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ABSTRACT: The importance of microRNA (miRNA) in modulating gene expression at the post-transcriptional level is well known. Such regulation has been shown to influence the dynamics of several regulatory networks including the cell cycle. In this study we incorporated regulatory effects of intronic miRNA into an existing mathematical model of the cell cycle through the use of an existing 'proxy' protein--the host protein. It was observed that the incorporation of intronic miRNA mediated regulation improved the performance of the model resulting in a closer match to experimental results. To test the universality of this approach we compared the effects of intronic miRNA mediated regulation and host protein mediated regulation. Further, we compared miRNA mediated and protein mediated positive and negative feedback regulations of the target protein. We found that the target protein profiles were predominantly similar. These observations show the applicability of our method for incorporating intronic miRNA mediated dynamic effects in models for regulation of gene expression.
Molecular BioSystems 06/2012; 8(8):2145-52. · 3.53 Impact Factor
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Anshu Bhardwaj,
Vinod Scaria,
Gajendra Pal Singh Raghava,
Andrew Michael Lynn,
Nagasuma Chandra,
Sulagna Banerjee,
Muthukurussi V Raghunandanan,
Vikas Pandey,
Bhupesh Taneja,
Jyoti Yadav,
Debasis Dash,
Jaijit Bhattacharya,
Amit Misra,
Anil Kumar,
Srinivasan Ramachandran,
Zakir Thomas, Samir K Brahmachari
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ABSTRACT: It is being realized that the traditional closed-door and market driven approaches for drug discovery may not be the best suited model for the diseases of the developing world such as tuberculosis and malaria, because most patients suffering from these diseases have poor paying capacity. To ensure that new drugs are created for patients suffering from these diseases, it is necessary to formulate an alternate paradigm of drug discovery process. The current model constrained by limitations for collaboration and for sharing of resources with confidentiality hampers the opportunities for bringing expertise from diverse fields. These limitations hinder the possibilities of lowering the cost of drug discovery. The Open Source Drug Discovery project initiated by Council of Scientific and Industrial Research, India has adopted an open source model to power wide participation across geographical borders. Open Source Drug Discovery emphasizes integrative science through collaboration, open-sharing, taking up multi-faceted approaches and accruing benefits from advances on different fronts of new drug discovery. Because the open source model is based on community participation, it has the potential to self-sustain continuous development by generating a storehouse of alternatives towards continued pursuit for new drug discovery. Since the inventions are community generated, the new chemical entities developed by Open Source Drug Discovery will be taken up for clinical trial in a non-exclusive manner by participation of multiple companies with majority funding from Open Source Drug Discovery. This will ensure availability of drugs through a lower cost community driven drug discovery process for diseases afflicting people with poor paying capacity. Hopefully what LINUX the World Wide Web have done for the information technology, Open Source Drug Discovery will do for drug discovery.
Tuberculosis (Edinburgh, Scotland) 07/2011; 91(5):479-86. · 2.54 Impact Factor
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05/2011: pages 321 - 334; , ISBN: 9781118026038
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ABSTRACT: Of the ∼4000 ORFs identified through the genome sequence of Mycobacterium tuberculosis (TB) H37Rv, experimentally determined structures are available for 312. Since knowledge of protein structures is essential to obtain a high-resolution understanding of the underlying biology, we seek to obtain a structural annotation for the genome, using computational methods. Structural models were obtained and validated for ∼2877 ORFs, covering ∼70% of the genome. Functional annotation of each protein was based on fold-based functional assignments and a novel binding site based ligand association. New algorithms for binding site detection and genome scale binding site comparison at the structural level, recently reported from the laboratory, were utilized. Besides these, the annotation covers detection of various sequence and sub-structural motifs and quaternary structure predictions based on the corresponding templates. The study provides an opportunity to obtain a global perspective of the fold distribution in the genome. The annotation indicates that cellular metabolism can be achieved with only 219 folds. New insights about the folds that predominate in the genome, as well as the fold-combinations that make up multi-domain proteins are also obtained. 1728 binding pockets have been associated with ligands through binding site identification and sub-structure similarity analyses. The resource (http://proline.physics.iisc.ernet.in/Tbstructuralannotation), being one of the first to be based on structure-derived functional annotations at a genome scale, is expected to be useful for better understanding of TB and for application in drug discovery. The reported annotation pipeline is fairly generic and can be applied to other genomes as well.
