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PubMed2007

Identification of putative cis-regulatory elements in Cryptosporidium parvum by de novo pattern finding.

BACKGROUND: Cryptosporidium parvum is a unicellular eukaryote in the phylum Apicomplexa. It is an obligate intracellular parasite that causes diarrhea and is a significant AIDS-related pathogen. Cryptosporidium parvum is not amenable to long-term laboratory cultivation or classical molecular genetic analysis. The parasite exhibits a complex life cycle, a broad host range, and fundamental mechanisms of gene regulation remain unknown. We have used data from the recently sequenced genome of this organism to uncover clues about gene regulation in C. parvum. We have applied two pattern finding algorithms MEME and AlignACE to identify conserved, over-represented motifs in the 5' upstream regions of genes in C. parvum. To support our findings, we have established comparative real-time -PCR expression profiles for the groups of genes examined computationally. RESULTS: We find that groups of genes that share a function or belong to a common pathway share upstream motifs. Different motifs are conserved upstream of different groups of genes. Comparative real-time PCR studies show co-expression of genes within each group (in sub-sets) during the life cycle of the parasite, suggesting co-regulation of these genes may be driven by the use of conserved upstream motifs. CONCLUSION: This is one of the first attempts to characterize cis-regulatory elements in the absence of any previously characterized elements and with very limited expression data (seven genes only). Using de novo pattern finding algorithms, we have identified specific DNA motifs that are conserved upstream of genes belonging to the same metabolic pathway or gene family. We have demonstrated the co-expression of these genes (often in subsets) using comparative real-time-PCR experiments thus establishing evidence for these conserved motifs as putative cis-regulatory elements. Given the lack of prior information concerning expression patterns and organization of promoters in C. parvum we present one of the first investigations of gene regulation in this important human pathogen.

Algorithms↗

PubMed2000

Qualitative gene profiling: a novel tool in genomics and in pharmacogenomics that deciphers messenger RNA isoforms diversity.

RNA splicing is a tightly regulated process. It is essential for gene expression and, therefore, intervenes in every biological phenomenon in mammals. RNA splicing regulation is cell type-specific in such a way that a cellular situation can be characterised by its repertoire of spliced events, the spliceome. Comparison of the splicing repertoire of two situations identifies alternative exons and introns. This regulation involves cis-acting sequences and transacting factors. Mutations, as well as modifications of signalling pathways, can alter the accuracy of splicing. Since deletion of exons or retention of introns within coding sequences modifies the corresponding proteins and functional domains of proteins are encoded by contiguous exons, identifying changes in the spliceome pinpoints functional domains, which are specifically regulated at the level of RNA splicing. We have developed a new method of gene profiling, qualitative gene profiling, that allows the comparative study of the repertoires of spliced events that characterise distinct physiopathological situations. We present in this review the different uses of this new genomic technique that can help each step of the R&D process in the pharmaceutical industry, and that represents a short cut towards functional genomics and pharmacogenomics.

Animals↗

PubMed2002

Integrated genomic and proteomic analysis of signaling pathways in dendritic cell differentiation and maturation.

Dendritic cells (DCs) are antigen-presenting cells that play a major role in initiating primary immune responses. Their phenotypic and functional characteristics are intimately linked to their stage of maturation. The specific biochemical pathways and genes whose expression mediates differentiation of progenitors to DCs and their maturation are largely undefined. We recently utilized two approaches, DNA microarrays and proteomics, to analyze the expression profile of human CD14(+) blood monocytes and their derived DCs. Approximately 4% of the genes or proteins expressed were found to be regulated during DC differentiation. Most of these genes were not previously associated with DCs and included genes highly relevant to DC functions (genes involved in antigen presentation, cell adhesion and motility, lipid metabolism). Genes involved in specific signaling pathways, including IkappaBalpha, PPAR-gamma and C/EBPalpha as well as two members of the family of transcription factors, interferon regulatory factors (IRFs), were also modified. Modulation of IRF gene expression is of particular interest because of their functional roles in innate and adaptive immune responses. IRF-family members control the expression of proteins that include type-1 interferons, interleukin-12, interleukin-15, MHC molecules and adhesion molecules. They have also been found to play an important role in lymphocyte development. In contrast to DC differentiation, very few genes were modified at the transcript level during DC maturation as determined by microarray experiments. Further analysis suggested that DC maturation is largely controlled by posttranscriptional and posttranslational modifications. The use of proteomics is therefore necessary for a full comprehension of DC maturation process.

