfere with HP function in recipient cells. Collectively, our study proposes that HP transfer is an intercellular communication method that couples the functions of interacting cells.


Assuntos
Comunicação Celular/genética , Proteínas de Homeodomínio/metabolismo , Transporte Proteico/genética , Motivos de Aminoácidos/genética , Animais , Encéfalo/embriologia , Encéfalo/metabolismo , Linhagem Celular , Feminino , Ensaios de Triagem em Larga Escala , Proteínas de Homeodomínio/genética , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Gravidez , Retina/metabolismo
3.
BMC Med Genomics ; 9 Suppl 1: 35, 2016 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-27535358

RESUMO

BACKGROUND: Exome sequencing has been emerged as a primary method to identify detailed sequence variants associated with complex diseases including Crohn's disease in the protein-coding regions of human genome. However, constructing an interpretable model for exome sequencing data is challenging because of the huge diversity of genomic variation. In addition, it has been known that utilizing biologically relevant information in a rigorous manner is essential for effectively extracting disease-associated information. RESULTS: In this paper, we incorporate three different types of biological knowledge such as predicted pathogenicity, disease gene annotation, and functional interaction network of human genes, and integrate them with exome sequence data in non-negative matrix tri-factorization framework. Based on the proposed method, we successfully identified Crohn's disease patients from exome sequencing data and achieved the area under the receiver operating characteristics curve (AUC) of 0.816, while other clustering methods not using biological information achieved the AUC of 0.786. Moreover, the disease association score derived from our method showed higher correlation with Crohn's disease genes than other unrelated genes. CONCLUSIONS: As a consequence, by integrating biological information across multiple levels such as variant, gene, and systems, our method could be useful for identifying disease susceptibility and its associated genes from exome sequencing data.


Assuntos
Biologia Computacional/métodos , Doença de Crohn/genética , Exoma/genética , Análise de Sequência de DNA , Estudos de Casos e Controles , Predisposição Genética para Doença/genética , Humanos , Mutação
4.
BMC Bioinformatics ; 17: 99, 2016 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-26911566

RESUMO

BACKGROUND: Elucidating the cooperative mechanism of interconnected residues is an important component toward understanding the biological function of a protein. Coevolution analysis has been developed to model the coevolutionary information reflecting structural and functional constraints. Recently, several methods have been developed based on a probabilistic graphical model called the Markov random field (MRF), which have led to significant improvements for coevolution analysis; however, thus far, the performance of these models has mainly been assessed by focusing on the aspect of protein structure. RESULTS: In this study, we built an MRF model whose graphical topology is determined by the residue proximity in the protein structure, and derived a novel positional coevolution estimate utilizing the node weight of the MRF model. This structure-based MRF method was evaluated for three data sets, each of which annotates catalytic site, allosteric site, and comprehensively determined functional site information. We demonstrate that the structure-based MRF architecture can encode the evolutionary information associated with biological function. Furthermore, we show that the node weight can more accurately represent positional coevolution information compared to the edge weight. Lastly, we demonstrate that the structure-based MRF model can be reliably built with only a few aligned sequences in linear time. CONCLUSIONS: The results show that adoption of a structure-based architecture could be an acceptable approximation for coevolution modeling with efficient computation complexity.


Assuntos
Sítio Alostérico/genética , Evolução Molecular , Proteínas/metabolismo , Evolução Biológica , Alinhamento de Sequência
5.
Protein Eng Des Sel ; 25(11): 705-13, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23077274