PLoS ONE 01/2011; 6(10):e27044. · 4.09 Impact Factor
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Sandeep Grover,
Mandaville Gourie-Devi,
Ruchi Baghel,
Sangeeta Sharma,
Kiran Bala,
Meena Gupta,
Krishnamoorthy Narayanasamy,
Binuja Varma,
Meenal Gupta,
Kavita Kaur,
Puneet Talwar,
Harpreet Kaur,
Sudheer Giddaluru,
Abhay Sharma, Samir K Brahmachari,
Indian Genome Variation Consortium,
Ritushree Kukreti
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ABSTRACT: The first-line antiepileptic drugs, although affordable and effective in the control of seizures, are associated with adverse drug effects, and there is large interindividual variability in the appropriate dose at which patients respond favorably. This variability may partly be explained by functional consequences of genetic polymorphisms in the drug-metabolizing enzymes, such as the CYP450 family, microsomal epoxide hydrolase and UDP-glucuronosyltransferases, drug transporters, mainly ATP-binding cassette transporters, and drug targets, including sodium channels. The purpose of this study was to determine the allele and genotype frequencies of such genetic variants in patients with epilepsy from North India administered first-line antiepileptic drugs, such as phenobarbitone, phenytoin, carbamazepine and valproic acid, and compare them with worldwide epilepsy populations.
SNP screening of 19 functional variants from 12 genes in 392 patients with epilepsy was carried out, and the patients were classified with respect to the metabolizing rate of their drug-metabolizing enzymes, efflux rate of drug transporters and sensitivity of drug targets.
A total of 16 SNPs were found to be polymorphic, and the allelic frequencies for these SNPs were in conformance with Hardy-Weinberg equilibrium. Among all the polymorphisms studied, functional variants from genes encoding CYP2C19, EPHX1, ABCB1 and SCN1A were highly polymorphic in North Indian epilepsy patients, and might account for differential drug response to first-line antiepileptic drugs.
Interethnic differences were elucidated for several polymorphisms that might be responsible for differential serum drug levels and optimal dose requirement for efficacious treatment.
Pharmacogenomics 07/2010; 11(7):927-41. · 3.97 Impact Factor
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Mahmood Ameen Abdulla,
Ikhlak Ahmed,
Anunchai Assawamakin,
Jong Bhak, Samir K Brahmachari,
Gayvelline C Calacal,
Amit Chaurasia,
Chien-Hsiun Chen,
Jieming Chen,
Yuan-Tsong Chen, [......],
Haifeng Wang,
Jer-Yuarn Wu,
Huasheng Xiao,
Shuhua Xu,
Jin Ok Yang,
Yin Yao Shugart,
Hyang-Sook Yoo,
Wentao Yuan,
Guoping Zhao,
Bin Alwi Zilfalil
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ABSTRACT: Asia harbors substantial cultural and linguistic diversity, but the geographic structure of genetic variation across the continent remains enigmatic. Here we report a large-scale survey of autosomal variation from a broad geographic sample of Asian human populations. Our results show that genetic ancestry is strongly correlated with linguistic affiliations as well as geography. Most populations show relatedness within ethnic/linguistic groups, despite prevalent gene flow among populations. More than 90% of East Asian (EA) haplotypes could be found in either Southeast Asian (SEA) or Central-South Asian (CSA) populations and show clinal structure with haplotype diversity decreasing from south to north. Furthermore, 50% of EA haplotypes were found in SEA only and 5% were found in CSA only, indicating that SEA was a major geographic source of EA populations.
