"Super Gene Set" Causal Relationship Discovery from Functional Genomics Data

In this article, we present a computational framework to identify "causal relationships" among super gene sets. For "causal relationships," we refer to both stimulatory and inhibitory regulatory relationships, regardless of through direct or indirect mechanisms. For super gene sets, we refer to "pathways, annotated lists, and gene signatures," or PAGs. To identify causal relationships among PAGs, we extend the previous work on identifying PAG-to-PAG regulatory relationships by further requiring them to be significantly enriched with gene-to-gene co-expression pairs across the two PAGs involved. This is achieved by developing a quantitative metric based on PAG-to-PAG Co-expressions (PPC), which we use to infer the likelihood that PAG-to-PAG relationships under examination are causal-either stimulatory or inhibitory. Since true causal relationships are unknown, we approximate the overall performance of inferring causal relationships with the performance of recalling known r-type PAG-to-PAG relationships from causal PAG-to-PAG inference, using a functional genomics benchmark dataset from the GEO database. We report the area-under-curve (AUC) performance for both precision and recall being 0.81. By applying our framework to a myeloid-derived suppressor cells (MDSC) dataset, we further demonstrate that this framework is effective in helping build multi-scale biomolecular systems models with new insights on regulatory and causal links for downstream biological interpretations

PAGER 2.0: an update to the pathway, annotated-list and gene-signature electronic repository for Human Network Biology

Integrative Gene-set, Network and Pathway Analysis (GNPA) is a powerful data analysis approach developed to help interpret high-throughput omics data. In PAGER 1.0, we demonstrated that researchers can gain unbiased and reproducible biological insights with the introduction of PAGs (Pathways, Annotated-lists and Gene-signatures) as the basic data representation elements. In PAGER 2.0, we improve the utility of integrative GNPA by significantly expanding the coverage of PAGs and PAG-to-PAG relationships in the database, defining a new metric to quantify PAG data qualities, and developing new software features to simplify online integrative GNPA. Specifically, we included 84 282 PAGs spanning 24 different data sources that cover human diseases, published gene-expression signatures, drug-gene, miRNA-gene interactions, pathways and tissue-specific gene expressions. We introduced a new normalized Cohesion Coefficient (nCoCo) score to assess the biological relevance of genes inside a PAG, and RP-score to rank genes and assign gene-specific weights inside a PAG. The companion web interface contains numerous features to help users query and navigate the database content. The database content can be freely downloaded and is compatible with third-party Gene Set Enrichment Analysis tools. We expect PAGER 2.0 to become a major resource in integrative GNPA. PAGER 2.0 is available at http://discovery.informatics.uab.edu/PAGER/

MODEST: a web-based design tool for oligonucleotide-mediated genome engineering and recombineering

Recombineering and multiplex automated genome engineering (MAGE) offer the possibility to rapidly modify multiple genomic or plasmid sites at high efficiencies. This enables efficient creation of genetic variants including both single mutants with specifically targeted modifications as well as combinatorial cell libraries. Manual design of oligonucleotides for these approaches can be tedious, time-consuming, and may not be practical for larger projects targeting many genomic sites. At present, the change from a desired phenotype (e.g. altered expression of a specific protein) to a designed MAGE oligo, which confers the corresponding genetic change, is performed manually. To address these challenges, we have developed the MAGE Oligo Design Tool (MODEST). This web-based tool allows designing of MAGE oligos for (i) tuning translation rates by modifying the ribosomal binding site, (ii) generating translational gene knockouts and (iii) introducing other coding or non-coding mutations, including amino acid substitutions, insertions, deletions and point mutations. The tool automatically designs oligos based on desired genotypic or phenotypic changes defined by the user, which can be used for high efficiency recombineering and MAGE. MODEST is available for free and is open to all users at http://modest.biosustain.dtu.dk

PAGER: constructing PAGs and new PAG-PAG relationships for network biology

In this article, we described a new database framework to perform integrative "gene-set, network, and pathway analysis" (GNPA). In this framework, we integrated heterogeneous data on pathways, annotated list, and gene-sets (PAGs) into a PAG electronic repository (PAGER). PAGs in the PAGER database are organized into P-type, A-type and G-type PAGs with a three-letter-code standard naming convention. The PAGER database currently compiles 44 313 genes from 5 species including human, 38 663 PAGs, 324 830 gene-gene relationships and two types of 3 174 323 PAG-PAG regulatory relationships-co-membership based and regulatory relationship based. To help users assess each PAG's biological relevance, we developed a cohesion measure called Cohesion Coefficient (CoCo), which is capable of disambiguating between biologically significant PAGs and random PAGs with an area-under-curve performance of 0.98. PAGER database was set up to help users to search and retrieve PAGs from its online web interface. PAGER enable advanced users to build PAG-PAG regulatory networks that provide complementary biological insights not found in gene set analysis or individual gene network analysis. We provide a case study using cancer functional genomics data sets to demonstrate how integrative GNPA help improve network biology data coverage and therefore biological interpretability. The PAGER database can be accessible openly at http://discovery.informatics.iupui.edu/PAGER/