RESUMO

Since the cooperative mechanism between interconnected residues plays a critical role in protein functions, the detection of coevolving residues is important for studying various biological functions of proteins. In this work, we developed a new correlated mutation analysis method that shows substantially better prediction accuracy than all other methods. More importantly, the prediction accuracy of our new method is insensitive to the characteristics of the multiple sequence alignments (MSAs) from which the correlated mutation scores are calculated. Thanks to this desirable property, not only it does it show a good performance even for MSAs automatically generated by sequence homology methodologies, which allows us to build a fully automatic easy-to-use server named CMAT, but its performance is also consistently high on the columns of MSAs containing a high fraction of gaps, which greatly extends the applicability of the correlated mutation analysis. The key development of this work is the joint probability estimation that can be greatly improved by utilizing sequence profile as prior knowledge, which is shown to be highly beneficial to the correlated mutation analysis and its applications. From the computational perspective, we made two important findings; the sequence profile can be used to estimate the pseudocounts, and the consistency rule on joint probabilities and marginal probabilities is important for accurately estimating the joint probability. The web server and standalone program are freely available on the web at http://binfolab12.kaist.ac.kr/cmat/.


Assuntos
Evolução Molecular , Proteínas/química , Proteínas/genética , Análise de Sequência de Proteína/métodos , Sequência de Aminoácidos , Bases de Dados de Proteínas , Dados de Sequência Molecular , Mutação , Probabilidade , Mapeamento de Interação de Proteínas , Multimerização Proteica , Proteínas/metabolismo , Alinhamento de Sequência , Software
6.
Pac Symp Biocomput ; : 140-51, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22174270

RESUMO

The evolution of intrinsically disordered proteins has been studied primarily by focusing on evolutionary changes at an individual position such as substitution and conservation, but the evolutionary association between disordered residues has not been comprehensively investigated. Here, we analyze the distribution of residue-residue coevolution for disordered proteins. We reveal that the degree of coevolved residues significantly decreases in disordered regions regardless of the sequence propensity, and the degree distribution of coevolved and conserved residues exclusively differs in each functional category. Consequently, the coevolution information can be useful for predicting intrinsic disorder and understanding biological functions of a disordered region from the sequence.


Assuntos
Proteínas/química , Proteínas/genética , Biologia Computacional , Sequência Conservada , Bases de Dados de Proteínas , Evolução Molecular , Conformação Proteica , Proteínas/fisiologia , Alinhamento de Sequência
7.
BMC Bioinformatics ; 11 Suppl 2: S2, 2010 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-20406500

RESUMO

BACKGROUND: Although both conservation and correlated mutation (CM) are important information reflecting the different sorts of context in multiple sequence alignment, most of alignment methods use sequence profiles that only represent conservation. There is no general way to represent correlated mutation and incorporate it with sequence alignment yet. METHODS: We develop a novel method, CM profile, to represent correlated mutation as the spectral feature derived by using linear predictive coding where correlated mutations among different positions are represented by a fixed number of values. We combine CM profile with conventional sequence profile to improve alignment quality. RESULTS: For distantly related protein pairs, using CM profile improves the profile-profile alignment with or without predicted secondary structure. Especially, at superfamily level, combining CM profile with sequence profile improves profile-profile alignment by 9.5% while predicted secondary structure does by 6.0%. More significantly, using both of them improves profile-profile alignment by 13.9%. We also exemplify the effectiveness of CM profile by demonstrating that the resulting alignment preserves share coevolution and contacts. CONCLUSIONS: In this work, we introduce a novel method, CM profile, which represents correlated mutation information as paralleled form, and apply it to the protein sequence alignment problem. When combined with conventional sequence profile, CM profile improves alignment quality significantly better than predicted secondary structure information, which should be beneficial for target-template alignment in protein structure prediction. Because of the generality of CM profile, it can be used for other bioinformatics applications in the same way of using sequence profile.


Assuntos
Sequência de Aminoácidos , Biologia Computacional/métodos , Modelos Lineares , Mutação , Proteínas/genética , Alinhamento de Sequência/métodos , Bases de Dados de Proteínas , Modelos Moleculares , Estrutura Secundária de Proteína , Proteínas/química , Análise de Sequência de Proteína
8.
BMC Bioinformatics ; 8: 471, 2007 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-18053160

