Biomedical subjects

Tsviya Olender

Publications and source records attributed to Tsviya Olender.

9 recordsLinked to original sources

PubMed2006

Ancient genomic architecture for mammalian olfactory receptor clusters.

BACKGROUND: Mammalian olfactory receptor (OR) genes reside in numerous genomic clusters of up to several dozen genes. Whole-genome sequence alignment nets of five mammals allow their comprehensive comparison, aimed at reconstructing the ancestral olfactory subgenome. RESULTS: We developed a new and general tool for genome-wide definition of genomic gene clusters conserved in multiple species. Syntenic orthologs, defined as gene pairs showing conservation of both genomic location and coding sequence, were subjected to a graph theory algorithm for discovering CLICs (clusters in conservation). When applied to ORs in five mammals, including the marsupial opossum, more than 90% of the OR genes were found within a framework of 48 multi-species CLICs, invoking a general conservation of gene order and composition. A detailed analysis of individual CLICs revealed multiple differences among species, interpretable through species-specific genomic rearrangements and reflecting complex mammalian evolutionary dynamics. One significant instance involves CLIC #1, which lacks a human member, implying the human-specific deletion of an OR cluster, whose mouse counterpart has been tentatively associated with isovaleric acid odorant detection. CONCLUSION: The identified multi-species CLICs demonstrate that most of the mammalian OR clusters have a common ancestry, preceding the split between marsupials and placental mammals. However, only two of these CLICs were capable of incorporating chicken OR genes, parsimoniously implying that all other CLICs emerged subsequent to the avian-mammalian divergence.

Animals↗

PubMed2006

Association of the dopamine receptor interacting protein gene, NEF3, with early response to antipsychotic medication.

Genetic variation in antipsychotic drug targets could underlie variability among patients in the time required for antipsychotic effects to be elicited. In a clinical, pharmacogenetic study we focused on the dopamine receptor interacting protein (DRIP) gene family. DRIPs are pivotally involved in regulating dopamine receptor signal transduction. Consecutively hospitalized, acutely psychotic patients with DSM-IV schizophrenia (n=121) were included in the study if they received treatment with typical antipsychotic medication (TYP, n=72) or TYP plus risperidone (TYP-R, n=49) for at least 2 wk. Clinical state and adverse effects were rated at baseline and after 2 wk. Patients improved significantly on both TYP and TYP-R with no significant difference between them. Early responders were defined as patients whose PANSS change scores were greater than the median. Twenty-two single nucleotide polymorphisms (SNPs) were analysed in five DRIP-encoding genes. Two SNPs in NEF3, which encodes the DRIP, neurofilament-medium (NF-M), were associated with early response (rs1457266, p=0.01; rs1379357, p=0.006). A 5 SNP haplotype spanning NEF3 was over-represented in early responders (p=0.015), in the combined patient group and in the TYP group alone. These findings suggest that variation in NEF3, most likely functional variants that are in linkage disequilibrium with the SNPs that we studied, influences rate of response to TYP. Since NEF3 is primarily associated with dopamine D1 receptor function, the evidence for a complementary role of dopamine D1 receptors in antipsychotic effects is considered. The findings reported here open an interesting research avenue in the pharmacogenetics of antipsychotic effects but require replication in larger samples treated in a controlled context.

Acute Disease↗

PubMed2006

Widespread ectopic expression of olfactory receptor genes.

BACKGROUND: Olfactory receptors (ORs) are the largest gene family in the human genome. Although they are expected to be expressed specifically in olfactory tissues, some ectopic expression has been reported, with special emphasis on sperm and testis. The present study systematically explores the expression patterns of OR genes in a large number of tissues and assesses the potential functional implication of such ectopic expression. RESULTS: We analyzed the expression of hundreds of human and mouse OR transcripts, via EST and microarray data, in several dozens of human and mouse tissues. Different tissues had specific, relatively small OR gene subsets which had particularly high expression levels. In testis, average expression was not particularly high, and very few highly expressed genes were found, none corresponding to ORs previously implicated in sperm chemotaxis. Higher expression levels were more common for genes with a non-OR genomic neighbor. Importantly, no correlation in expression levels was detected for human-mouse orthologous pairs. Also, no significant difference in expression levels was seen between intact and pseudogenized ORs, except for the pseudogenes of subfamily 7E which has undergone a human-specific expansion. CONCLUSION: The OR superfamily as a whole, show widespread, locus-dependent and heterogeneous expression, in agreement with a neutral or near neutral evolutionary model for transcription control. These results cannot reject the possibility that small OR subsets might play functional roles in different tissues, however considerable care should be exerted when offering a functional interpretation for ectopic OR expression based only on transcription information.

Animals↗

PubMed2004

The olfactory receptor universe--from whole genome analysis to structure and evolution.