Science 12/2009; 326(5959):1541-5. · 31.20 Impact Factor
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ABSTRACT: IL-10 is a key regulator of the immune system that critically determines health and disease. Its expression is finely tuned both at the transcriptional and posttranscriptional levels. Although the importance of posttranscriptional regulation of IL-10 has been previously shown, understanding the underlying mechanisms is still in its infancy. In this study, using a combination of bioinformatics and molecular approaches, we report that microRNA (hsa-miR-106a) regulates IL-10 expression. The hsa-miR-106a binding site in the 3' UTR of IL10 has been identified by site-directed mutagenesis studies. Also, the involvement of transcription factors, Sp1 and Egr1, in the regulation of hsa-miR-106a expression and concomitant decrease in the IL-10 expression, has also been demonstrated. In summary, our results showed that IL-10 expression may be regulated by miR-106a, which is in turn transcriptionally regulated by Egr1 and Sp1.
Proceedings of the National Academy of Sciences 05/2009; 106(14):5761-6. · 9.68 Impact Factor
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Biotechnology Journal 04/2009; 4(3):348-60.
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Meenal Gupta,
Pallav Bhatnagar,
Sandeep Grover,
Harpreet Kaur,
Ruchi Baghel,
Yasha Bhasin,
Chitra Chauhan,
Binuja Verma,
Vallikiran Manduva,
Odity Mukherjee,
Meera Purushottam,
Abhay Sharma,
Sanjeev Jain, Samir K Brahmachari,
Ritushree Kukreti
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ABSTRACT: We investigated the catechol-O-methyltrasferase (COMT) gene, which is a strong functional and positional candidate gene for schizophrenia and therapeutic response to antipsychotic medication.
Single-locus as well as detailed haplotype-based association analysis of the COMT gene with schizophrenia and antipsychotic treatment response was carried out using seven COMT polymorphisms in 398 schizophrenia patients and 241 healthy individuals from a homogeneous south Indian population. Further responsiveness to risperidone treatment was assessed in 117 schizophrenia patients using Clinical Global Impressions (CGI). A total of 69 patients with a CGI score of 2 or less met the criteria of good responders and 48 were patients who continued to have a score of 3 and above and were classified as poor responders to risperidone treatment.
The association of SNP rs4680 with schizophrenia did not remain significant after adjusting for multiple testing. Haplotype analysis showed highly significant association of seven COMT marker haplotypes with schizophrenia (CLUMP T4 p-value = 0.0001). Our results also demonstrated initial significant allelic associations of two SNPs with drug response (rs4633: chi(2) = 4.36, p-value = 0.036, OR: 1.80, 95% CI: 1.03-3.15; and rs4680: chi(2) = 4.02, p-value = 0.044, OR: 1.76, 95% CI: 1.01-3.06) before multiple correction. We employed two-marker sliding window analysis for haplotype association and observed a significant association of markers located between intron 1 and intron 2 (rs737865, rs6269: CLUMP T4 p-value = 0.021); and in exon 4 (rs4818, rs4680: CLUMP T4 p-value = 0.028) with drug response.
The present study thus indicates that the interacting effects within the COMT gene polymorphisms may influence the disease status and response to risperidone in schizophrenia patients. However, the study needs to be replicated in a larger sample set for confirmation, followed by functional studies.
Pharmacogenomics 03/2009; 10(3):385-97. · 3.97 Impact Factor
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Meenal Gupta,
Chitra Chauhan,
Pallav Bhatnagar,
Simone Gupta,
Sandeep Grover,
Prashant K Singh,
Meera Purushottam,
Odity Mukherjee,
Sanjeev Jain, Samir K Brahmachari,
Ritushree Kukreti
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ABSTRACT: We investigated 16 polymorphisms from three genes, dopamine receptor D2 (DRD2), catechol-O-methyl transferase (COMT) and brain derived neurotrophic factor (BDNF), which are involved in the dopaminergic pathways, and have been reported to be associated with susceptibility to schizophrenia and response to antipsychotic therapy.
Single-locus association analyses of these polymorphisms were carried out in 254 patients with schizophrenia and 225 controls, all of southern Indian origin. Additionally, multifactor-dimensionality reduction analysis was performed in 422 samples (243 cases and 179 controls) to examine the gene-gene interactions and to identify combinations of multilocus genotypes associated with either high or low risk for the disease.
