Batch Blast Extractor: an automated blastx parser application

MotivationBLAST programs are very efficient in finding similarities for sequences. However for large datasets such as ESTs, manual extraction of the information from the batch BLAST output is needed. This can be time consuming, insufficient, and inaccurate. Therefore implementation of a parser application would be extremely useful in extracting information from BLAST outputs. ResultsWe have developed a java application, Batch Blast Extractor, with a user friendly graphical interface to extract information from BLAST output. The application generates a tab delimited text file that can be easily imported into any statistical package such as Excel or SPSS for further analysis. For each BLAST hit, the program obtains and saves the essential features from the BLAST output file that would allow further analysis. The program was written in Java and therefore is OS independent. It works on both Windows and Linux OS with java 1.4 and higher. It is freely available from: http://mcbc.usm.edu/BatchBlastExtractor

An Ensemble Learning Approach to Reverse-Engineering Transcriptional Regulatory Networks from Time-Series Gene Expression Data

Background One of the most challenging tasks in the post-genomic era is to reconstruct the transcriptional regulatory networks. The goal is to reveal, for each gene that responds to a certain biological event, which transcription factors affect its expression, and how a set of transcription factors coordinate to accomplish temporal and spatial specific regulations. Results Here we propose a supervised machine learning approach to address these questions. We focus our study on the gene transcriptional regulation of the cell cycle in the budding yeast, thanks to the large amount of data available and relatively well-understood biology, although the main ideas of our method can be applied to other data as well. Our method starts with building an ensemble of decision trees for each microarray data to capture the association between the expression levels of yeast genes and the binding of transcription factors to gene promoter regions, as determined by chromatin immunoprecipitation microarray (ChIP-chip) experiment. Cross-validation experiments show that the method is more accurate and reliable than the naive decision tree algorithm and several other ensemble learning methods. From the decision tree ensembles, we extract logical rules that explain how a set of transcription factors act in concert to regulate the expression of their targets. We further compute a profile for each rule to show its regulation strengths at different time points. We also propose a spline interpolation method to integrate the rule profiles learned from several time series expression data sets that measure the same biological process. We then combine these rule profiles to build a transcriptional regulatory network for the yeast cell cycle. Compared to the results in the literature, our method correctly identifies all major known yeast cell cycle transcription factors, and assigns them into appropriate cell cycle phases. Our method also identifies many interesting synergetic relationships among these transcription factors, most of which are well known, while many of the rest can also be supported by other evidences. Conclusion The high accuracy of our method indicates that our method is valid and robust. As more gene expression and transcription factor binding data become available, we believe that our method is useful for reconstructing large-scale transcriptional regulatory networks in other species as well

An ensemble learning approach to reverse-engineering transcriptional regulatory networks from time-series gene expression data

Background One of the most challenging tasks in the post-genomic era is to reconstruct the transcriptional regulatory networks. The goal is to reveal, for each gene that responds to a certain biological event, which transcription factors affect its expression, and how a set of transcription factors coordinate to accomplish temporal and spatial specific regulations. Results Here we propose a supervised machine learning approach to address these questions. We focus our study on the gene transcriptional regulation of the cell cycle in the budding yeast, thanks to the large amount of data available and relatively well-understood biology, although the main ideas of our method can be applied to other data as well. Our method starts with building an ensemble of decision trees for each microarray data to capture the association between the expression levels of yeast genes and the binding of transcription factors to gene promoter regions, as determined by chromatin immunoprecipitation microarray (ChIP-chip) experiment. Cross-validation experiments show that the method is more accurate and reliable than the naive decision tree algorithm and several other ensemble learning methods. From the decision tree ensembles, we extract logical rules that explain how a set of transcription factors act in concert to regulate the expression of their targets. We further compute a profile for each rule to show its regulation strengths at different time points. We also propose a spline interpolation method to integrate the rule profiles learned from several time series expression data sets that measure the same biological process. We then combine these rule profiles to build a transcriptional regulatory network for the yeast cell cycle. Compared to the results in the literature, our method correctly identifies all major known yeast cell cycle transcription factors, and assigns them into appropriate cell cycle phases. Our method also identifies many interesting synergetic relationships among these transcription factors, most of which are well known, while many of the rest can also be supported by other evidences. Conclusion The high accuracy of our method indicates that our method is valid and robust. As more gene expression and transcription factor binding data become available, we believe that our method is useful for reconstructing large-scale transcriptional regulatory networks in other species as well

Generation, Analysis and Functional Annotation of Expressed Sequence Tags From the Sheepshead Minnow (\u3ci\u3eCyprinodon variegatus\u3c/i\u3e)

