Refining orthologue groups at the transcript level

<p>Abstract</p> <p>Background</p> <p>Orthologues are genes in different species that are related through divergent evolution from a common ancestor and are expected to have similar functions. Many databases have been created to describe orthologous genes based on existing sequence data. However, alternative splicing (in eukaryotes) is usually disregarded in the determination of orthologue groups and the functional consequences of alternative splicing have not been considered. Most multi-exon genes can encode multiple protein isoforms which often have different functions and can be disease-related. Extending the definition of orthologue groups to take account of alternate splicing and the functional differences it causes requires further examination.</p> <p>Results</p> <p>A subset of the orthologous gene groups between human and mouse was selected from the InParanoid database for this study. Each orthologue group was divided into sub-clusters, at the transcript level, using a method based on the sequence similarity of the isoforms. Transcript based sub-clusters were verified by functional signatures of the cluster members in the InterPro database. Functional similarity was higher within than between transcript-based sub-clusters of a defined orthologous group. In certain cases, cancer-related isoforms of a gene could be distinguished from other isoforms of the gene. Predictions of intrinsic disorder in protein regions were also correlated with the isoform sub-clusters within an orthologue group.</p> <p>Conclusions</p> <p>Sub-clustering of orthologue groups at the transcript level is an important step to more accurately define functionally equivalent orthologue groups. This work appears to be the first effort to refine orthologous groupings of genes based on the consequences of alternative splicing on function. Further investigation and refinement of the methodology to classify and verify isoform sub-clusters is needed, particularly to extend the technique to more distantly related species.</p

Refining orthologue groups at the transcript level

<p>Abstract</p> <p>Background</p> <p>Orthologues are genes in different species that are related through divergent evolution from a common ancestor and are expected to have similar functions. Many databases have been created to describe orthologous genes based on existing sequence data. However, alternative splicing (in eukaryotes) is usually disregarded in the determination of orthologue groups and the functional consequences of alternative splicing have not been considered. Most multi-exon genes can encode multiple protein isoforms which often have different functions and can be disease-related. Extending the definition of orthologue groups to take account of alternate splicing and the functional differences it causes requires further examination.</p> <p>Results</p> <p>A subset of the orthologous gene groups between human and mouse was selected from the InParanoid database for this study. Each orthologue group was divided into sub-clusters, at the transcript level, using a method based on the sequence similarity of the isoforms. Transcript based sub-clusters were verified by functional signatures of the cluster members in the InterPro database. Functional similarity was higher within than between transcript-based sub-clusters of a defined orthologous group. In certain cases, cancer-related isoforms of a gene could be distinguished from other isoforms of the gene. Predictions of intrinsic disorder in protein regions were also correlated with the isoform sub-clusters within an orthologue group.</p> <p>Conclusions</p> <p>Sub-clustering of orthologue groups at the transcript level is an important step to more accurately define functionally equivalent orthologue groups. This work appears to be the first effort to refine orthologous groupings of genes based on the consequences of alternative splicing on function. Further investigation and refinement of the methodology to classify and verify isoform sub-clusters is needed, particularly to extend the technique to more distantly related species.</p

Promoter-sharing by different genes in human genome – CPNE1 and RBM12 gene pair as an example

<p>Abstract</p> <p>Background</p> <p>Regulation of gene expression plays important role in cellular functions. Co-regulation of different genes may indicate functional connection or even physical interaction between gene products. Thus analysis on genomic structures that may affect gene expression regulation could shed light on the functions of genes.</p> <p>Results</p> <p>In a whole genome analysis of alternative splicing events, we found that two distinct genes, <it>copine I </it>(<it>CPNE1</it>) and <it>RNA binding motif protein 12 </it>(<it>RBM12</it>), share the most 5' exons and therefore the promoter region in human. Further analysis identified many gene pairs in human genome that share the same promoters and 5' exons but have totally different coding sequences. Analysis of genomic and expressed sequences, either cDNAs or expressed sequence tags (ESTs) for <it>CPNE1 </it>and <it>RBM12</it>, confirmed the conservation of this phenomenon during evolutionary courses. The co-expression of the two genes initiated from the same promoter is confirmed by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) in different tissues in both human and mouse. High degrees of sequence conservation among multiple species in the 5'UTR region common to <it>CPNE1 </it>and <it>RBM12 </it>were also identified.</p> <p>Conclusion</p> <p>Promoter and 5'UTR sharing between <it>CPNE1 </it>and <it>RBM12 </it>is observed in human, mouse and zebrafish. Conservation of this genomic structure in evolutionary courses indicates potential functional interaction between the two genes. More than 20 other gene pairs in human genome were found to have the similar genomic structure in a genome-wide analysis, and it may represent a unique pattern of genomic arrangement that may affect expression regulation of the corresponding genes.</p

