A 3-D model for the CD40 ligand predicts that it is a compact trimer similar to the tumor necrosis factors

Based on the similarity in primary structure between the newly characterized ligand for CD40 (CD40L) and the tumor necrosis factors (TNFs), we have modeled a detailed 3-D structure for CD40L. We used the known structure of TNFα as a template for the generation of the CD40L model. The soundness of the model-building algorithms was verified by constructing a 3-D model of TNFβ and comparing it to its crystallographically determined structure. The CD40L sequence is entirety compatible with the ‘Jelly-roll' β-strand structure characteristic of the TNFs. Like the TNFs, CD40L is predicted to form a compact trimer, although the interactions between monomers are distinct from those found in the TNFs. The model predicts which regions of CD40L could interact with its receptor(s) and which amino acids are essential for the maintenance of its trimeric structur

Rapid and selective surveillance of Arabidopsis thaliana genome annotations with Centrifuge

Summary: Centrifuge is a user-friendly system to simultaneously access Arabidopsis gene annotations and intra- and inter-organism sequence comparison data. The tool allows rapid retrieval of user-selected data for each annotated Arabidopsis gene providing, in any combination, data on the following features: predicted protein properties such as mass, pI, cellular location and transmembrane domains; SWISS-PROT annotations; Interpro domains; Gene Ontology records; verified transcription; BLAST matches to the proteomes of A.thaliana, Oryza sativa (rice), Caenorhabditis elegans, Drosophila melanogaster and Homo sapiens. The tool lends itself particularly well to the rapid analysis of contigs or of tens or hundreds of genes identified by high-throughput gene expression experiments. In these cases, a summary table of principal predicted protein features for all genes is given followed by more detailed reports for each individual gene. Centrifuge can also be used for single gene analysis or in a word search mode. Availability: http://centrifuge.unil.ch/ Contact: [email protected]

Swiss EMBnet node web server

EMBnet is a consortium of collaborating bioinformatics groups located mainly within Europe (http://www.embnet.org). Each member country is represented by a ‘node', a group responsible for the maintenance of local services for their users (e.g. education, training, software, database distribution, technical support, helpdesk). Among these services a web portal with links and access to locally developed and maintained software is essential and different for each node. Our web portal targets biomedical scientists in Switzerland and elsewhere, offering them access to a collection of important sequence analysis tools mirrored from other sites or developed locally. We describe here the Swiss EMBnet node web site (http://www.ch.embnet.org), which presents a number of original services not available anywhere els

Vertebrate conserved non coding DNA regions have a high persistence length and a short persistence time

BACKGROUND: The comparison of complete genomes has revealed surprisingly large numbers of conserved non-protein-coding (CNC) DNA regions. However, the biological function of CNC remains elusive. CNC differ in two aspects from conserved protein-coding regions. They are not conserved across phylum boundaries, and they do not contain readily detectable sub-domains. Here we characterize the persistence length and time of CNC and conserved protein-coding regions in the vertebrate and insect lineages. RESULTS: The persistence length is the length of a genome region over which a certain level of sequence identity is consistently maintained. The persistence time is the evolutionary period during which a conserved region evolves under the same selective constraints.Our main findings are: (i) Insect genomes contain 1.60 times less conserved information than vertebrates; (ii) Vertebrate CNC have a higher persistence length than conserved coding regions or insect CNC; (iii) CNC have shorter persistence times as compared to conserved coding regions in both lineages. CONCLUSION: Higher persistence length of vertebrate CNC indicates that the conserved information in vertebrates and insects is organized in functional elements of different lengths. These findings might be related to the higher morphological complexity of vertebrates and give clues about the structure of active CNC elements.Shorter persistence time might explain the previously puzzling observations of highly conserved CNC within each phylum, and of a lack of conservation between phyla. It suggests that CNC divergence might be a key factor in vertebrate evolution. Further evolutionary studies will help to relate individual CNC to specific developmental processes

Nickel and skin irritants up-regulate tumor necrosis factor-α mRNA in keratinocytes by different but potentially synergistic mechanisms

A critical role of tumor necrosis factor (TNF)-α in irritant contact dermatitis and in the challenge phase of allergic contact dermatitis has recently been demonstrated in vivo. As in situ hybridization studies have indicated that keratinocytes were the cellular source of TNF-α in these reactions, we studied the mechanisms of TNF-α mRNA induction in keratinocytes by agents that induce contact dermatitis. Murine Ia−;/CD3− epidermal cells were stimulated with phorbol myristate acetate (PMA), dimethylsulfoxide (DMSO), sodium dodecyl sulfate (SDS) and NiSO4, all of which up-regulated epidermal cell TNF-α mRNA production. In contrast, trinitrobenzenesulfonic acid and trinitrochlorobenzene did not significantly up-regulate TNF-α mRNA. These results were confirmed with murine keratinocyte cell lines. In keratinocytes transfected with a chloramphenicol acetyltransferase construct containing the −1059 to +138 base pair TNF-α promoter, increased promoter activity was observed upon stimulation with PMA and DMSO. In addition, PMA stimulation did not affect the stability of TNF-α mRNA. The PMA- but also the DMSO- and SDSinduced up-regulation of TNF-α mRNA was abolished by an inhibitor of protein kinase C (PKC). In contrast, NISO4 up-regulated TNF-α mRNA by a PKC-independent mechanism, did not increase TNF-α promoter activity, but markedly increased the stability of the TNF-α mRNA. Co-stimulation with PMA and NISO4 induced a marked increase in TNF-a mRNA over that obtained with each agent alone. Thus, whereas PKC-dependent irritants act by up-regulating TNF-α promoter activity, nickel acts via post-transcrlptional regulation. Our results, also establish that some irritants and irritant sensitizers directly induce TNF-α in keratinocytes without intermediate Langerhans cell derived signal