Background: Sheepshead minnow (Cyprinodon variegatus) are small fish capable of withstanding exposure to very low levels of dissolved oxygen, as well as extreme temperatures and salinities. It is an important model in understanding the impacts and biological response to hypoxia and co-occurring compounding stressors such as polycyclic aromatic hydrocarbons, endocrine disrupting chemicals, metals and herbicides. Here, we initiated a project to sequence and analyze over 10,000 ESTs generated from the Sheepshead minnow (Cyprinodon variegatus) as a resource for investigating stressor responses. Results: We sequenced 10,858 EST clones using a normalized cDNA library made from larval, embryonic and adult suppression subtractive hybridization-PCR (SSH) libraries. Post- sequencing processing led to 8,099 high quality sequences. Clustering analysis of these ESTs indentified 4,223 unique sequences containing 1,053 contigs and 3,170 singletons. BLASTX searches produced 1,394 significant (E-value \u3c 10(-5)) hits and further Gene Ontology (GO) analysis annotated 388 of these genes. All the EST sequences were deposited by Expressed Sequence Tags database (dbEST) in GenBank (GenBank: GE329585 to GE337683). Gene discovery and annotations are presented and discussed. This set of ESTs represents a significant proportion of the Sheepshead minnow (Cyprinodon variegatus) transcriptome, and provides a material basis for the development of microarrays useful for further gene expression studies in association with stressors such as hypoxia, cadmium, chromium and pyrene

Comparison of Probabilistic Boolean Network and Dynamic Bayesian Network Approaches for Inferring Gene Regulatory Networks

Background: The regulation of gene expression is achieved through gene regulatory networks (GRNs) in which collections of genes interact with one another and other substances in a cell. In order to understand the underlying function of organisms, it is necessary to study the behavior of genes in a gene regulatory network context. Several computational approaches are available for modeling gene regulatory networks with different datasets. In order to optimize modeling of GRN, these approaches must be compared and evaluated in terms of accuracy and efficiency. Results: In this paper, two important computational approaches for modeling gene regulatory networks, probabilistic Boolean network methods and dynamic Bayesian network methods, are compared using a biological time-series dataset from the Drosophila Interaction Database to construct a Drosophila gene network. A subset of time points and gene samples from the whole dataset is used to evaluate the performance of these two approaches. Conclusions: The comparison indicates that both approaches had good performance in modeling the gene regulatory networks. The accuracy in terms of recall and precision can be improved if a smaller subset of genes is selected for inferring GRNs. The accuracy of both approaches is dependent upon the number of selected genes and time points of gene samples. In all tested cases, DBN identified more gene interactions and gave better recall than PBN

A Novel Gene Network Inference Algorithm Using Predictive Minimum Description Length Approach

Background: Reverse engineering of gene regulatory networks using information theory models has received much attention due to its simplicity, low computational cost, and capability of inferring large networks. One of the major problems with information theory models is to determine the threshold which defines the regulatory relationships between genes. The minimum description length (MDL) principle has been implemented to overcome this problem. The description length of the MDL principle is the sum of model length and data encoding length. A user-specified fine tuning parameter is used as control mechanism between model and data encoding, but it is difficult to find the optimal parameter. In this work, we proposed a new inference algorithm which incorporated mutual information (MI), conditional mutual information (CMI) and predictive minimum description length (PMDL) principle to infer gene regulatory networks from DNA microarray data. In this algorithm, the information theoretic quantities MI and CMI determine the regulatory relationships between genes and the PMDL principle method attempts to determine the best MI threshold without the need of a user-specified fine tuning parameter. Results: The performance of the proposed algorithm was evaluated using both synthetic time series data sets and a biological time series data set for the yeast Saccharomyces cerevisiae. The benchmark quantities precision and recall were used as performance measures. The results show that the proposed algorithm produced less false edges and significantly improved the precision, as compared to the existing algorithm. For further analysis the performance of the algorithms was observed over different sizes of data. Conclusions: We have proposed a new algorithm that implements the PMDL principle for inferring gene regulatory networks from time series DNA microarray data that eliminates the need of a fine tuning parameter. The evaluation results obtained from both synthetic and actual biological data sets show that the PMDL principle is effective in determining the MI threshold and the developed algorithm improves precision of gene regulatory network inference. Based on the sensitivity analysis of all tested cases, an optimal CMI threshold value has been identified. Finally it was observed that the performance of the algorithms saturates at a certain threshold of data size

\u3ci\u3eIn Vitro\u3c/i\u3e Gene Regulatory Networks Predict In Vivo Function of Liver

Background: Evolution of toxicity testing is predicated upon using in vitro cell based systems to rapidly screen and predict how a chemical might cause toxicity to an organ in vivo. However, the degree to which we can extend in vitro results to in vivo activity and possible mechanisms of action remains to be fully addressed. Results: Here we use the nitroaromatic 2,4,6-trinitrotoluene (TNT) as a model chemical to compare and determine how we might extrapolate from in vitro data to in vivo effects. We found 341 transcripts differentially expressed in common among in vitro and in vivo assays in response to TNT. The major functional term corresponding to these transcripts was cell cycle. Similarly modulated common pathways were identified between in vitro and in vivo. Furthermore, we uncovered the conserved common transcriptional gene regulatory networks between in vitro and in vivo cellular liver systems that responded to TNT exposure, which mainly contain 2 subnetwork modules: PTTG1 and PIR centered networks. Interestingly, all 7 genes in the PTTG1 module were involved in cell cycle and downregulated by TNT both in vitro and in vivo. Conclusions: The results of our investigation of TNT effects on gene expression in liver suggest that gene regulatory networks obtained from an in vitro system can predict in vivo function and mechanisms. Inhibiting PTTG1 and its targeted cell cyle related genes could be key machanism for TNT induced liver toxicity