RESUMO

BACKGROUND: For successful protein structure prediction by comparative modeling, in addition to identifying a good template protein with known structure, obtaining an accurate sequence alignment between a query protein and a template protein is critical. It has been known that the alignment accuracy can vary significantly depending on our choice of various alignment parameters such as gap opening penalty and gap extension penalty. Because the accuracy of sequence alignment is typically measured by comparing it with its corresponding structure alignment, there is no good way of evaluating alignment accuracy without knowing the structure of a query protein, which is obviously not available at the time of structure prediction. Moreover, there is no universal alignment parameter option that would always yield the optimal alignment. RESULTS: In this work, we develop a method to predict the quality of the alignment between a query and a template. We train the support vector regression (SVR) models to predict the MaxSub scores as a measure of alignment quality. The alignment between a query protein and a template of length n is transformed into a (n + 1)-dimensional feature vector, then it is used as an input to predict the alignment quality by the trained SVR model. Performance of our work is evaluated by various measures including Pearson correlation coefficient between the observed and predicted MaxSub scores. Result shows high correlation coefficient of 0.945. For a pair of query and template, 48 alignments are generated by changing alignment options. Trained SVR models are then applied to predict the MaxSub scores of those and to select the best alignment option which is chosen specifically to the query-template pair. This adaptive selection procedure results in 7.4% improvement of MaxSub scores, compared to those when the single best parameter option is used for all query-template pairs. CONCLUSION: The present work demonstrates that the alignment quality can be predicted with reasonable accuracy. Our method is useful not only for selecting the optimal alignment parameters for a chosen template based on predicted alignment quality, but also for filtering out problematic templates that are not suitable for structure prediction due to poor alignment accuracy. This is implemented as a part in FORECAST, the server for fold-recognition and is freely available on the web at http://pbil.kaist.ac.kr/forecast.


Assuntos
Inteligência Artificial , Proteínas/ultraestrutura , Análise de Regressão , Alinhamento de Sequência , Sequência de Aminoácidos , Animais , Humanos , Modelos Moleculares , Reconhecimento Automatizado de Padrão/métodos , Reconhecimento Automatizado de Padrão/normas , Valor Preditivo dos Testes , Conformação Proteica , Controle de Qualidade , Valores de Referência , Alinhamento de Sequência/métodos , Alinhamento de Sequência/normas , Alinhamento de Sequência/estatística & dados numéricos , Análise de Sequência de Proteína , Homologia de Sequência de Aminoácidos , Homologia Estrutural de Proteína
9.
Bioinformatics ; 21(11): 2667-73, 2005 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15769835

RESUMO

MOTIVATION: Currently, the most accurate fold-recognition method is to perform profile-profile alignments and estimate the statistical significances of those alignments by calculating Z-score or E-value. Although this scheme is reliable in recognizing relatively close homologs related at the family level, it has difficulty in finding the remote homologs that are related at the superfamily or fold level. RESULTS: In this paper, we present an alternative method to estimate the significance of the alignments. The alignment between a query protein and a template of length n in the fold library is transformed into a feature vector of length n + 1, which is then evaluated by support vector machine (SVM). The output from SVM is converted to a posterior probability that a query sequence is related to a template, given SVM output. Results show that a new method shows significantly better performance than PSI-BLAST and profile-profile alignment with Z-score scheme. While PSI-BLAST and Z-score scheme detect 16 and 20% of superfamily-related proteins, respectively, at 90% specificity, a new method detects 46% of these proteins, resulting in more than 2-fold increase in sensitivity. More significantly, at the fold level, a new method can detect 14% of remotely related proteins at 90% specificity, a remarkable result considering the fact that the other methods can detect almost none at the same level of specificity.


Assuntos
Algoritmos , Inteligência Artificial , Reconhecimento Automatizado de Padrão/métodos , Proteínas/química , Alinhamento de Sequência/métodos , Análise de Sequência de Proteína/métodos , Sítios de Ligação , Bases de Dados de Proteínas , Perfilação da Expressão Gênica/métodos , Ligação Proteica , Dobramento de Proteína , Proteínas/análise , Proteínas/classificação , Homologia de Sequência de Aminoácidos
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