Animals↗

PubMed2005

[Screening of differentially expressed genes in colorectal cancer using human whole genomic oligonucleotide microarrays].

OBJECTIVE: To screen the differentially expressed genes in human colorectal cancer (CRC) tissue. METHODS: Affymetrix oligonucleotide microarrays HG-U133 representing 32,264 human genes including 19,308 known genes and 12,956 expressed sequence tags (ESTs) were used to detect the gene expressions of CRC tissue paired with normal mucosa tissue. The microarray findings were confirmed by real-time quantitative reverse transcriptase-polymerase chain reaction (FQ-PCR). The gene expression profiles were analyzed by intersection and complement, rank sum test and t test. RESULTS: Totally 3,125 genes and ESTs expressed differentially were detected in normal and cancer tissues, consisting of 974 up-regulated and 2,151 down-regulated genes with 247 ESTs present in CRC tissue and absent in normal mucosa and 162 ESTs absent in CRC tissue but present in normal mucosa. A percent of 80.1% of the differentially expressed genes were not reported in the literatures. CONCLUSION: The strategy of data mining provides a foundation for filtering molecular markers and interpreting molecular carcinogenesis of CRC.

Colorectal Neoplasms↗

PubMed2001

Genomics approaches to drug discovery.

New approaches to drug discovery have come about in recent years as a result of important advances in genomics and bioinformatics. The availability of genome-scale sequence data, the development of new tools for high-throughput gene expression monitoring, and improvements in the ability to analyze large data sets have revolutionized the field. In this article, we discuss three applications of genomics data in the drug discovery process: target discovery, prodrug strategies, and vaccine development.

Amino Acid Sequence↗

PubMedDate not supplied

Cardiovascular genomics.

The ongoing explosion of genomic information is revolutionizing cardiovascular science. More complete genomic maps allow easier identification of genes that cause monogenic inherited diseases. In addition, analyses of variations in gene expression in cardiovascular diseases are revealing new potential candidate genes as well as novel biomarkers for many common, multifactorial diseases. While experiments are revealing new pathophysiologic pathways, these genomic studies are also generating enormous amounts of data. Even as we learn how to sift through mountains of genomic information, new technologies in proteomics are rapidly advancing and promise to provide additional critical tools for diagnosis and for identifying new therapies.

Biomarkers↗

PubMed2002

Genome-wide internal tagging of bacterial exported proteins.

As a result of the explosive growth of bacterial genomic and postgenomic information, there is a pressing need for efficient, inexpensive strategies for characterizing the in vivo behavior and function of newly identified gene products. We describe here an internal tagging procedure, based on transposon technology, to facilitate the analysis of membrane-bound and secreted proteins in Gram-negative bacteria. The technique is based on a broad host range transposon (ISphoA/hah), which may be used to generate both alkaline phosphatase (AP) gene fusions and 63-codon in-frame insertions in the genome. The 63-codon insertion encodes an influenza hemagglutinin epitope and a hexahistidine sequence, permitting sensitive detection and metal affinity purification of tagged proteins. For each gene targeted, it is thus possible to monitor the disruption of phenotype (using the transposon insertion), the gene's transcription and translation (using the AP reporter activity), and the behavior of the unfused protein (using the internal tag). Studies on a sequence-defined collection of Escherichia coli strains generated using the transposon showed that the synthesis and subcellular localization of tagged proteins could be readily monitored. The use of ISphoA/hah should provide a cost-effective approach for genome-wide in vivo studies of the behavior of exported proteins in a number of bacterial species.

Bacterial Proteins↗

PubMed2025

WinPCA: a package for windowed principal component analysis.

