GRYFUN: A Web Application for GO Term Annotation Visualization and Analysis in Protein Sets

Functional context for biological sequence is provided in the form of annotations. However, within a group of similar sequences there can be annotation heterogeneity in terms of coverage and specificity. This in turn can introduce issues regarding the interpretation of actual functional similarity and overall functional coherence of such a group. One way to mitigate such issues is through the use of visualization and statistical techniques. Therefore, in order to help interpret this annotation heterogeneity we created a web application that generates Gene Ontology annotation graphs for protein sets and their associated statistics from simple frequencies to enrichment values and Information Content based metrics. The publicly accessible website http://xldb.di.fc.ul.pt/gryfun/ currently accepts lists of UniProt accession numbers in order to create user-defined protein sets for subsequent annotation visualization and statistical assessment. GRYFUN is a freely available web application that allows GO annotation visualization of protein sets and which can be used for annotation coherence and cohesiveness analysis and annotation extension assessments within under-annotated protein sets.     

DIACAN: Integrated Database for Antidiabetic and Anticancer Medicinal Plants

Medicinal plants and plant derived molecules are widely used in traditional cultures all over the world and they are becoming large popular among biomedical researchers and pharmaceutical companies as a natural alternative to synthetic medicine. Information related to medicinal plants and herbal drugs accumulated over the ages are scattered and unstructured which make it prudent to develop a curated database for medicinal plants. The Antidiabetic and Anticancer Medicinal Plants Database (DIACAN) aims to collect and provide an integrated platform for plants and phytochemiclas having antidiabetic or anticancer activity.

Availability

http://www.kaubic.in/diacan     

Genomic Resources for Gene Discovery,Functional Genome Annotation,and Evolutionary Studies of Maize and Its Close Relatives

Maize is one of the most important food crops and a key model for genetics and developmental biology. A genetically anchored and high-quality draft genome sequence of maize inbred B73 has been obtained to serve as a reference sequence. To facilitate evolutionary studies in maize and its close relatives, much like the Oryza Map Alignment Project (OMAP) (www.OMAP.org) bacterial artificial chromosome (BAC) resource did for the rice community, we constructed BAC libraries for maize inbred lines Zheng58, Chang7-2, and Mo17 and maize wild relatives Zea mays ssp. parviglumis and Tripsacum dactyloides. Furthermore, to extend functional genomic studies to maize and sorghum, we also constructed binary BAC (BIBAC) libraries for the maize inbred B73 and the sorghum landrace Nengsi-1. The BAC/BIBAC vectors facilitate transfer of large intact DNA inserts from BAC clones to the BIBAC vector and functional complementation of large DNA fragments. These seven Zea Map Alignment Project (ZMAP) BAC/BIBAC libraries have average insert sizes ranging from 92 to 148 kb, organellar DNA from 0.17 to 2.3%, empty vector rates between 0.35 and 5.56%, and genome equivalents of 4.7- to 8.4-fold. The usefulness of the Parviglumis and Tripsacum BAC libraries was demonstrated by mapping clones to the reference genome. Novel genes and alleles present in these ZMAP libraries can now be used for functional complementation studies and positional or homology-based cloning of genes for translational genomics.     

CIRCpedia v2: An Updated Database for Comprehensive Circular RNA Annotation and Expression Comparison

Circular RNAs (circRNAs) from back-splicing of exon(s) have been recently identified to be broadly expressed in eukaryotes, in tissue- and species-specific manners. Although functions of most circRNAs remain elusive, some circRNAs are shown to be functional in gene expression regulation and potentially relate to diseases. Due to their stability, circRNAs can also be used as biomarkers for diagnosis. Profiling circRNAs by integrating their expression among different samples thus provides molecular basis for further functional study of circRNAs and their potential application in clinic. Here, we report CIRCpedia v2, an updated database for comprehensive circRNA annotation from over 180 RNA-seq datasets across six different species. This atlas allows users to search, browse, and download circRNAs with expression features in various cell types/tissues, including disease samples. In addition, the updated database incorporates conservation analysis of circRNAs between humans and mice. Finally, the web interface also contains computational tools to compare circRNA expression among samples. CIRCpedia v2 is accessible at http://www.picb.ac.cn/rnomics/circpedia.     

pDAWG: An Integrated Database for Plant Cell Wall Genes

We have recently developed a database, pDAWG, focused on information related to plant cell walls. Currently, pDAWG contains seven complete plant genomes, 12 complete algal genomes, along with computed information for individual proteins encoded in these genomes of the following types: (a) carbohydrate active enzyme (CAZy) family information when applicable; (b) phylogenetic trees of cell wall-related CAZy family proteins; (c) protein structure models if available; (d) physical and predicted interactions among proteins; (e) subcellular localization; (f) Pfam domain information; and (g) homology-based functional prediction. A querying system with a graphical interface allows a user to quickly compose information of different sorts about individual genes/proteins and to display the composite information in an intuitive manner, facilitating comparative analyses and knowledge discovery about cell wall genes. pDAWG can be accessed at http://csbl1.bmb.uga.edu/pDAWG/.     

PharmDB-K: Integrated Bio-Pharmacological Network Database for Traditional Korean Medicine

Despite the growing attention given to Traditional Medicine (TM) worldwide, there is no well-known, publicly available, integrated bio-pharmacological Traditional Korean Medicine (TKM) database for researchers in drug discovery. In this study, we have constructed PharmDB-K, which offers comprehensive information relating to TKM-associated drugs (compound), disease indication, and protein relationships. To explore the underlying molecular interaction of TKM, we integrated fourteen different databases, six Pharmacopoeias, and literature, and established a massive bio-pharmacological network for TKM and experimentally validated some cases predicted from the PharmDB-K analyses. Currently, PharmDB-K contains information about 262 TKMs, 7,815 drugs, 3,721 diseases, 32,373 proteins, and 1,887 side effects. One of the unique sets of information in PharmDB-K includes 400 indicator compounds used for standardization of herbal medicine. Furthermore, we are operating PharmDB-K via phExplorer (a network visualization software) and BioMart (a data federation framework) for convenient search and analysis of the TKM network. Database URL: http://pharmdb-k.org, http://biomart.i-pharm.org.     