A view on genomic medicine activities in Africa: Implications for policy

Genomics policy development involves assessing a wide range of issues extending from specimen collection and data sharing to whether and howto utilize advanced technologies in clinical practice and public health initiatives. A survey was conducted among African scientists and stakeholders with an interest in genomic medicine, seeking to evaluate: 1) Their knowledge and understanding of the field. 2) The institutional environment and infrastructure available to them. 3) The state and awareness of the field in their country. 4) Their perception of potential barriers to implementation of precision medicine

Rapid evolution of cancer/testis genes on the X chromosome

BACKGROUND: Cancer/testis (CT) genes are normally expressed only in germ cells, but can be activated in the cancer state. This unusual property, together with the finding that many CT proteins elicit an antigenic response in cancer patients, has established a role for this class of genes as targets in immunotherapy regimes. Many families of CT genes have been identified in the human genome, but their biological function for the most part remains unclear. While it has been shown that some CT genes are under diversifying selection, this question has not been addressed before for the class as a whole. RESULTS: To shed more light on this interesting group of genes, we exploited the generation of a draft chimpanzee (Pan troglodytes) genomic sequence to examine CT genes in an organism that is closely related to human, and generated a high-quality, manually curated set of human:chimpanzee CT gene alignments. We find that the chimpanzee genome contains homologues to most of the human CT families, and that the genes are located on the same chromosome and at a similar copy number to those in human. Comparison of putative human:chimpanzee orthologues indicates that CT genes located on chromosome X are diverging faster and are undergoing stronger diversifying selection than those on the autosomes or than a set of control genes on either chromosome X or autosomes. CONCLUSION: Given their high level of diversifying selection, we suggest that CT genes are primarily responsible for the observed rapid evolution of protein-coding genes on the X chromosome

Indexing Strategies for Rapid Searches of Short Words in Genome Sequences

Searching for matches between large collections of short (14–30 nucleotides) words and sequence databases comprising full genomes or transcriptomes is a common task in biological sequence analysis. We investigated the performance of simple indexing strategies for handling such tasks and developed two programs, fetchGWI and tagger, that index either the database or the query set. Either strategy outperforms megablast for searches with more than 10,000 probes. FetchGWI is shown to be a versatile tool for rapidly searching multiple genomes, whose performance is limited in most cases by the speed of access to the filesystem. We have made publicly available a Web interface for searching the human, mouse, and several other genomes and transcriptomes with oligonucleotide queries

Decomposing Genomics Algorithms: Core Computations for Accelerating Genomics

Technological advances in genomic analyses and computing sciences has led to a burst in genomics data. With those advances, there has also been parallel growth in dedicated accelerators for specific genomic analyses. However, biologists are in need of a reconfigurable machine that can allow them to perform multiple analyses without needing to go for dedicated compute platforms for each analysis. This work addresses the first steps in the design of such a reconfigurable machine. We hypothesize that this machine design can consist of some accelerators of computations common across various genomic analyses. This work studies a subset of genomic analyses and identifies such core computations. We further investigate the possibility of further accelerating through a deeper analysis of the computation primitives.National Science Foundation (NSF CNS 13-37732); Infosys; IBM Faculty Award; Office of the Vice Chancellor for Research, University of Illinois at Urbana-ChampaignOpe

Gene expression variation and expression quantitative trait mapping of human chromosome 21 genes

Inter-individual differences in gene expression are likely to account for an important fraction of phenotypic differences, including susceptibility to common disorders. Recent studies have shown extensive variation in gene expression levels in humans and other organisms, and that a fraction of this variation is under genetic control. We investigated the patterns of gene expression variation in a 25 Mb region of human chromosome 21, which has been associated with many Down syndrome (DS) phenotypes. Taqman real-time PCR was used to measure expression variation of 41 genes in lymphoblastoid cells of 40 unrelated individuals. For 25 genes found to be differentially expressed, additional analysis was performed in 10 CEPH families to determine heritabilities and map loci harboring regulatory variation. Seventy-six percent of the differentially expressed genes had significant heritabilities, and genomewide linkage analysis led to the identification of significant eQTLs for nine genes. Most eQTLs were in trans, with the best result (P=7.46×10−8) obtained for TMEM1 on chromosome 12q24.33. A cis-eQTL identified for CCT8 was validated by performing an association study in 60 individuals from the HapMap project. SNP rs965951 located within CCT8 was found to be significantly associated with its expression levels (P=2.5×10−5) confirming cis-regulatory variation. The results of our study provide a representative view of expression variation of chromosome 21 genes, identify loci involved in their regulation and suggest that genes, for which expression differences are significantly larger than 1.5-fold in control samples, are unlikely to be involved in DS-phenotypes present in all affected individual