Local structural alignment of RNA with affine gap model

Predicting new non-coding RNAs (ncRNAs) of a family can be done by aligning the potential candidate with a member of the family with known sequence and secondary structure. Existing tools either only consider the sequence similarity or cannot handle local alignment with gaps. In this paper, we consider the problem of finding the optimal local structural alignment between a query RNA sequence (with known secondary structure) and a target sequence (with unknown secondary structure) with the affine gap penalty model. We provide the algorithm to solve the problem. Based on a preliminary experiment, we show that there are ncRNA families in which considering local structural alignment with gap penalty model can identify real hits more effectively than using global alignment or local alignment without gap penalty model.The project is partially supported by the Seed Funding Programme for Basic Research (Project number: 200911159065) of the University of Hong Kong

Panax notoginseng Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

Panax notoginseng (PN) is a traditional Chinese herb experimentally proven to have anti-inflammatory effects, and it is used clinically for the treatment of atherosclerosis, cerebral infarction, and cerebral ischemia. This study aimed to determine the anti-inflammatory effects of PN against bleomycin-induced pulmonary fibrosis in mice. First, in an in vitro study, culture media containing lipopolysaccharide (LPS) was used to stimulate macrophage cells (RAW 264.7 cell line). TNF-α and IL-6 levels were then determined before and after treatment with PN extract. In an animal model (C57BL/6 mice), a single dose of PN (0.5 mg/kg) was administered orally on Day 2 or Day 7 postbleomycin treatment. The results showed that TNF-α and IL-6 levels increased in the culture media of LPS-stimulated macrophage cells, and this effect was significantly inhibited in a concentration-dependent manner by PN extract. Histopathologic examination revealed that PN administered on Day 7 postbleomycin treatment significantly decreased inflammatory cell infiltrates, fibrosis scores, and TNF-α, TGF-β, IL-1β, and IL-6 levels in bronchoalveolar lavage fluid when compared with PN given on Day 2 postbleomycin treatment. These results suggest that PN administered in the early fibrotic stage can attenuate pulmonary fibrosis in an animal model of idiopathic pulmonary fibrosis

SOAP3-dp: Fast, Accurate and Sensitive GPU-based Short Read Aligner

To tackle the exponentially increasing throughput of Next-Generation Sequencing (NGS), most of the existing short-read aligners can be configured to favor speed in trade of accuracy and sensitivity. SOAP3-dp, through leveraging the computational power of both CPU and GPU with optimized algorithms, delivers high speed and sensitivity simultaneously. Compared with widely adopted aligners including BWA, Bowtie2, SeqAlto, GEM and GPU-based aligners including BarraCUDA and CUSHAW, SOAP3-dp is two to tens of times faster, while maintaining the highest sensitivity and lowest false discovery rate (FDR) on Illumina reads with different lengths. Transcending its predecessor SOAP3, which does not allow gapped alignment, SOAP3-dp by default tolerates alignment similarity as low as 60 percent. Real data evaluation using human genome demonstrates SOAP3-dp's power to enable more authentic variants and longer Indels to be discovered. Fosmid sequencing shows a 9.1 percent FDR on newly discovered deletions. SOAP3-dp natively supports BAM file format and provides a scoring scheme same as BWA, which enables it to be integrated into existing analysis pipelines. SOAP3-dp has been deployed on Amazon-EC2, NIH-Biowulf and Tianhe-1A.Comment: 21 pages, 6 figures, submitted to PLoS ONE, additional files available at "https://www.dropbox.com/sh/bhclhxpoiubh371/O5CO_CkXQE". Comments most welcom