SUMMARY: With chromosomal reference genomes and population-scale whole genome-sequencing becoming increasingly accessible, contemporary studies often include characterizations of the genomic landscape as it varies along chromosomes, commonly termed genome scans. While traditional summary statistics like FST and dXY between pre-assigned populations remain integral to characterizing the genomic divergence profile, PCA differs by providing single-sample resolution, thereby supporting the identification of polymorphic inversions, introgression and other types of divergent sequence that may not be fully aligned with global population structure. Here, we introduce WinPCA, a user-friendly package to compute, polarize and visualize genetic principal components in windows along the genome. To accommodate low-coverage whole genome-sequencing datasets, WinPCA can optionally make use of PCAngsd methods to compute principal components in a genotype likelihood framework. WinPCA accepts variant data in either VCF or BEAGLE format and can generate rich plots for interactive data exploration and downstream presentation. AVAILABILITY AND IMPLEMENTATION: WinPCA is implemented in Python and freely available at https://github.com/MoritzBlumer/winpca and https://doi.org/10.5281/zenodo.15614979.

Software↗

PubMed2006

Chromosome-wide identification of novel imprinted genes using microarrays and uniparental disomies.

Genomic imprinting refers to a specialized form of epigenetic gene regulation whereby the expression of a given allele is dictated by parental origin. Defining the extent and distribution of imprinting across genomes will be crucial for understanding the roles played by imprinting in normal mammalian growth and development. Using mice carrying uniparental disomies or duplications, microarray screening and stringent bioinformatics, we have developed the first large-scale tissue-specific screen for imprinted gene detection. We quantify the stringency of our methodology and relate it to previous non-tissue-specific large-scale studies. We report the identification in mouse of four brain-specific novel paternally expressed transcripts and an additional three genes that show maternal expression in the placenta. The regions of conserved linkage in the human genome are associated with the Prader-Willi Syndrome (PWS) and Beckwith-Wiedemann Syndrome (BWS) where imprinting is known to be a contributing factor. We conclude that large-scale systematic analyses of this genre are necessary for the full impact of genomic imprinting on mammalian gene expression and phenotype to be elucidated.

Animals↗

PubMed2004

Mitotic errors in chromosome 21 of human preimplantation embryos are associated with non-viability.

Fluorescent in situ hybridization (FISH) studies of human preimplantation embryos have demonstrated a high proportion of chromosomal mosaicism. To investigate the different timings and nature of chromosomal mosaicism, we developed single cell multiplex fluorescent (FL)-PCR to distinguish meiotic and mitotic cell division errors. Chromosome 21 was investigated as the model chromosome as trisomy 21 (Down's syndrome) represents the most common chromosomal aneuploidy that reaches live birth. Sister blastomeres from a total of 25 chromosome 21 aneuploid embryos were analysed. Of these, 13 (52%) comprised cells with concordant DNA fingerprints indicative of meiotic non-disjunction errors. The remaining 12 (48%) aneuploid embryos comprised discordant sister blastomere allelic profiles and thus were mosaic. Errors at all stages including metaphase (MI) (12%) and first (38%), second (31%) and third (19%) mitotic cleavage divisions were identified from the types and proportion of different allelic profiles. In addition, three embryos showed combined meiotic and mitotic cell division errors including non-disjunction and anaphase lag, suggesting that diploid cells had resulted from an aneuploid zygote. However, the majority of the mosaic aneuploid embryos showed mitotic gains and losses from a diploid zygote occurring prior to the activation of the embryonic genome. Allelic profiling of amniocytes from 15 prenatal diagnosis samples displayed only meiotic errors. There appears to be a large difference between the proportion of mosaic mitotic-derived trisomy 21 embryos and fetuses. These findings indicate that mosaic mitotic error of chromosome 21 is associated with non-viability.

Adult↗

PubMed2002

A functional genomics approach to Kaposi's sarcoma.

