Biomedical subjects

Razvan Sultana

Publications and source records attributed to Razvan Sultana.

12 recordsLinked to original sources

PubMed2026

CanVar-UK: A collaborative platform for germline interpretation in cancer susceptibility genes.

Germline variants in cancer susceptibility genes (CSGs) are typically inherited rather than arising de novo. Hence, wide cascade testing of families across geographies is common, meaning consistency in variant classification is particularly critical. Variant interpretation requires collation of variant-level data from diverse sources, as well as assembly of comprehensive clinical data, often necessitating sharing of information between genomic testing centers. Here, we describe CanVar-UK, a freely accessible web platform bespoke designed to support interpretation of germline CSG variants. CanVar-UK contains variant-level data for over 1.1 million single-nucleotide variants (SNVs), comprising all possible coding SNVs in 116 established CSGs. The data sources with which variants are annotated include in silico scores from 11 clinically relevant tools, population allele frequencies from gnomAD v4.1, case counts from multiple cohorts, including National Health Service (NHS) clinical laboratory testing, variant-level readouts from 47 selected functional and splicing datasets across 19 CSGs, genetic epidemiology studies, and live linkage to existing consensus classifications in the ClinVar database. The diagnostic discussion forum is only available to registered diagnostic scientist users. Through this, a variant-tagged email message can be dispatched in real time across the diagnostic forum community of >1,500 users, with all exchanges and classifications captured and stored in the platform. Already widely used by NHS diagnostic clinical scientists in the UK, CanVar-UK has a rapidly growing international diagnostic user base (>800 UK and >600 non-UK registered users). Survey of the NHS diagnostic user community illustrates the wide-ranging utility of CanVar-UK within their clinical workflows for interpretation of germline CSG variants.

Journal Article↗

PubMed2006

Physiogenomic resources for rat models of heart, lung and blood disorders.

Cardiovascular disorders are influenced by genetic and environmental factors. The TIGR rodent expression web-based resource (TREX) contains over 2,200 microarray hybridizations, involving over 800 animals from 18 different rat strains. These strains comprise genetically diverse parental animals and a panel of chromosomal substitution strains derived by introgressing individual chromosomes from normotensive Brown Norway (BN/NHsdMcwi) rats into the background of Dahl salt sensitive (SS/JrHsdMcwi) rats. The profiles document gene-expression changes in both genders, four tissues (heart, lung, liver, kidney) and two environmental conditions (normoxia, hypoxia). This translates into almost 400 high-quality direct comparisons (not including replicates) and over 100,000 pairwise comparisons. As each individual chromosomal substitution strain represents on average less than a 5% change from the parental genome, consomic strains provide a useful mechanism to dissect complex traits and identify causative genes. We performed a variety of data-mining manipulations on the profiles and used complementary physiological data from the PhysGen resource to demonstrate how TREX can be used by the cardiovascular community for hypothesis generation.

Animals↗

PubMed2005

Transcriptional profiling with a blood pressure QTL interval-specific oligonucleotide array.

Although the evidence for a genetic predisposition to human essential hypertension is compelling, the genetic control of blood pressure (BP) is poorly understood. The Dahl salt-sensitive (S) rat is a model for studying the genetic component of BP. Using this model, we previously reported the identification of 16 different genomic regions that contain one or more BP quantitative trait loci (QTLs). The proximal region of rat chromosome 1 contains multiple BP QTLs. Of these, we have localized the BP QTL1b region to a 13.5-cM (20.92 Mb) region. Interestingly, five additional independent studies in rats and four independent studies in humans have reported genetic linkage for BP control by regions homologous to QTL1b. To view the overall renal transcriptional topography of the positional candidate genes for this QTL, we sought a comparative gene expression profiling between a congenic strain containing QTL1b and control S rats by employing 1) a saturated QTL1b interval-specific oligonucleotide array and 2) a whole genome cDNA microarray representing 20,465 unique genes that are positioned outside the QTL. Results indicated that 17 of the 231 positional candidate genes for this QTL are differentially expressed between the two strains tested. Surprisingly, >1,500 genes outside of QTL1b were differentially expressed between the two rat strains. Integrating the results from the two approaches revealed at least one complex network of transcriptional control initiated by the positional candidate Nr2f2. This network appears to account for the majority of gene expression differences occurring outside of the QTL interval. Further substitution mapping is currently underway to test the validity of each of these differentially expressed positional candidate genes. These results demonstrate the importance of using a saturated oligonucleotide array for identifying and prioritizing differentially expressed positional candidate genes of a BP QTL.

Animals↗

PubMed2005

Independence and reproducibility across microarray platforms.