Olfactory receptors (ORs) constitute the largest gene-family in the vertebrate genome. We have attempted to provide a comprehensive view of the OR universe through diverse tools of bioinformatics and computational biology. Among others, we have constructed the Human Olfactory Receptor Data Exploratorium (HORDE, http://bioportal.weizmann.ac.il/HORDE/) as a free online resource, which integrates information on ORs from different species. We studied the genomic organization of 853 human ORs and divided the repertoire into 135 clusters, accessible through our new cluster viewer feature. An analysis of intact and pseudogenized ORs in different clusters, as well as of OR expression patterns, is provided, relevant to OR transcription control. Coding single nucleotide polymorphisms were integrated; these are to be used for genotype-phenotype correlation studies. HORDE allows a unique opportunity for discerning protein structural and functional information of the individual OR proteins. By applying novel data analysis strategies to the >3000 OR genes of mouse, dog and human within HORDE, we have generated a set of refined rhodopsin-based homology models for ORs. For model improvement, we employed a novel analysis of specific positions along the seven transmembrane helices at which prolines generate helix-breaking kinks. The model shows family-specific structural features, including idiosyncratic kink patterns, which lead to significant differences in the inferred odorant binding site structure. Such analyses form a basis for a comprehensive sequence-based classification of OR proteins in terms of potential odorant binding specificities.

Amino Acid Sequence↗

PubMed2004

The canine olfactory subgenome.

We identified 971 olfactory receptor (OR) genes in the dog genome, estimated to constitute approximately 80% of the canine OR repertoire. This was achieved by directed genomic DNA cloning of olfactory sequence tags as well as by mining the Celera canine genome sequences. The dog OR subgenome is estimated to have 12% pseudogenes, suggesting a functional repertoire similar to that of mouse and considerably larger than for humans. No novel OR families were discovered, but as many as 34 gene subfamilies were unique to the dog. "Fish-like" Class I ancient ORs constituted 18% of the repertoire, significantly more than in human and mouse. A set of 122 dog-human-mouse ortholog triplets was identified, with a relatively high fraction of Class I ORs. The elucidation of a large portion of the canine olfactory receptor gene superfamily, with some dog-specific attributes, may help us understand the unique chemosensory capacities of this species.

Animals↗

PubMed2003

Human Gene-Centric Databases at the Weizmann Institute of Science: GeneCards, UDB, CroW 21 and HORDE.

Recent enhancements and current research in the GeneCards (GC) (http://bioinfo.weizmann.ac.il/cards/) project are described, including the addition of gene expression profiles and integrated gene locations. Also highlighted are the contributions of specialized associated human gene-centric databases developed at the Weizmann Institute. These include the Unified Database (UDB) (http://bioinfo.weizmann.ac.il/udb) for human genome mapping, the human Chromosome 21 database at the Weizmann Insti-tute (CroW 21) (http://bioinfo.weizmann.ac.il/crow21), and the Human Olfactory Receptor Data Explora-torium (HORDE) (http://bioinfo.weizmann.ac.il/HORDE). The synergistic relationships amongst these efforts have positively impacted the quality, quantity and usefulness of the GeneCards gene compendium.

Algorithms↗

PubMed2003

From subgenome analysis to protein structure.

Groups of related genes abound in large eukaryotic genomes. In such 'subgenomes', homology modeling carried out for a few genes will probably have relevance to the entire group. Subgenomes also afford unique ways of determining protein structural information. In addition to analyses based on the quantification of residue variability in paralogs, two-way comparisons, both within and among species, help to disclose functional amino acids. Comparative studies of gene families throughout the mammalian genome will also help elucidate the functional significance of single nucleotide polymorphisms in coding regions.

Animals↗

PubMed2002

USH3A transcripts encode clarin-1, a four-transmembrane-domain protein with a possible role in sensory synapses.

Usher syndrome type 3 (USH3) is an autosomal recessive disorder characterised by the association of post-lingual progressive hearing loss, progressive visual loss due to retinitis pigmentosa and variable presence of vestibular dysfunction. Because the previously defined transcripts do not account for all USH3 cases, we performed further analysis and revealed the presence of additional exons embedded in longer human and mouse USH3A transcripts and three novel USH3A mutations. Expression of Ush3a transcripts was localised by whole mount in situ hybridisation to cochlear hair cells and spiral ganglion cells. The full length USH3A transcript encodes clarin-1, a four-transmembrane-domain protein, which defines a novel vertebrate-specific family of three paralogues. Limited sequence homology to stargazin, a cerebellar synapse four-transmembrane-domain protein, suggests a role for clarin-1 in hair cell and photoreceptor cell synapses, as well as a common pathophysiological pathway for different Usher syndromes.

Amino Acid Sequence↗

PubMed2002

GeneCards 2002: towards a complete, object-oriented, human gene compendium.

MOTIVATION: In the post-genomic era, functional analysis of genes requires a sophisticated interdisciplinary arsenal. Comprehensive resources are challenged to provide consistently improving, state-of-the-art tools. RESULTS: GeneCards (Rebhan et al., 1998) has made innovative strides: (a). regular updates and enhancements incorporating new genes enriched with sequences, genomic locations, cDNA assemblies, orthologies, medical information, 3D protein structures, gene expression, and focused SNP summaries; (b). restructured software using object-oriented Perl, migration to schema-driven XML, and (c). pilot studies, introducing methods to produce cards for novel and predicted genes.

Algorithms↗