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1.  Exploring Neighborhoods in the Metagenome Universe 
The variety of metagenomes in current databases provides a rapidly growing source of information for comparative studies. However, the quantity and quality of supplementary metadata is still lagging behind. It is therefore important to be able to identify related metagenomes by means of the available sequence data alone. We have studied efficient sequence-based methods for large-scale identification of similar metagenomes within a database retrieval context. In a broad comparison of different profiling methods we found that vector-based distance measures are well-suitable for the detection of metagenomic neighbors. Our evaluation on more than 1700 publicly available metagenomes indicates that for a query metagenome from a particular habitat on average nine out of ten nearest neighbors represent the same habitat category independent of the utilized profiling method or distance measure. While for well-defined labels a neighborhood accuracy of 100% can be achieved, in general the neighbor detection is severely affected by a natural overlap of manually annotated categories. In addition, we present results of a novel visualization method that is able to reflect the similarity of metagenomes in a 2D scatter plot. The visualization method shows a similarly high accuracy in the reduced space as compared with the high-dimensional profile space. Our study suggests that for inspection of metagenome neighborhoods the profiling methods and distance measures can be chosen to provide a convenient interpretation of results in terms of the underlying features. Furthermore, supplementary metadata of metagenome samples in the future needs to comply with readily available ontologies for fine-grained and standardized annotation. To make profile-based k-nearest-neighbor search and the 2D-visualization of the metagenome universe available to the research community, we included the proposed methods in our CoMet-Universe server for comparative metagenome analysis.
doi:10.3390/ijms150712364
PMCID: PMC4139848  PMID: 25026170
metagenomics; functional profile; taxonomic profile; metagenome comparison
2.  Protein signature-based estimation of metagenomic abundances including all domains of life and viruses 
Bioinformatics  2013;29(8):973-980.
Motivation: Metagenome analysis requires tools that can estimate the taxonomic abundances in anonymous sequence data over the whole range of biological entities. Because there is usually no prior knowledge about the data composition, not only all domains of life but also viruses have to be included in taxonomic profiling. Such a full-range approach, however, is difficult to realize owing to the limited coverage of available reference data. In particular, archaea and viruses are generally not well represented by current genome databases.
Results: We introduce a novel approach to taxonomic profiling of metagenomes that is based on mixture model analysis of protein signatures. Our results on simulated and real data reveal the difficulties of the existing methods when measuring achaeal or viral abundances and show the overall good profiling performance of the protein-based mixture model. As an application example, we provide a large-scale analysis of data from the Human Microbiome Project. This demonstrates the utility of our method as a first instance profiling tool for a fast estimate of the community structure.
Availability: http://gobics.de/TaxyPro.
Contact: pmeinic@gwdg.de
Supplementary information: Supplementary Material is available at Bioinformatics online.
doi:10.1093/bioinformatics/btt077
PMCID: PMC3624802  PMID: 23418187
3.  Non-canonical peroxisome targeting signals: identification of novel PTS1 tripeptides and characterization of enhancer elements by computational permutation analysis 
BMC Plant Biology  2012;12:142.
Background
High-accuracy prediction tools are essential in the post-genomic era to define organellar proteomes in their full complexity. We recently applied a discriminative machine learning approach to predict plant proteins carrying peroxisome targeting signals (PTS) type 1 from genome sequences. For Arabidopsis thaliana 392 gene models were predicted to be peroxisome-targeted. The predictions were extensively tested in vivo, resulting in a high experimental verification rate of Arabidopsis proteins previously not known to be peroxisomal.
Results
In this study, we experimentally validated the predictions in greater depth by focusing on the most challenging Arabidopsis proteins with unknown non-canonical PTS1 tripeptides and prediction scores close to the threshold. By in vivo subcellular targeting analysis, three novel PTS1 tripeptides (QRL>, SQM>, and SDL>) and two novel tripeptide residues (Q at position −3 and D at pos. -2) were identified. To understand why, among many Arabidopsis proteins carrying the same C-terminal tripeptides, these proteins were specifically predicted as peroxisomal, the residues upstream of the PTS1 tripeptide were computationally permuted and the changes in prediction scores were analyzed. The newly identified Arabidopsis proteins were found to contain four to five amino acid residues of high predicted targeting enhancing properties at position −4 to −12 in front of the non-canonical PTS1 tripeptide. The identity of the predicted targeting enhancing residues was unexpectedly diverse, comprising besides basic residues also proline, hydroxylated (Ser, Thr), hydrophobic (Ala, Val), and even acidic residues.