Our results demonstrated initial significant associations of two SNPs for DRD2 (rs11608185, genotype: chi(2) = 6.29, p-value = 0.043; rs6275, genotype: chi(2) = 8.91, p-value = 0.011), and one SNP in the COMT gene (rs4680, genotype: chi(2) = 6.67, p-value = 0.035 and allele: chi(2) = 4.75, p-value = 0.029; odds ratio: 1.33, 95% confidence interval: 1.02-1.73), but not after correction for multiple comparisons indicating a weak association of individual markers of DRD2 and COMT with schizophrenia. Multifactor-dimensionality reduction analysis suggested a two locus model (rs6275/DRD2 and rs4680/COMT) as the best model for gene-gene interaction with 90% cross-validation consistency and 42.42% prediction error in predicting disease risk among schizophrenia patients.
The present study thus emphasizes the need for multigene interaction studies in complex disorders such as schizophrenia and to understand response to drug treatment, which could lead to a targeted and more effective treatment.
Pharmacogenomics 02/2009; 10(2):277-91. · 3.97 Impact Factor
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ABSTRACT: India currently has the world's second-largest population along with a fast-growing economy and significant economic disparity. It also continues to experience a high rate of infectious disease and increasingly higher rates of chronic diseases. However, India cannot afford to import expensive technologies and therapeutics nor can it, as an emerging economy, emulate the health-delivery systems of the developed world. Instead, to address these challenges it is looking to biotechnology-based innovation in the field of genomics. The Indian Genome Variation (IGV) consortium, a government-funded collaborative network among seven local institutions, is a reflection of these efforts. The IGV has recently developed the first large-scale database of genomic diversity in the Indian population that will facilitate research on disease predisposition, adverse drug reactions and population migration.
Nature Reviews Genetics 10/2008; 9 Suppl 1:S9-14. · 38.08 Impact Factor
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ABSTRACT: A multitude of complex diseases have been linked to elevated homocysteine levels; however, till date there is no plausible explanation for a single amino acid's involvement in so many diseases. Since homocysteine is a reactive thiol amino acid and the majority of plasma homocysteine is protein thiol bound, we hypothesized that homocysteine might bind to accessible cysteine residues in target proteins, thereby modulating its structure or function or both. The parameters that dictate homocysteine-protein interaction are not well understood, and the few known homocysteine binding proteins were identified by a candidate protein approach. In this study, we identified potential homocysteine interacting proteins based on cysteine content, solvent accessibility of cysteine residues, and dihedral strain energies and pKa of these cysteines. Pathway mapping of the cysteine-rich proteins revealed that proteins in the coagulation cascade, notch receptor-mediated signaling, LDL endocytosis, programmed cell death, and extracellular matrix proteins were significantly over-represented with cysteine-rich proteins, and we believe that homocysteine has a high probability to bind to proteins in these pathways. In fact, several clinical studies have implicated high homocysteine levels to be associated with diseases like thrombosis, neural tube defects, and so forth, which result from dysfunction of one or more of the proteins identified in our study. Further, we successfully validated our prediction parameters on the proteins that have already been experimentally shown to bind homocysteine, and our structural analysis argues a plausible explanation for these prior reported protein interactions with homocysteine that could not be previously explained.
Proteins Structure Function and Bioinformatics 06/2008; 71(3):1475-83. · 3.39 Impact Factor
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ABSTRACT: MicroRNAs are recently discovered small endogenous non-coding RNAs. These small RNAs of approximately 22 nucleotide length are crucial post-transcriptional regulators of gene expression in a wide spectrum of normal and abnormal biological processes including antiviral defence, oncogenesis and development in higher eukaryotes. Of late, a number of viruses have also been shown to encode for microRNAs. The host- and virus-encoded microRNAs and their targets together thus form a novel regulatory layer of genetic interactions between the host and the virus. Recent reports have thrown light on this new regulatory layer. A clear understanding of the cross-talk between the host and virus would not only enable us to understand the molecular basis of viral pathogenesis, but also enable us to develop better therapeutic strategies. This review discusses the intricacies of host-virus cross-talk mediated by microRNAs. Recent trends in this field and the challenges that need to be addressed are also discussed.