Kaposi's sarcoma (KS) is the most frequent malignancy afflicting acquired immune-deficiency syndrome (AIDS) patients. Tumor lesions are characterized by spindle cells of vascular origin and vascularization. Kaposi's sarcoma-associated herpes virus (KSHV) is consistently found in all forms of KS. Infection of dermal microvascular endothelial cells (DMVEC) with KSHV recapitulates spindle cell formation in vitro. We studied this transformation process by DNA microarray analysis comparing the RNA expression profiles of KSHV-infected and mock-infected DMVEC. Genes involved in tumorigenesis, angiogenesis, host defense, cell growth and differentiation, transcription, and metabolism were observed to change significantly upon infection with KSHV. One of the most consistently KSHV-induced genes was the receptor tyrosine kinase and proto-oncogene c-Kit. Inhibition of c-Kit activity with the pharmacological inhibitor of c-Kit signaling STI571 reversed the KSHV-induced morphological transformation of DMVEC. Moreover, overexpression studies showed that c-Kit was sufficient to induce spindle cell formation (Moses et al. J. Virol. 76(16): 8383-8399). These data demonstrate that microarrays are useful for the identification of pharmacological targets essential for KS tumorigenesis.

Benzamides↗

PubMed2004

A computational approach for ordering signal transduction pathway components from genomics and proteomics Data.

BACKGROUND: Signal transduction is one of the most important biological processes by which cells convert an external signal into a response. Novel computational approaches to mapping proteins onto signaling pathways are needed to fully take advantage of the rapid accumulation of genomic and proteomics information. However, despite their importance, research on signaling pathways reconstruction utilizing large-scale genomics and proteomics information has been limited. RESULTS: We have developed an approach for predicting the order of signaling pathway components, assuming all the components on the pathways are known. Our method is built on a score function that integrates protein-protein interaction data and microarray gene expression data. Compared to the individual datasets, either protein interactions or gene transcript abundance measurements, the integrated approach leads to better identification of the order of the pathway components. CONCLUSIONS: As demonstrated in our study on the yeast MAPK signaling pathways, the integration analysis of high-throughput genomics and proteomics data can be a powerful means to infer the order of pathway components, enabling the transformation from molecular data into knowledge of cellular mechanisms.

Computational Biology↗

PubMed2006

Development of computations in bioscience and bioinformatics and its application: review of the Symposium of Computations in Bioinformatics and Bioscience (SCBB06).

The first symposium of computations in bioinformatics and bioscience (SCBB06) was held in Hangzhou, China on June 21-22, 2006. Twenty-six peer-reviewed papers were selected for publication in this special issue of BMC Bioinformatics. These papers cover a broad range of topics including bioinformatics theories, algorithms, applications and tool development. The main technical topics contain gene expression analysis, sequence analysis, genome analysis, phylogenetic analysis, gene function prediction, molecular interaction and system biology, genetics and population study, immune strategy, protein structure prediction and proteomics.

Biological Science Disciplines↗

PubMed1996

A study of combined structure/sequence profiles.

BACKGROUND: For genome sequencing projects to achieve their full impact on biology and medicine, each protein sequence must be identified with its three-dimensional structure. Fold assignment methods (also called profile and threading methods) attempt to assign sequences to known protein folds by computing the compatibility of sequence to fold. RESULTS: We have extended profile methods for the detection of protein folds having structural similarity but low sequence similarity to sequence probes. Our extension combines sequence substitution tables with structural properties to form a combined profile. The structural properties used in this study include distances between residues, exposed areas, areas buried by polar atoms, and properties of the original three-dimensional profile method. We compared the performance of these combined profiles with different sequence matrices and with the original three-dimensional profile method. To determine the optimal gap penalties and weights used with these profiles, we employed a genetic algorithm. The performance of these combined profiles was tested by cross validation using independent test and training sets. CONCLUSIONS: These studies show that the combined profiles perform better than profiles based on either structural or sequence information alone.

Algorithms↗

PubMed2026

Genome-wide Identification and Expression Profiling Reveal the Galectin Gene Family Diversity and their Possible Role in Antibacterial Mucosal Immunity in Japanese Flounder (Paralichthys olivaceus).

