RESUMO
Mass spectrometry (MS)-based quantitative proteomics experiments typically assay a subset of up to 60% of the ≈20 000 human protein coding genes. Computational methods for imputing the missing values using RNA expression data usually allow only for imputations of proteins measured in at least some of the samples. In silico methods for comprehensively estimating abundances across all proteins are still missing. Here, a novel method is proposed using deep learning to extrapolate the observed protein expression values in label-free MS experiments to all proteins, leveraging gene functional annotations and RNA measurements as key predictive attributes. This method is tested on four datasets, including human cell lines and human and mouse tissues. This method predicts the protein expression values with average R2 scores between 0.46 and 0.54, which is significantly better than predictions based on correlations using the RNA expression data alone. Moreover, it is demonstrated that the derived models can be "transferred" across experiments and species. For instance, the model derived from human tissues gave a R2=0.51 when applied to mouse tissue data. It is concluded that protein abundances generated in label-free MS experiments can be computationally predicted using functional annotated attributes and can be used to highlight aberrant protein abundance values.
Assuntos
Aprendizado Profundo , Animais , Espectrometria de Massas , Camundongos , Anotação de Sequência Molecular , Proteínas , ProteômicaRESUMO
BACKGROUND: Current Hi-C technologies for chromosome conformation capture allow to understand a broad spectrum of functional interactions between genome elements. Although significant progress has been made into analysis of Hi-C data to identify biologically significant features, many questions still remain open, in particular regarding potential biological significance of various topological features that are characteristic for chromatin interaction networks. RESULTS: It has been previously observed that promoter capture Hi-C (PCHi-C) interaction networks tend to separate easily into well-defined connected components that can be related to certain biological functionality, however, such evidence was based on manual analysis and was limited. Here we present a novel method for analysis of chromatin interaction networks aimed towards identifying characteristic topological features of interaction graphs and confirming their potential significance in chromatin architecture. Our method automatically identifies all connected components with an assigned significance score above a given threshold. These components can be subjected afterwards to different assessment methods for their biological role and/or significance. The method was applied to the largest PCHi-C data set available to date that contains interactions for 17 haematopoietic cell types. The results demonstrate strong evidence of well-pronounced component structure of chromatin interaction networks and provide some characterisation of this component structure. We also performed an indicative assessment of potential biological significance of identified network components with the results confirming that the network components can be related to specific biological functionality. CONCLUSIONS: The obtained results show that the topological structure of chromatin interaction networks can be well described in terms of isolated connected components of the network and that formation of these components can be often explained by biological features of functionally related gene modules. The presented method allows automatic identification of all such components and evaluation of their significance in PCHi-C dataset for 17 haematopoietic cell types. The method can be adapted for exploration of other chromatin interaction data sets that include information about sufficiently large number of different cell types, and, in principle, also for analysis of other kinds of cell type-specific networks.
Assuntos
Cromatina/química , Redes Reguladoras de Genes , Algoritmos , Regulação da Expressão Gênica , Hematopoese/genética , Humanos , Regiões Promotoras GenéticasRESUMO
PURPOSE: Patients with resected localized clear-cell renal cell carcinoma (ccRCC) remain at variable risk of recurrence. Incorporation of biomarkers may refine risk prediction and inform adjuvant treatment decisions. We explored the role of tumor genomics in this setting, leveraging the largest cohort to date of localized ccRCC tissues subjected to targeted gene sequencing. EXPERIMENTAL DESIGN: The somatic mutation status of 12 genes was determined in 943 ccRCC cases from a multinational cohort of patients, and associations to outcomes were examined in a Discovery (n = 469) and Validation (n = 474) framework. RESULTS: Tumors containing a von-Hippel Lindau (VHL) mutation alone were associated with significantly improved outcomes in comparison with tumors containing a VHL plus additional mutations. Within the Discovery cohort, those with VHL+0, VHL+1, VHL+2, and VHL+≥3 tumors had disease-free survival (DFS) rates of 90.8%, 80.1%, 68.2%, and 50.7% respectively, at 5 years. This trend was replicated in the Validation cohort. Notably, these genomically defined groups were independent of tumor mutational burden. Amongst patients eligible for adjuvant therapy, those with a VHL+0 tumor (29%) had a 5-year DFS rate of 79.3% and could, therefore, potentially be spared further treatment. Conversely, patients with VHL+2 and VHL+≥3 tumors (32%) had equivalent DFS rates of 45.6% and 35.3%, respectively, and should be prioritized for adjuvant therapy. CONCLUSIONS: Genomic characterization of ccRCC identified biologically distinct groups of patients with divergent relapse rates. These groups account for the â¼80% of cases with VHL mutations and could be used to personalize adjuvant treatment discussions with patients as well as inform future adjuvant trial design.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/genética , Neoplasias Renais/terapia , Neoplasias Renais/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Recidiva Local de Neoplasia/genética , MutaçãoRESUMO