SWEETLEAD: an In Silico Database of Approved Drugs,Regulated Chemicals,and Herbal Isolates for Computer-Aided Drug Discovery

In the face of drastically rising drug discovery costs, strategies promising to reduce development timelines and expenditures are being pursued. Computer-aided virtual screening and repurposing approved drugs are two such strategies that have shown recent success. Herein, we report the creation of a highly-curated in silico database of chemical structures representing approved drugs, chemical isolates from traditional medicinal herbs, and regulated chemicals, termed the SWEETLEAD database. The motivation for SWEETLEAD stems from the observance of conflicting information in publicly available chemical databases and the lack of a highly curated database of chemical structures for the globally approved drugs. A consensus building scheme surveying information from several publicly accessible databases was employed to identify the correct structure for each chemical. Resulting structures are filtered for the active pharmaceutical ingredient, standardized, and differing formulations of the same drug were combined in the final database. The publically available release of SWEETLEAD (https://simtk.org/home/sweetlead) provides an important tool to enable the successful completion of computer-aided repurposing and drug discovery campaigns.     

Discovery and Functional Annotation of SIX6 Variants in Primary Open-Angle Glaucoma

Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10⁻¹¹). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10⁻¹⁰) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.     

The Duplicated Genes Database: Identification and Functional Annotation of Co-Localised Duplicated Genes across Genomes

Background

There has been a surge in studies linking genome structure and gene expression, with special focus on duplicated genes. Although initially duplicated from the same sequence, duplicated genes can diverge strongly over evolution and take on different functions or regulated expression. However, information on the function and expression of duplicated genes remains sparse. Identifying groups of duplicated genes in different genomes and characterizing their expression and function would therefore be of great interest to the research community. The ‘Duplicated Genes Database’ (DGD) was developed for this purpose.

Methodology

Nine species were included in the DGD. For each species, BLAST analyses were conducted on peptide sequences corresponding to the genes mapped on a same chromosome. Groups of duplicated genes were defined based on these pairwise BLAST comparisons and the genomic location of the genes. For each group, Pearson correlations between gene expression data and semantic similarities between functional GO annotations were also computed when the relevant information was available.

Conclusions

The Duplicated Gene Database provides a list of co-localised and duplicated genes for several species with the available gene co-expression level and semantic similarity value of functional annotation. Adding these data to the groups of duplicated genes provides biological information that can prove useful to gene expression analyses. The Duplicated Gene Database can be freely accessed through the DGD website at http://dgd.genouest.org.     

Trait-Associated SNPs Are More Likely to Be eQTLs: Annotation to Enhance Discovery from GWAS

Although genome-wide association studies (GWAS) of complex traits have yielded more reproducible associations than had been discovered using any other approach, the loci characterized to date do not account for much of the heritability to such traits and, in general, have not led to improved understanding of the biology underlying complex phenotypes. Using a web site we developed to serve results of expression quantitative trait locus (eQTL) studies in lymphoblastoid cell lines from HapMap samples (http://www.scandb.org), we show that single nucleotide polymorphisms (SNPs) associated with complex traits (from http://www.genome.gov/gwastudies/) are significantly more likely to be eQTLs than minor-allele-frequency–matched SNPs chosen from high-throughput GWAS platforms. These findings are robust across a range of thresholds for establishing eQTLs (p-values from 10⁻⁴–10⁻⁸), and a broad spectrum of human complex traits. Analyses of GWAS data from the Wellcome Trust studies confirm that annotating SNPs with a score reflecting the strength of the evidence that the SNP is an eQTL can improve the ability to discover true associations and clarify the nature of the mechanism driving the associations. Our results showing that trait-associated SNPs are more likely to be eQTLs and that application of this information can enhance discovery of trait-associated SNPs for complex phenotypes raise the possibility that we can utilize this information both to increase the heritability explained by identifiable genetic factors and to gain a better understanding of the biology underlying complex traits.     

Insect Innate Immunity Database (IIID): An Annotation Tool for Identifying Immune Genes in Insect Genomes

The innate immune system is an ancient component of host defense. Since innate immunity pathways are well conserved throughout many eukaryotes, immune genes in model animals can be used to putatively identify homologous genes in newly sequenced genomes of non-model organisms. With the initiation of the “i5k” project, which aims to sequence 5,000 insect genomes by 2016, many novel insect genomes will soon become publicly available, yet few annotation resources are currently available for insects. Thus, we developed an online tool called the Insect Innate Immunity Database (IIID) to provide an open access resource for insect immunity and comparative biology research (http://www.vanderbilt.edu/IIID). The database provides users with simple exploratory tools to search the immune repertoires of five insect models (including Nasonia), spanning three orders, for specific immunity genes or genes within a particular immunity pathway. As a proof of principle, we used an initial database with only four insect models to annotate potential immune genes in the parasitoid wasp genus Nasonia. Results specify 306 putative immune genes in the genomes of N. vitripennis and its two sister species N. giraulti and N. longicornis. Of these genes, 146 were not found in previous annotations of Nasonia immunity genes. Combining these newly identified immune genes with those in previous annotations, Nasonia possess 489 putative immunity genes, the largest immune repertoire found in insects to date. While these computational predictions need to be complemented with functional studies, the IIID database can help initiate and augment annotations of the immune system in the plethora of insect genomes that will soon become available.