Conclusions
Our computational and experimental analyses demonstrate that the plant PTS1 tripeptide motif is more diverse than previously thought, including an increasing number of non-canonical sequences and allowed residues. Specific targeting enhancing elements can be predicted for particular sequences of interest and are far more diverse in amino acid composition and positioning than previously assumed. Machine learning methods become indispensable to predict which specific proteins, among numerous candidate proteins carrying the same non-canonical PTS1 tripeptide, contain sufficient enhancer elements in terms of number, positioning and total strength to cause peroxisome targeting.
doi:10.1186/1471-2229-12-142
PMCID: PMC3487989  PMID: 22882975
4.  Experimental and statistical post-validation of positive example EST sequences carrying peroxisome targeting signals type 1 (PTS1) 
Plant Signaling & Behavior  2012;7(2):263-268.
We recently developed the first algorithms specifically for plants to predict proteins carrying peroxisome targeting signals type 1 (PTS1) from genome sequences.1 As validated experimentally, the prediction methods are able to correctly predict unknown peroxisomal Arabidopsis proteins and to infer novel PTS1 tripeptides. The high prediction performance is primarily determined by the large number and sequence diversity of the underlying positive example sequences, which mainly derived from EST databases. However, a few constructs remained cytosolic in experimental validation studies, indicating sequencing errors in some ESTs. To identify erroneous sequences, we validated subcellular targeting of additional positive example sequences in the present study. Moreover, we analyzed the distribution of prediction scores separately for each orthologous group of PTS1 proteins, which generally resembled normal distributions with group-specific mean values. The cytosolic sequences commonly represented outliers of low prediction scores and were located at the very tail of a fitted normal distribution. Three statistical methods for identifying outliers were compared in terms of sensitivity and specificity.” Their combined application allows elimination of erroneous ESTs from positive example data sets. This new post-validation method will further improve the prediction accuracy of both PTS1 and PTS2 protein prediction models for plants, fungi, and mammals.
doi:10.4161/psb.18720
PMCID: PMC3405698  PMID: 22415050
genome screens; machine learning methods; peroxisome; statistics; targeting
5.  PredPlantPTS1: A Web Server for the Prediction of Plant Peroxisomal Proteins 
Prediction of subcellular protein localization is essential to correctly assign unknown proteins to cell organelle-specific protein networks and to ultimately determine protein function. For metazoa, several computational approaches have been developed in the past decade to predict peroxisomal proteins carrying the peroxisome targeting signal type 1 (PTS1). However, plant-specific PTS1 protein prediction methods have been lacking up to now, and pre-existing methods generally were incapable of correctly predicting low-abundance plant proteins possessing non-canonical PTS1 patterns. Recently, we presented a machine learning approach that is able to predict PTS1 proteins for higher plants (spermatophytes) with high accuracy and which can correctly identify unknown targeting patterns, i.e., novel PTS1 tripeptides and tripeptide residues. Here we describe the first plant-specific web server PredPlantPTS1 for the prediction of plant PTS1 proteins using the above-mentioned underlying models. The server allows the submission of protein sequences from diverse spermatophytes and also performs well for mosses and algae. The easy-to-use web interface provides detailed output in terms of (i) the peroxisomal targeting probability of the given sequence, (ii) information whether a particular non-canonical PTS1 tripeptide has already been experimentally verified, and (iii) the prediction scores for the single C-terminal 14 amino acid residues. The latter allows identification of predicted residues that inhibit peroxisome targeting and which can be optimized using site-directed mutagenesis to raise the peroxisome targeting efficiency. The prediction server will be instrumental in identifying low-abundance and stress-inducible peroxisomal proteins and defining the entire peroxisomal proteome of Arabidopsis and agronomically important crop plants. PredPlantPTS1 is freely accessible at ppp.gobics.de.
doi:10.3389/fpls.2012.00194
PMCID: PMC3427985  PMID: 22969783
PTS1; peroxisome; machine learning; Arabidopsis; orthologs; subcellular targeting; proteome
6.  CoMet—a web server for comparative functional profiling of metagenomes 
Nucleic Acids Research  2011;39(Web Server issue):W518-W523.
Analyzing the functional potential of newly sequenced genomes and metagenomes has become a common task in biomedical and biological research. With the advent of high-throughput sequencing technologies comparative metagenomics opens the way to elucidate the genetically determined similarities and differences of complex microbial communities. We developed the web server ‘CoMet’ (http://comet.gobics.de), which provides an easy-to-use comparative metagenomics platform that is well-suitable for the analysis of large collections of metagenomic short read data. CoMet combines the ORF finding and subsequent assignment of protein sequences to Pfam domain families with a comparative statistical analysis. Besides comprehensive tabular data files, the CoMet server also provides visually interpretable output in terms of hierarchical clustering and multi-dimensional scaling plots and thus allows a quick overview of a given set of metagenomic samples.
doi:10.1093/nar/gkr388
PMCID: PMC3125781  PMID: 21622656
7.  Mixture models for analysis of the taxonomic composition of metagenomes 
Bioinformatics  2011;27(12):1618-1624.
