Appearance frequency modulated gene set enrichment testing

Abstract Background Gene set enrichment testing has helped bridge the gap from an individual gene to a systems biology interpretation of microarray data. Although gene sets are defined a priori based on biological knowledge, current methods for gene set enrichment testing treat all genes equal. It is well-known that some genes, such as those responsible for housekeeping functions, appear in many pathways, whereas other genes are more specialized and play a unique role in a single pathway. Drawing inspiration from the field of information retrieval, we have developed and present here an approach to incorporate gene appearance frequency (in KEGG pathways) into two current methods, Gene Set Enrichment Analysis (GSEA) and logistic regression-based LRpath framework, to generate more reproducible and biologically meaningful results. Results Two breast cancer microarray datasets were analyzed to identify gene sets differentially expressed between histological grade 1 and 3 breast cancer. The correlation of Normalized Enrichment Scores (NES) between gene sets, generated by the original GSEA and GSEA with the appearance frequency of genes incorporated (GSEA-AF), was compared. GSEA-AF resulted in higher correlation between experiments and more overlapping top gene sets. Several cancer related gene sets achieved higher NES in GSEA-AF as well. The same datasets were also analyzed by LRpath and LRpath with the appearance frequency of genes incorporated (LRpath-AF). Two well-studied lung cancer datasets were also analyzed in the same manner to demonstrate the validity of the method, and similar results were obtained. Conclusions We introduce an alternative way to integrate KEGG PATHWAY information into gene set enrichment testing. The performance of GSEA and LRpath can be enhanced with the integration of appearance frequency of genes. We conclude that, generally, gene set analysis methods with the integration of information from KEGG PATHWAY performs better both statistically and biologically.http://deepblue.lib.umich.edu/bitstream/2027.42/112430/1/12859_2010_Article_4457.pd

THINK Back: KNowledge-based Interpretation of High Throughput data

Results of high throughput experiments can be challenging to interpret. Current approaches have relied on bulk processing the set of expression levels, in conjunction with easily obtained external evidence, such as co-occurrence. While such techniques can be used to reason probabilistically, they are not designed to shed light on what any individual gene, or a network of genes acting together, may be doing. Our belief is that today we have the information extraction ability and the computational power to perform more sophisticated analyses that consider the individual situation of each gene. The use of such techniques should lead to qualitatively superior results

Pathway-GPS and SIGORA: identifying relevant pathways based on the over-representation of their gene-pair signatures

peer-reviewedMotivation. Predominant pathway analysis approaches treat pathways as collections of individual genes and consider all pathway members as equally informative. As a result, at times spurious and misleading pathways are inappropriately identified as statistically significant, solely due to components that they share with the more relevant pathways. Results. We introduce the concept of Pathway Gene-Pair Signatures (Pathway-GPS) as pairs of genes that, as a combination, are specific to a single pathway. We devised and implemented a novel approach to pathway analysis, Signature Over-representation Analysis (SIGORA), which focuses on the statistically significant enrichment of Pathway-GPS in a user-specified gene list of interest. In a comparative evaluation of several published datasets, SIGORA outperformed traditional methods by delivering biologically more plausible and relevant results. Availability. An efficient implementation of SIGORA, as an R package with precompiled GPS data for several human and mouse pathway repositories is available for download from http://sigora.googlecode.com/svn/

Pancreatic cancer patient survival correlates with DNA methylation of pancreas development genes.

DNA methylation is an epigenetic mark associated with regulation of transcription and genome structure. These markers have been investigated in a variety of cancer settings for their utility in differentiating normal tissue from tumor tissue. Here, we examine the direct correlation between DNA methylation and patient survival. We find that changes in the DNA methylation of key pancreatic developmental genes are strongly associated with patient survival

A Role for Pre-mRNA-PROCESSING PROTEIN 40C in the Control of Growth, Development, and Stress Tolerance in Arabidopsis thaliana