Galectins are a family of proteins that bind specifically to β-galactosides. Their importance in innate immunity of mammals has been well-documented. However, the systematic identification and characterization of galectin gene family remain limited in teleost. In this study, we identified 13 galectin genes (lgals2, lgals2a, lgals2b, lgals3, lgals3a, lgals3b, lgals4, lgals8, lgals8a, lgals9, grp, grp-b, grp-c) from Paralichthys olivaceus genome and analyzed their tissue expressions and expressions in response to Gram-negative and Gram-positive bacterial infections in mucosal tissues (gills, intestine and skin). The P. olivaceus galections were classified into three distinct types based on carbohydrate recognition domains (CRDs). Phylogenetic and syntenic analyses revealed that these galectins are closely related to their counterparts in turbot and zebrafish. Moreover, the transcripts of the 13 galectins were widespread across all tested tissues of healthy fish and regulated following challenge with Vibrio anguillarum or Streptococcus iniae in mucosal tissues, indicating their involvement in P. olivaceus immune response to bacterial infections. The lgals2a was significantly upregulated in the three mucosal tissues by either bacterial infection, whereas lgals9 and grp were basically downregulated in these tissues by either infection. On the other hand, the lgals3b and lgals4 exhibited a bacteria-specific responsive expression as they were upregulated by V. anguillarum whereas remained stable upon S. iniae infection in the gills. We also observed a positive correlation between expression level and bacterial load for the upregulated galectin genes and a negative correlation for the downregulated galectin genes. These results suggest a functional divergence among galectin members in mucosal immunity against bacterial infection in P. olivaceus.

Animals↗

PubMed2002

How can we deliver the large plant genomes? Strategies and perspectives.

The first sequenced plant genome, from the small mustard plant Arabidopsis thaliana, was published at the end of 2000. The sequencing of the rice genome is well under way. The sizes of plant genomes vary by a factor of up to 1000, and many important crop plants have genomes that are several times larger than the human genome. To gain insight into the gene toolbox of plant species, numerous large-scale EST sequencing projects have been launched successfully, and analysis procedures are constantly being refined to add maximum value to the sequence data. In addition, an alternative approach to exclude repetitive noncoding DNA and to enrich sequence libraries for gene-containing genomic regions has been developed. This strategy has the potential to deliver information about both genes and regulatory regions outside the transcribed regions.

Arabidopsis↗

PubMed2002

Identifying novel transcripts and novel genes in the human genome by using novel SAGE tags.

The number of genes in the human genome is still a controversial issue. Whereas most of the genes in the human genome are said to have been physically or computationally identified, many short cDNA sequences identified as tags by use of serial analysis of gene expression (SAGE) do not match these genes. By performing experimental verification of more than 1,000 SAGE tags and analyzing 4,285,923 SAGE tags of human origin in the current SAGE database, we examined the nature of the unmatched SAGE tags. Our study shows that most of the unmatched SAGE tags are truly novel SAGE tags that originated from novel transcripts not yet identified in the human genome, including alternatively spliced transcripts from known genes and potential novel genes. Our study indicates that by using novel SAGE tags as probes, we should be able to identify efficiently many novel transcripts/novel genes in the human genome that are difficult to identify by conventional methods.

Base Pair Mismatch↗

PubMed2004

Common structural patterns in human genes.

MOTIVATION: A graphical representation of the exon-intron structure of various genes, such as that presented by the National Center for Biotechnology Information Map Viewer, suggests a digital waveform or pattern that varies either in amplitude or frequency. This observation suggests that different genes may have portions of their total exon-intron structure in common. The existence of common structural patterns across unrelated genes suggests the repeated insertion of transposable elements throughout the human genome and/or a common structural function. RESULTS: We compared the exon-intron size patterns of a number of human genes and discovered numerous conserved arrangements with similarity at a high degree of stringency (>99%) across the otherwise unrelated and diverse genomic landscape. In our experimental analyses, more than 200 patterns of length 2 or greater at 99% stringency were found among the 72 genes we compared.

Algorithms↗