Cellular Microbiology 01/2008; 9(12):2784-94. · 5.46 Impact Factor
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ABSTRACT: Motifs that are evolutionarily conserved in proteins are crucial to their structure and function. In one of our earlier studies, we demonstrated that the conserved motifs occurring invariantly across several organisms could act as structural determinants of the proteins. We observed the abundance of glycyl residues in these invariantly conserved motifs. The role of glycyl residues in highly conserved motifs has not been studied extensively. Thus, it would be interesting to examine the structural perturbations induced by mutation in these conserved glycyl sites. In this work, we selected a representative set of invariant signature (IS) peptides for which both the PDB structure and mutation information was available. We thoroughly analyzed the conformational features of the glycyl sites and their local interactions with the surrounding residues. Using Ramachandran angles, we showed that the glycyl residues occurring in these IS peptides, which have undergone mutation, occurred more often in the L-disallowed as compared with the L-allowed region of the Ramachandran plot. Short range contacts around the mutation site were analyzed to study the steric effects. With the results obtained from our analysis, we hypothesize that any change of activity arising because of such mutations must be attributed to the long-range interaction(s) of the new residue if the glycyl residue in the IS peptide occurred in the L-allowed region of the Ramachandran plot. However, the mutation of those conserved glycyl residues that occurred in the L-disallowed region of the Ramachandran plot might lead to an altered activity of the protein as a result of an altered conformation of the backbone in the immediate vicinity of the glycyl residue, in addition to long range effects arising from the long side chains of the new residue. Thus, the loss of activity because of mutation in the conserved glycyl site might either relate to long range interactions or to local perturbations around the site depending upon the conformational preference of the glycyl residue.
Proteins Structure Function and Bioinformatics 12/2007; 69(3):617-32. · 3.39 Impact Factor
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ABSTRACT: High and broad transcription of eukaryotic genes is facilitated by cost minimization, clustered localization in the genome, elevated G+C content, and low nucleosome formation potential. In this scenario, illumination of correlation between abundance of (TG/CA)(n>or=12) repeats, which are negative cis modulators of transcription, and transcriptional levels and other commonly occurring dinucleotide repeats, is required. Three independent microarray datasets were used to examine the correlation of (TG/CA)(n>or=12) and other dinucleotide repeats with gene expression. Compared with the expected equi-distribution pattern under neutral model, highly transcribed genes were poor in repeats, and conversely, weakly transcribed genes were rich in repeats. Furthermore, the inverse correlation between repeat abundance and transcriptional levels appears to be a global phenomenon encompassing all genes regardless of their breadth of transcription. This selective pattern of exclusion of (TG/CA)(n>or=12) and (AT)(n>or=12) repeats in highly transcribed genes is an additional factor along with cost minimization and elevated GC, and therefore, multiple factors govern high transcription of genes. We observed that even after controlling for the effects of GC and average intron lengths, the effect of repeats albeit somewhat weaker was persistent and definite. In the ribosomal protein coding genes, sequence analysis of orthologs suggests that negative selection for repeats perhaps occurred early in evolution. These observations suggest that negative selection of (TG/CA)(n>or=12) microsatellites in the evolution of the highly expressed genes was also controlled by gene function in addition to intron length.
Physiological Genomics 09/2007; 31(1):96-103. · 2.73 Impact Factor
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ChemMedChem 07/2007; 2(6):789-92. · 3.15 Impact Factor
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ABSTRACT: A Boolean network is a simple computational model that may provide insight into the overall behavior of genetic networks and is represented by variables with two possible states (on/off), of the individual nodes/genes of the network. In this study, a Boolean network model has been used to simulate a molecular pathway between two neurotransmitter receptor, dopamine and glutamate receptor, systems in order to understand the consequence of using logic gate rules between nodes, which have two possible states (active and inactive).
The dynamical properties of this Boolean network model of the biochemical pathway shows that, the pathway is stable and that, deletion/knockout of certain biologically important nodes cause significant perturbation to this network. The analysis clearly shows that in addition to the expected components dopamine and dopamine receptor 2 (DRD2), Ca(2+) ions play a critical role in maintaining stability of the pathway.