Microarrays have been widely used for the analysis of gene expression, but the issue of reproducibility across platforms has yet to be fully resolved. To address this apparent problem, we compared gene expression between two microarray platforms: the short oligonucleotide Affymetrix Mouse Genome 430 2.0 GeneChip and a spotted cDNA array using a mouse model of angiotensin II-induced hypertension. RNA extracted from treated mice was analyzed using Affymetrix and cDNA platforms and then by quantitative RT-PCR (qRT-PCR) for validation of specific genes. For the 11,710 genes present on both arrays, we assessed the relative impact of experimental treatment and platform on measured expression and found that biological treatment had a far greater impact on measured expression than did platform for more than 90% of genes, a result validated by qRT-PCR. In the small number of cases in which platforms yielded discrepant results, qRT-PCR generally did not confirm either set of data, suggesting that sequence-specific effects may make expression predictions difficult to make using any technique.

Angiotensin II↗

PubMed2005

The institute for genomic research Osa1 rice genome annotation database.

We have developed a rice (Oryza sativa) genome annotation database (Osa1) that provides structural and functional annotation for this emerging model species. Using the sequence of O. sativa subsp. japonica cv Nipponbare from the International Rice Genome Sequencing Project, pseudomolecules, or virtual contigs, of the 12 rice chromosomes were constructed. Our most recent release, version 3, represents our third build of the pseudomolecules and is composed of 98% finished sequence. Genes were identified using a series of computational methods developed for Arabidopsis (Arabidopsis thaliana) that were modified for use with the rice genome. In release 3 of our annotation, we identified 57,915 genes, of which 14,196 are related to transposable elements. Of these 43,719 non-transposable element-related genes, 18,545 (42.4%) were annotated with a putative function, 5,777 (13.2%) were annotated as encoding an expressed protein with no known function, and the remaining 19,397 (44.4%) were annotated as encoding a hypothetical protein. Multiple splice forms (5,873) were detected for 2,538 genes, resulting in a total of 61,250 gene models in the rice genome. We incorporated experimental evidence into 18,252 gene models to improve the quality of the structural annotation. A series of functional data types has been annotated for the rice genome that includes alignment with genetic markers, assignment of gene ontologies, identification of flanking sequence tags, alignment with homologs from related species, and syntenic mapping with other cereal species. All structural and functional annotation data are available through interactive search and display windows as well as through download of flat files. To integrate the data with other genome projects, the annotation data are available through a Distributed Annotation System and a Genome Browser. All data can be obtained through the project Web pages at http://rice.tigr.org.

Computational Biology↗

PubMed2003

TIGR Gene Indices clustering tools (TGICL): a software system for fast clustering of large EST datasets.

TGICL is a pipeline for analysis of large Expressed Sequence Tags (EST) and mRNA databases in which the sequences are first clustered based on pairwise sequence similarity, and then assembled by individual clusters (optionally with quality values) to produce longer, more complete consensus sequences. The system can run on multi-CPU architectures including SMP and PVM.

Cluster Analysis↗

PubMed2003

The TIGR rice genome annotation resource: annotating the rice genome and creating resources for plant biologists.

Rice is not only a major food staple for the world's population but it also is a model species for a major group of flowering plants, the monocotyledonous plants. Draft genomic sequence of two subspecies of rice, Oryza sativa spp. japonica and indica ssp. are publicly available. To provide the community with a resource to data-mine the rice genome, we have constructed an annotation resource for rice (http://www.tigr.org/tdb/e2k1/osa1/). In this resource, we have annotated the rice genome for gene content, identified motifs/domains within the predicted genes, constructed a rice repeat database, identified related sequences in other plant species, and identified syntenic sequences between rice and maize. All of the data is available through web-based interfaces, FTP downloads, and a Distributed Annotation System.

Chromosomes, Artificial↗

PubMed2003

Continued discovery of transcriptional units expressed in cells of the mouse mononuclear phagocyte lineage.

The current RIKEN transcript set represents a significant proportion of the mouse transcriptome but transcripts expressed in the innate and acquired immune systems are poorly represented. In the present study we have assessed the complexity of the transcriptome expressed in mouse macrophages before and after treatment with lipopolysaccharide, a global regulator of macrophage gene expression, using existing RIKEN 19K arrays. By comparison to array profiles of other cells and tissues, we identify a large set of macrophage-enriched genes, many of which have obvious functions in endocytosis and phagocytosis. In addition, a significant number of LPS-inducible genes were identified. The data suggest that macrophages are a complex source of mRNA for transcriptome studies. To assess complexity and identify additional macrophage expressed genes, cDNA libraries were created from purified populations of macrophage and dendritic cells, a functionally related cell type. Sequence analysis revealed a high incidence of novel mRNAs within these cDNA libraries. These studies provide insights into the depths of transcriptional complexity still untapped amongst products of inducible genes, and identify macrophage and dendritic cell populations as a starting point for sampling the inducible mammalian transcriptome.

Animals↗

PubMed2003

Comparative analyses of potato expressed sequence tag libraries.