Motivation: Inferring the taxonomic profile of a microbial community from a large collection of anonymous DNA sequencing reads is a challenging task in metagenomics. Because existing methods for taxonomic profiling of metagenomes are all based on the assignment of fragmentary sequences to phylogenetic categories, the accuracy of results largely depends on fragment length. This dependence complicates comparative analysis of data originating from different sequencing platforms or resulting from different preprocessing pipelines.
Results: We here introduce a new method for taxonomic profiling based on mixture modeling of the overall oligonucleotide distribution of a sample. Our results indicate that the mixture-based profiles compare well with taxonomic profiles obtained with other methods. However, in contrast to the existing methods, our approach shows a nearly constant profiling accuracy across all kinds of read lengths and it operates at an unrivaled speed.
Availability: A platform-independent implementation of the mixture modeling approach is available in terms of a MATLAB/Octave toolbox at http://gobics.de/peter/taxy. In addition, a prototypical implementation within an easy-to-use interactive tool for Windows can be downloaded.
Contact: pmeinic@gwdg.de; thomas@gobics.de
Supplementary Information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr266
PMCID: PMC3106201  PMID: 21546400
8.  Predicting phenotypic traits of prokaryotes from protein domain frequencies 
BMC Bioinformatics  2010;11:481.
Background
Establishing the relationship between an organism's genome sequence and its phenotype is a fundamental challenge that remains largely unsolved. Accurately predicting microbial phenotypes solely based on genomic features will allow us to infer relevant phenotypic characteristics when the availability of a genome sequence precedes experimental characterization, a scenario that is favored by the advent of novel high-throughput and single cell sequencing techniques.
Results
We present a novel approach to predict the phenotype of prokaryotes directly from their protein domain frequencies. Our discriminative machine learning approach provides high prediction accuracy of relevant phenotypes such as motility, oxygen requirement or spore formation. Moreover, the set of discriminative domains provides biological insight into the underlying phenotype-genotype relationship and enables deriving hypotheses on the possible functions of uncharacterized domains.
Conclusions
Fast and accurate prediction of microbial phenotypes based on genomic protein domain content is feasible and has the potential to provide novel biological insights. First results of a systematic check for annotation errors indicate that our approach may also be applied to semi-automatic correction and completion of the existing phenotype annotation.
doi:10.1186/1471-2105-11-481
PMCID: PMC2955703  PMID: 20868492
9.  Orphelia: predicting genes in metagenomic sequencing reads 
Nucleic Acids Research  2009;37(Web Server issue):W101-W105.
Metagenomic sequencing projects yield numerous sequencing reads of a diverse range of uncultivated and mostly yet unknown microorganisms. In many cases, these sequencing reads cannot be assembled into longer contigs. Thus, gene prediction tools that were originally developed for whole-genome analysis are not suitable for processing metagenomes. Orphelia is a program for predicting genes in short DNA sequences that is available through a web server application (http://orphelia.gobics.de). Orphelia utilizes prediction models that were created with machine learning techniques on the basis of a wide range of annotated genomes. In contrast to other methods for metagenomic gene prediction, Orphelia has fragment length-specific prediction models for the two most popular sequencing techniques in metagenomics, chain termination sequencing and pyrosequencing. These models ensure highly specific gene predictions.
doi:10.1093/nar/gkp327
PMCID: PMC2703946  PMID: 19429689
10.  MarVis: a tool for clustering and visualization of metabolic biomarkers 
BMC Bioinformatics  2009;10:92.
Background
A central goal of experimental studies in systems biology is to identify meaningful markers that are hidden within a diffuse background of data originating from large-scale analytical intensity measurements as obtained from metabolomic experiments. Intensity-based clustering is an unsupervised approach to the identification of metabolic markers based on the grouping of similar intensity profiles. A major problem of this basic approach is that in general there is no prior information about an adequate number of biologically relevant clusters.
Results
We present the tool MarVis (Marker Visualization) for data mining on intensity-based profiles using one-dimensional self-organizing maps (1D-SOMs). MarVis can import and export customizable CSV (Comma Separated Values) files and provides aggregation and normalization routines for preprocessing of intensity profiles that contain repeated measurements for a number of different experimental conditions. Robust clustering is then achieved by training of an 1D-SOM model, which introduces a similarity-based ordering of the intensity profiles. The ordering allows a convenient visualization of the intensity variations within the data and facilitates an interactive aggregation of clusters into larger blocks. The intensity-based visualization is combined with the presentation of additional data attributes, which can further support the analysis of experimental data.