Physiological concentration of protocatechuic acid directly protects vascular endothelial function against inflammation in diabetes through Akt/eNOS pathway

BackgroundCardiovascular diseases (CVDs) have been the major cause of mortality in type 2 diabetes. However, new approaches are still warranted since current diabetic medications, which focus mainly on glycemic control, do not effectively lower cardiovascular mortality rate in diabetic patients. Protocatechuic acid (PCA) is a phenolic acid widely distributed in garlic, onion, cauliflower and other plant-based foods. Given the anti-oxidative effects of PCA in vitro, we hypothesized that PCA would also have direct beneficial effects on endothelial function in addition to the systemic effects on vascular health demonstrated by previous studies.Methods and resultsSince IL-1β is the major pathological contributor to endothelial dysfunction in diabetes, the anti-inflammatory effects of PCA specific on endothelial cells were further verified by the use of IL-1β-induced inflammation model. Direct incubation of db/db mouse aortas with physiological concentration of PCA significantly ameliorated endothelium-dependent relaxation impairment, as well as reactive oxygen species overproduction mediated by diabetes. In addition to the well-studied anti-oxidative activity, PCA demonstrated strong anti-inflammatory effects by suppressing the pro-inflammatory cytokines MCP1, VCAM1 and ICAM1, as well as increasing the phosphorylation of eNOS and Akt in the inflammatory endothelial cell model induced by the key player in diabetic endothelial dysfunction IL-1β. Upon blocking of Akt phosphorylation, p-eNOS/eNOS remained low and the inhibition of pro-inflammatory cytokines by PCA ceased.ConclusionPCA exerts protection on vascular endothelial function against inflammation through Akt/eNOS pathway, suggesting daily acquisition of PCA may be encouraged for diabetic patients

SOAP3-dp: Fast, Accurate and Sensitive GPU-Based Short Read Aligner

To tackle the exponentially increasing throughput of Next-Generation Sequencing (NGS), most of the existing short-read aligners can be configured to favor speed in trade of accuracy and sensitivity. SOAP3-dp, through leveraging the computational power of both CPU and GPU with optimized algorithms, delivers high speed and sensitivity simultaneously. Compared with widely adopted aligners including BWA, Bowtie2, SeqAlto, CUSHAW2, GEM and GPU-based aligners BarraCUDA and CUSHAW, SOAP3-dp was found to be two to tens of times faster, while maintaining the highest sensitivity and lowest false discovery rate (FDR) on Illumina reads with different lengths. Transcending its predecessor SOAP3, which does not allow gapped alignment, SOAP3-dp by default tolerates alignment similarity as low as 60%. Real data evaluation using human genome demonstrates SOAP3-dp's power to enable more authentic variants and longer Indels to be discovered. Fosmid sequencing shows a 9.1% FDR on newly discovered deletions. SOAP3-dp natively supports BAM file format and provides the same scoring scheme as BWA, which enables it to be integrated into existing analysis pipelines. SOAP3-dp has been deployed on Amazon-EC2, NIH-Biowulf and Tianhe-1A

iCartiGD: the Integrated Cartilage Gene Database

BACKGROUND: Diseases of cartilage, such as arthritis and degenerative disc disease, affect the majority of the general population, particularly with ageing. Discovery and understanding of the genes and pathways involved in cartilage biology will greatly assist research on the development, degeneration and disorders of cartilage. DESCRIPTION: We have established the Integrated Cartilage Gene Database (iCartiGD) of genes that are known, based on results from high throughput experiments, to be expressed in cartilage. Information about these genes is extracted automatically from public databases and presented as a single page report via a web-browser. A variety of flexible search options are provided and the chromosomal distribution of cartilage associated genes can be presented. CONCLUSION: iCartiGD provides a comprehensive source of information on genes known to be expressed in cartilage. It will remain current due to its automatic update capability and provide researchers with an easily accessible resource for studies involving cartilage. Genetic studies of the development and disorders of cartilage will benefit from this database