201 research outputs found
Systems-biology dissection of eukaryotic cell growth
A recent article in BMC Biology illustrates the use of a systems-biology approach to integrate data across the transcriptome, proteome and metabolome of budding yeast in order to dissect the relationship between nutrient conditions and cell growth
Bridging the Gap between Genotype and Phenotype via Network Approaches
In the last few years we have witnessed tremendous progress in detecting associations between genetic variations and complex traits. While genome-wide association studies have been able to discover genomic regions that may influence many common human diseases, these discoveries created an urgent need for methods that extend the knowledge of genotype-phenotype relationships to the level of the molecular mechanisms behind them. To address this emerging need, computational approaches increasingly utilize a pathway-centric perspective. These new methods often utilize known or predicted interactions between genes and/or gene products. In this review, we survey recently developed network based methods that attempt to bridge the genotype-phenotype gap. We note that although these methods help narrow the gap between genotype and phenotype relationships, these approaches alone cannot provide the precise details of underlying mechanisms and current research is still far from closing the gap
Secondary structure spatial conformation footprint: a novel method for fast protein structure comparison and classification
BACKGROUND: Recently a new class of methods for fast protein structure comparison has emerged. We call the methods in this class projection methods as they rely on a mapping of protein structure into a high-dimensional vector space. Once the mapping is done, the structure comparison is reduced to distance computation between corresponding vectors. As structural similarity is approximated by distance between projections, the success of any projection method depends on how well its mapping function is able to capture the salient features of protein structure. There is no agreement on what constitutes a good projection technique and the three currently known projection methods utilize very different approaches to the mapping construction, both in terms of what structural elements are included and how this information is integrated to produce a vector representation. RESULTS: In this paper we propose a novel projection method that uses secondary structure information to produce the mapping. First, a diverse set of spatial arrangements of triplets of secondary structure elements, a set of structural models, is automatically selected. Then, each protein structure is mapped into a high-dimensional vector of "counts" or footprint, where each count corresponds to the number of times a given structural model is observed in the structure, weighted by the precision with which the model is reproduced. We perform the first comprehensive evaluation of our method together with all other currently known projection methods. CONCLUSION: The results of our evaluation suggest that the type of structural information used by a projection method affects the ability of the method to detect structural similarity. In particular, our method that uses the spatial conformations of triplets of secondary structure elements outperforms other methods in most of the tests
BeWith: A Between-Within Method to Discover Relationships between Cancer Modules via Integrated Analysis of Mutual Exclusivity, Co-occurrence and Functional Interactions
The analysis of the mutational landscape of cancer, including mutual
exclusivity and co-occurrence of mutations, has been instrumental in studying
the disease. We hypothesized that exploring the interplay between
co-occurrence, mutual exclusivity, and functional interactions between genes
will further improve our understanding of the disease and help to uncover new
relations between cancer driving genes and pathways. To this end, we designed a
general framework, BeWith, for identifying modules with different combinations
of mutation and interaction patterns. We focused on three different settings of
the BeWith schema: (i) BeME-WithFun in which the relations between modules are
enriched with mutual exclusivity while genes within each module are
functionally related; (ii) BeME-WithCo which combines mutual exclusivity
between modules with co-occurrence within modules; and (iii) BeCo-WithMEFun
which ensures co-occurrence between modules while the within module relations
combine mutual exclusivity and functional interactions. We formulated the
BeWith framework using Integer Linear Programming (ILP), enabling us to find
optimally scoring sets of modules. Our results demonstrate the utility of
BeWith in providing novel information about mutational patterns, driver genes,
and pathways. In particular, BeME-WithFun helped identify functionally coherent
modules that might be relevant for cancer progression. In addition to finding
previously well-known drivers, the identified modules pointed to the importance
of the interaction between NCOR and NCOA3 in breast cancer. Additionally, an
application of the BeME-WithCo setting revealed that gene groups differ with
respect to their vulnerability to different mutagenic processes, and helped us
to uncover pairs of genes with potentially synergetic effects, including a
potential synergy between mutations in TP53 and metastasis related DCC gene
Differences in evolutionary pressure acting within highly conserved ortholog groups
<p>Abstract</p> <p>Background</p> <p>In highly conserved widely distributed ortholog groups, the main evolutionary force is assumed to be purifying selection that enforces sequence conservation, with most divergence occurring by accumulation of neutral substitutions. Using a set of ortholog groups from prokaryotes, with a single representative in each studied organism, we asked the question if this evolutionary pressure is acting similarly on different subgroups of orthologs defined as major lineages (e.g. Proteobacteria or Firmicutes).</p> <p>Results</p> <p>Using correlations in entropy measures as a proxy for evolutionary pressure, we observed two distinct behaviors within our ortholog collection. The first subset of ortholog groups, called here informational, consisted mostly of proteins associated with information processing (i.e. translation, transcription, DNA replication) and the second, the non-informational ortholog groups, mostly comprised of proteins involved in metabolic pathways. The evolutionary pressure acting on non-informational proteins is more uniform relative to their informational counterparts. The non-informational proteins show higher level of correlation between entropy profiles and more uniformity across subgroups.</p> <p>Conclusion</p> <p>The low correlation of entropy profiles in the informational ortholog groups suggest that the evolutionary pressure acting on the informational ortholog groups is not uniform across different clades considered this study. This might suggest "fine-tuning" of informational proteins in each lineage leading to lineage-specific differences in selection. This, in turn, could make these proteins less exchangeable between lineages. In contrast, the uniformity of the selective pressure acting on the non-informational groups might allow the exchange of the genetic material via lateral gene transfer.</p
Predicting domain-domain interactions using a parsimony approach
We propose a novel approach to predict domain-domain interactions from a protein-protein interaction network. In our method we apply a parsimony-driven explanation of the network, where the domain interactions are inferred using linear programming optimization, and false positives in the protein network are handled by a probabilistic construction. This method outperforms previous approaches by a considerable margin. The results indicate that the parsimony principle provides a correct approach for detecting domain-domain contacts
Epigenetic functions enriched in transcription factors binding to mouse recombination hotspots
The regulatory mechanism of recombination is a fundamental problem in genomics, with wide applications in genome-wide association studies, birth-defect diseases, molecular evolution, cancer research, etc. In mammalian genomes, recombination events cluster into short genomic regions called "recombination hotspots". Recently, a 13-mer motif enriched in hotspots is identified as a candidate cis-regulatory element of human recombination hotspots; moreover, a zinc finger protein, PRDM9, binds to this motif and is associated with variation of recombination phenotype in human and mouse genomes, thus is a trans-acting regulator of recombination hotspots. However, this pair of cis and trans-regulators covers only a fraction of hotspots, thus other regulators of recombination hotspots remain to be discovered. In this paper, we propose an approach to predicting additional trans-regulators from DNA-binding proteins by comparing their enrichment of binding sites in hotspots. Applying this approach on newly mapped mouse hotspots genome-wide, we confirmed that PRDM9 is a major trans-regulator of hotspots. In addition, a list of top candidate trans-regulators of mouse hotspots is reported. Using GO analysis we observed that the top genes are enriched with function of histone modification, highlighting the epigenetic regulatory mechanisms of recombination hotspots
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