Conclusion
MarVis is a user-friendly and interactive tool for exploration of complex pattern variation in a large set of experimental intensity profiles. The application of 1D-SOMs gives a convenient overview on relevant profiles and groups of profiles. The specialized visualization effectively supports researchers in analyzing a large number of putative clusters, even though the true number of biologically meaningful groups is unknown. Although MarVis has been developed for the analysis of metabolomic data, the tool may be applied to gene expression data as well.
doi:10.1186/1471-2105-10-92
PMCID: PMC2666665  PMID: 19302701
11.  Metabolite-based clustering and visualization of mass spectrometry data using one-dimensional self-organizing maps 
Background
One of the goals of global metabolomic analysis is to identify metabolic markers that are hidden within a large background of data originating from high-throughput analytical measurements. Metabolite-based clustering is an unsupervised approach for marker identification based on grouping similar concentration profiles of putative metabolites. A major problem of this approach is that in general there is no prior information about an adequate number of clusters.
Results
We present an approach for data mining on metabolite intensity profiles as obtained from mass spectrometry measurements. We propose one-dimensional self-organizing maps for metabolite-based clustering and visualization of marker candidates. In a case study on the wound response of Arabidopsis thaliana, based on metabolite profile intensities from eight different experimental conditions, we show how the clustering and visualization capabilities can be used to identify relevant groups of markers.
Conclusion
Our specialized realization of self-organizing maps is well-suitable to gain insight into complex pattern variation in a large set of metabolite profiles. In comparison to other methods our visualization approach facilitates the identification of interesting groups of metabolites by means of a convenient overview on relevant intensity patterns. In particular, the visualization effectively supports researchers in analyzing many putative clusters when the true number of biologically meaningful groups is unknown.
doi:10.1186/1748-7188-3-9
PMCID: PMC2464586  PMID: 18582365
12.  Word correlation matrices for protein sequence analysis and remote homology detection 
BMC Bioinformatics  2008;9:259.
Background
Classification of protein sequences is a central problem in computational biology. Currently, among computational methods discriminative kernel-based approaches provide the most accurate results. However, kernel-based methods often lack an interpretable model for analysis of discriminative sequence features, and predictions on new sequences usually are computationally expensive.
Results
In this work we present a novel kernel for protein sequences based on average word similarity between two sequences. We show that this kernel gives rise to a feature space that allows analysis of discriminative features and fast classification of new sequences. We demonstrate the performance of our approach on a widely-used benchmark setup for protein remote homology detection.
Conclusion
Our word correlation approach provides highly competitive performance as compared with state-of-the-art methods for protein remote homology detection. The learned model is interpretable in terms of biologically meaningful features. In particular, analysis of discriminative words allows the identification of characteristic regions in biological sequences. Because of its high computational efficiency, our method can be applied to ranking of potential homologs in large databases.
doi:10.1186/1471-2105-9-259
PMCID: PMC2438326  PMID: 18522726
13.  Gene prediction in metagenomic fragments: A large scale machine learning approach 
BMC Bioinformatics  2008;9:217.
Background
Metagenomics is an approach to the characterization of microbial genomes via the direct isolation of genomic sequences from the environment without prior cultivation. The amount of metagenomic sequence data is growing fast while computational methods for metagenome analysis are still in their infancy. In contrast to genomic sequences of single species, which can usually be assembled and analyzed by many available methods, a large proportion of metagenome data remains as unassembled anonymous sequencing reads. One of the aims of all metagenomic sequencing projects is the identification of novel genes. Short length, for example, Sanger sequencing yields on average 700 bp fragments, and unknown phylogenetic origin of most fragments require approaches to gene prediction that are different from the currently available methods for genomes of single species. In particular, the large size of metagenomic samples requires fast and accurate methods with small numbers of false positive predictions.
Results
We introduce a novel gene prediction algorithm for metagenomic fragments based on a two-stage machine learning approach. In the first stage, we use linear discriminants for monocodon usage, dicodon usage and translation initiation sites to extract features from DNA sequences. In the second stage, an artificial neural network combines these features with open reading frame length and fragment GC-content to compute the probability that this open reading frame encodes a protein. This probability is used for the classification and scoring of gene candidates. With large scale training, our method provides fast single fragment predictions with good sensitivity and specificity on artificially fragmented genomic DNA. Additionally, this method is able to predict translation initiation sites accurately and distinguishes complete from incomplete genes with high reliability.
Conclusion
Large scale machine learning methods are well-suited for gene prediction in metagenomic DNA fragments. In particular, the combination of linear discriminants and neural networks is promising and should be considered for integration into metagenomic analysis pipelines. The data sets can be downloaded from the URL provided (see Availability and requirements section).
doi:10.1186/1471-2105-9-217
PMCID: PMC2409338  PMID: 18442389

Results 1-13 (13)