Because of their sessile nature, plants have adopted varied strategies for growing and reproducing in an ever-changing environment. Control of mRNA levels and pre-mRNA alternative splicing are key regulatory layers that contribute to adjust and synchronize plant growth and development with environmental changes. Transcription and alternative splicing are thought to be tightly linked and coordinated, at least in part, through a network of transcriptional and splicing regulatory factors that interact with the carboxyl-terminal domain (CTD) of the largest subunit of RNA polymerase II. One of the proteins that has been shown to play such a role in yeast and mammals is pre-mRNA-PROCESSING PROTEIN 40 (PRP40, also known as CA150, or TCERG1). In plants, members of the PRP40 family have been identified and shown to interact with the CTD of RNA Pol II, but their biological functions remain unknown. Here, we studied the role of AtPRP40C, in Arabidopsis thaliana growth, development and stress tolerance, as well as its impact on the global regulation of gene expression programs. We found that the prp40c knockout mutants display a late-flowering phenotype under long day conditions, associated with minor alterations in red light signaling. An RNA-seq based transcriptome analysis revealed differentially expressed genes related to biotic stress responses and also differentially expressed as well as differentially spliced genes associated with abiotic stress responses. Indeed, the characterization of stress responses in prp40c mutants revealed an increased sensitivity to salt stress and an enhanced tolerance to Pseudomonas syringae pv. maculicola (Psm) infections. This constitutes the most thorough analysis of the transcriptome of a prp40 mutant in any organism, as well as the first characterization of the molecular and physiological roles of a member of the PRP40 protein family in plants. Our results suggest that PRP40C is an important factor linking the regulation of gene expression programs to the modulation of plant growth, development, and stress responses.Fil: Hernando, Carlos Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: García Hourquet, Mariano. Fundación Instituto Leloir; ArgentinaFil: de Leone, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Careno, Daniel Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Iserte, Javier Alonso. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Mora Garcia, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Yanovsky, Marcelo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

Connectomic-genetic signatures in the cerebral small vessel disease

Small vessel disease (SVD) is a disorder that causes vascular lesions in the entire parenchyma of the human brain. At present, it is not well understood how primary and secondary damage interact to give rise to the complex scenario of white matter (WM) and grey matter (GM) lesions. Using novel cross-sectional and longitudinal connectomic approaches, we unveil the bidirectional nature of GM and WM changes, that is, primary cortical neurodegeneration that leads to secondary alterations in vascular border zones, and WM lesions that lead to secondary neurodegeneration in cortical projecting areas. We found this GM-WM interaction to be essential for executive cognitive performance. Moreover, we also observed that the interlocked degeneration of GM and WM over time associates with prototypical expression levels of genes potentially linked to SVD. Among these connectomic-genetic intersections, we found that the Androgen Receptor (AR) gene, is a particularly central candidate gene that might confer key vulnerability for brain lesion development in SVD. In conclusion, this study advances in the understanding of the bidirectional relationships between GM and WM lesions, primary and secondary vascular neurodegeneration, and sheds light on the genetic signatures of SV

Affiliative Behavior, Ultrasonic Communication and Social Reward Are Influenced by Genetic Variation in Adolescent Mice

Social approach is crucial for establishing relationships among individuals. In rodents, social approach has been studied primarily within the context of behavioral phenomena related to sexual reproduction, such as mating, territory defense and parental care. However, many forms of social interaction occur before the onset of reproductive maturity, which suggests that some processes underlying social approach among juvenile animals are probably distinct from those in adults. We conducted a longitudinal study of social investigation (SI) in mice from two inbred strains to assess the extent to which genetic factors influence the motivation for young mice to approach one another. Early-adolescent C57BL/6J (B6) mice, tested 4–6 days after weaning, investigated former cage mates to a greater degree than BALB/cJ (BALB) mice, irrespective of the sex composition within an interacting pair. This strain difference was not due to variation in maternal care, the phenotypic characteristics of stimulus mice or sensitivity to the length of isolation prior to testing, nor was it attributable to a general difference in appetitive motivation. Ultrasonic vocalization (USV) production was positively correlated with the SI responses of mice from both strains. Interestingly, several USV characteristics segregated with the genetic background of young mice, including a higher average frequency and shorter duration for the USVs emitted by B6 mice. An assessment of conditioned place preference responses indicated that there was a strain-dependent difference in the rewarding nature of social contact. As adolescent mice aged, SI responses gradually became less sensitive to genetic background and more responsive to the particular sex of individuals within an interacting pair. We have thus identified a specific, genetic influence on the motivation of early-adolescent mice to approach one another. Consistent with classical theories of motivation, which propose a functional relationship between behavioral approach and reward, our findings indicate that reward is a proximal mechanism through which genetic factors affect social motivation during early adolescence