The cultivated potato (Solanum tuberosum) shares similar biology with other members of the Solanaceae, yet has features unique within the family, such as modified stems (stolons) that develop into edible tubers. To better understand potato biology, we have undertaken a survey of the potato transcriptome using expressed sequence tags (ESTs) from diverse tissues. A total of 61,940 ESTs were generated from aerial tissues, below-ground tissues, and tissues challenged with the late-blight pathogen (Phytophthora infestans). Clustering and assembly of these ESTs resulted in a total of 19,892 unique sequences with 8,741 tentative consensus sequences and 11,151 singleton ESTs. We were able to identify a putative function for 43.7% of these sequences. A number of sequences (48) were expressed throughout the libraries sampled, representing constitutively expressed sequences. Other sequences (13,068, 21%) were uniquely expressed and were detected only in a single library. Using hierarchal and k means clustering of the EST sequences, we were able to correlate changes in gene expression with major physiological events in potato biology. Using pair-wise comparisons of tuber-related tissues, we were able to associate genes with tuber initiation, dormancy, and sprouting. We also were able to identify a number of characterized as well as novel sequences that were unique to the incompatible interaction of late-blight pathogen, thereby providing a foundation for further understanding the mechanism of resistance.

Cluster Analysis↗

PubMed2002

Porcine gene discovery by normalized cDNA-library sequencing and EST cluster assembly.

Genetic and environmental factors affect the efficiency of pork production by influencing gene expression during porcine reproduction, tissue development, and growth. The identification and functional analysis of gene products important to these processes would be greatly enhanced by the development of a database of expressed porcine gene sequence. Two normalized porcine cDNA libraries (MARC 1PIG and MARC 2PIG), derived respectively from embryonic and reproductive tissues, were constructed, sequenced, and analyzed. A total of 66,245 clones from these two libraries were 5?-end sequenced and deposited in GenBank. Cluster analysis revealed that within-library redundancy is low, and comparison of all porcine ESTs with the human database suggests that the sequences from these two libraries represent portions of a significant number of independent pig genes. A Porcine Gene Index (PGI), comprising 15,616 tentative consensus sequences and 31,466 singletons, includes all sequences in public repositories and has been developed to facilitate further comparative map development and characterization of porcine genes (http://www.tigr.org/tdb/ssgi/). The clones and sequences from these libraries provide a catalog of expressed porcine genes and a resource for development of high-density hybridization arrays for transcriptional profiling of porcine tissues. In addition, comparison of porcine ESTs with sequences from other species serves as a valuable resource for comparative map development. Both arrayed cDNA libraries are available for unrestricted public use.

Animals↗

PubMed2002

Analysis of bovine mammary gland EST and functional annotation of the Bos taurus gene index.

Functional genomic studies of the mammary gland require an appropriate collection of cDNA sequences to assess gene expression patterns from the different developmental and operational states of underlying cell types. To better capture the range of gene expression, a normalized cDNA library was constructed from pooled bovine mammary tissues, and 23,202 expressed sequence tags (EST) were produced and deposited into GenBank. Assembly of these EST with sequences in the Bos taurus Gene Index (BtGI) helped to form 5751 of the current 23,883 tentative consensus (TC) sequences. The majority (87%) of these 5751 assemblies contained only one to three mammary-derived EST. In contrast, 18% of the mammary EST assembled with TC sequences corresponding to 12 genes. These results suggest library normalization was only partially effective, because the reduction in EST for genes abundantly transcribed during lactation could be attributed to pooling. For better assessment of novel content in the mammary library and to add to existing annotation of all bovine sequence elements, gene ontology assignments, and comparative sequence analyses against human genome sequence, human and rodent gene indices, and an index of orthologous alignments of genes across eukaryotes (TOGA) were performed, and results were added to existing BtGI annotation. Over 35,000 of the bovine elements significantly matched human genome sequence, and the positions of some alignments (3%) were unique relative to those using human expressed sequences. Because 3445 TC sequences had no significant match with any data set, mammary-derived cDNA clones representing 23 of these elements were analyzed further for expression and novelty. Only one clone met criteria suggesting the corresponding gene was a divergent ortholog or expressed sequence unique to cattle. These results demonstrate that bovine sequence expression data serve as a resource for characterizing mammalian transcriptomes and identifying those genes potentially unique to ruminants.

Animals↗

PubMed2002

Cross-referencing eukaryotic genomes: TIGR Orthologous Gene Alignments (TOGA).

Comparative genomics promises to rapidly accelerate the identification and functional classification of biologically important human genes. We developed the TIGR Orthologous Gene Alignment (TOGA; ) database to provide a cross-reference between fully and partially sequenced eukaryotic transcribed sequences. Starting with the assembled expressed sequence tag (EST) and gene sequences that comprise the 28 TIGR Gene Indices, we used high-stringency pair-wise sequence searches and a reflexive, transitive closure process to associate sequence-specific best hits, generating 32,652 tentative ortholog groups (TOGs). This has allowed us to identify putative orthologs and paralogs for known genes, as well as those that exist only as uncharacterized ESTs and to provide links to additional information including genome sequence and mapping data. TOGA provides an important new resource for the analysis of gene function in eukaryotes. In addition, an analysis of the most widely represented sequences can begin to provide insight into eukaryotic biological processes.

Algorithms↗