So this method may be useful for the identification of potential genetic targets, whose loss of function in biochemical pathways may be responsible for disease onset. The molecular pathway considered in this study has been implicated with a complex disorder like schizophrenia, which has a complex multifactorial etiology.
Journal of Theoretical Biology 03/2007; 244(3):463-9. · 2.21 Impact Factor
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ABSTRACT: Expansion of trinucleotide repeats in coding and non-coding regions of genes is associated with sixteen neurodegenerative disorders. However, the molecular effects that lead to neurodegeneration have remained elusive. We have explored the role of transcriptional dysregulation by TATA-box binding protein (TBP) containing an expanded polyglutamine stretch in a mouse neuronal cell culture based model. We find that mouse neuronal cells expressing a variant of human TBP harboring an abnormally expanded polyQ tract not only form intranuclear aggregates, but also show transcription dysregulation of the voltage dependent anion channel, Vdac1, increased cytochrome c release from the mitochondria and upregulation of genes involved in localized neuronal translation. On the other hand, unfolded protein response seemed to be unaffected. Consistent with an increased transcriptional effect, we observe an elevated promoter occupancy by TBP in vivo in TATA containing and TATA-less promoters of differentially expressed genes. Our study suggests a link between transcriptional dysfunction and cell death in trinucleotide repeat mediated neuronal dysfunction through voltage dependent anion channel, Vdac1, which has been recently recognized as a critical determinant of cell death.
PLoS ONE 02/2007; 2(11):e1170. · 4.09 Impact Factor
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ABSTRACT: A significant variability is observed among patients in response to antipsychotics, and is caused by a variety of factors. This review summarizes the available knowledge of associations between pharmacogenetics and drug response in schizophrenia. The multifactorial etiology of schizophrenia makes it a complex interaction of symptoms. Adopting a pharmacogenomics approach represents a unique opportunity for the prediction of response to antipsychotic drugs by investigating genes implicated with specific symptoms and side effects. A network model of the interaction/crosstalk between the neurotransmitter signaling systems is presented to emphasize the importance of the genes associated with the molecular mechanisms of the disease and drug response. These genes may serve as potential susceptibility genes and drug targets for schizophrenia. The crucial point for the identification of a significant biologic marker(s) will include not only the experimental validation of the genes involved in the neurotransmitter signaling systems, but also the availability of large exactly comparable phenotyped patients samples. Coupling our knowledge of genetic polymorphisms with clinical response data promises a bright future for rapid advances in personalized medicine.
Pharmacogenomics 02/2006; 7(1):31-47. · 3.97 Impact Factor
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ABSTRACT: Quantitative variation in gene expression has been proposed to underlie phenotypic variation among human individuals. A facilitating step towards understanding the basis for gene expression variability is associating genome wide transcription patterns with potential cis modifiers of gene expression.
EXPOLDB, a novel Database, is a new effort addressing this need by providing information on gene expression levels variability across individuals, as well as the presence and features of potentially polymorphic (TG/CA)n repeats. EXPOLDB thus enables associating transcription levels with the presence and length of (TG/CA)n repeats. One of the unique features of this database is the display of expression data for 5 pairs of monozygotic twins, which allows identification of genes whose variability in expression, are influenced by non-genetic factors including environment. In addition to queries by gene name, EXPOLDB allows for queries by a pathway name. Users can also upload their list of HGNC (HUGO (The Human Genome Organisation) Gene Nomenclature Committee) symbols for interrogating expression patterns. The online application 'SimRep' can be used to find simple repeats in a given nucleotide sequence. To help illustrate primary applications, case examples of Housekeeping genes and the RUNX gene family, as well as one example of glycolytic pathway genes are provided.
The uniqueness of EXPOLDB is in facilitating the association of genome wide transcription variations with the presence and type of polymorphic repeats while offering the feature for identifying genes whose expression variability are influenced by non genetic factors including environment. In addition, the database allows comprehensive querying including functional information on biochemical pathways of the human genes. EXPOLDB can be accessed at http://expoldb.igib.res.in/expol.
BMC Genomics 02/2006; 7:258. · 4.07 Impact Factor