Current high-throughput experimental techniques make it feasible to infer gene regulatory interactions at the whole-genome level with reasonably good accuracy. Such experimentally inferred regulatory networks have become available for a number of simpler model organisms such as S. cerevisiae, and others. The availability of such networks provides an opportunity to compare gene regulatory processes at the whole genome level, and in particular, to assess similarity of regulatory interactions for homologous gene pairs either from the same or from different species. We present here a new technique for analyzing the regulatory interaction neighborhoods of paralogous gene pairs. Our central focus is the analysis of S. cerevisiae gene interaction graphs, which are of particular interest due to the ancestral whole-genome duplication (WGD) that allows to distinguish between paralogous transcription factors that are traceable to this duplication event and other paralogues. Similar analysis is also applied to E. coli and C. elegans networks. We compare paralogous gene pairs according to the presence and size of bi-fan arrays, classically associated in the literature with gene duplication, within other network motifs. We further extend this framework beyond transcription factor comparison to obtain topology-based similarity metrics based on the overlap of interaction neighborhoods applicable to most genes in a given organism. We observe that our network divergence metrics show considerably larger similarity between paralogues, especially those traceable to WGD. This is the case for both yeast and C. elegans, but not for E. coli regulatory network. While there is no obvious cross-species link between metrics, different classes of paralogues show notable differences in interaction overlap, with traceable duplications tending toward higher overlap compared to genes with shared protein families. Our findings indicate that divergence in paralogous interaction networks reflects a shared genetic origin, and that our approach may be useful for investigating structural similarity in the interaction networks of paralogous genes.
Assuntos
Caenorhabditis elegans/genética , Biologia Computacional/métodos , Escherichia coli/genética , Redes Reguladoras de Genes , Saccharomyces cerevisiae/genética , Animais , Evolução Molecular , Duplicação Gênica , Genoma , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: One of the crucial aspects of day-to-day laboratory information management is collection, storage and retrieval of information about research subjects and biomedical samples. An efficient link between sample data and experiment results is absolutely imperative for a successful outcome of a biomedical study. Currently available software solutions are largely limited to large-scale, expensive commercial Laboratory Information Management Systems (LIMS). Acquiring such LIMS indeed can bring laboratory information management to a higher level, but often implies sufficient investment of time, effort and funds, which are not always available. There is a clear need for lightweight open source systems for patient and sample information management. RESULTS: We present a web-based tool for submission, management and retrieval of sample and research subject data. The system secures confidentiality by separating anonymized sample information from individuals' records. It is simple and generic, and can be customised for various biomedical studies. Information can be both entered and accessed using the same web interface. User groups and their privileges can be defined. The system is open-source and is supplied with an on-line tutorial and necessary documentation. It has proven to be successful in a large international collaborative project. CONCLUSION: The presented system closes the gap between the need and the availability of lightweight software solutions for managing information in biomedical studies involving human research subjects.
Assuntos
Sistemas de Gerenciamento de Base de Dados , Bases de Dados Factuais , Armazenamento e Recuperação da Informação/métodos , Sistemas Computadorizados de Registros Médicos , Software , Interface Usuário-Computador , Inteligência Artificial , Engenharia Biomédica/métodos , Pesquisa Biomédica/métodos , Ensaios Clínicos como Assunto/métodos , Linguagens de ProgramaçãoRESUMO
The incidence of renal cell carcinoma (RCC) is increasing worldwide, and its prevalence is particularly high in some parts of Central Europe. Here we undertake whole-genome and transcriptome sequencing of clear cell RCC (ccRCC), the most common form of the disease, in patients from four different European countries with contrasting disease incidence to explore the underlying genomic architecture of RCC. Our findings support previous reports on frequent aberrations in the epigenetic machinery and PI3K/mTOR signalling, and uncover novel pathways and genes affected by recurrent mutations and abnormal transcriptome patterns including focal adhesion, components of extracellular matrix (ECM) and genes encoding FAT cadherins. Furthermore, a large majority of patients from Romania have an unexpected high frequency of A:T>T:A transversions, consistent with exposure to aristolochic acid (AA). These results show that the processes underlying ccRCC tumorigenesis may vary in different populations and suggest that AA may be an important ccRCC carcinogen in Romania, a finding with major public health implications.