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Doron Lancet

Publications and source records attributed to Doron Lancet.

At least 37 records · Page 2Linked to original sources
PubMed2004

Genome-wide midrange transcription profiles reveal expression level relationships in human tissue specification.

MOTIVATION: Genes are often characterized dichotomously as either housekeeping or single-tissue specific. We conjectured that crucial functional information resides in genes with midrange profiles of expression. RESULTS: To obtain such novel information genome-wide, we have determined the mRNA expression levels for one of the largest hitherto analyzed set of 62 839 probesets in 12 representative normal human tissues. Indeed, when using a newly defined graded tissue specificity index tau, valued between 0 for housekeeping genes and 1 for tissue-specific genes, genes with midrange profiles having 0.15< tau<0.85 were found to constitute >50% of all expression patterns. We developed a binary classification, indicating for every gene the I(B) tissues in which it is overly expressed, and the 12-I(B) tissues in which it shows low expression. The 85 dominant midrange patterns with I(B)=2-11 were found to be bimodally distributed, and to contribute most significantly to the definition of tissue specification dendrograms. Our analyses provide a novel route to infer expression profiles for presumed ancestral nodes in the tissue dendrogram. Such definition has uncovered an unsuspected correlation, whereby de novo enhancement and diminution of gene expression go hand in hand. These findings highlight the importance of gene suppression events, with implications to the course of tissue specification in ontogeny and phylogeny. AVAILABILITY: All data and analyses are publically available at the GeneNote website, http://genecards.weizmann.ac.il/genenote/ and, GEO accession GSE803. CONTACT: doron.lancet@weizmann.ac.il SUPPLEMENTARY INFORMATION: Four tables available at the above site.

Algorithms↗
PubMed2004

Is the G72/G30 locus associated with schizophrenia? single nucleotide polymorphisms, haplotypes, and gene expression analysis.

BACKGROUND: The genes G72/G30 were recently implicated in schizophrenia in both Canadian and Russian populations. We hypothesized that 1) polymorphic changes in this gene region might be associated with schizophrenia in the Ashkenazi Jewish population and that 2) changes in G72/G30 gene expression might be expected in schizophrenic patients compared with control subjects. METHODS: Eleven single nucleotide polymorphisms (SNPs) encompassing the G72/G30 genes were typed in the genomic deoxyribonucleic acid (DNA) from 60 schizophrenic patients and 130 matched control subjects of Ashkenazi ethnic origin. Case-control comparisons were based on linkage disequilibrium (LD) and haplotype frequency estimations. Gene expression analysis of G72 and G30 was performed on 88 postmortem dorsolateral prefrontal cortex samples. RESULTS: Linkage disequilibrium analysis revealed two main SNP blocks. Haplotype analysis on block II, containing three SNPs external to the genes, demonstrated an association with schizophrenia. Gene expression analysis exhibited correlations between expression levels of the G72 and G30 genes, as well as a tendency toward overexpression of the G72 gene in schizophrenic brain samples of 44 schizophrenic patients compared with 44 control subjects. CONCLUSIONS: It is likely that the G72/G30 region is involved in susceptibility to schizophrenia in the Ashkenazi population. The elevation in expression of the G72 gene coincides with the glutamatergic theory of schizophrenia.

Adolescent↗
PubMed2004

GeneAnnot: comprehensive two-way linking between oligonucleotide array probesets and GeneCards genes.

MOTIVATION: High density oligonucleotide arrays are usually annotated in a one-to-one fashion, with each probeset assigned to one gene. However, in reality, subsets of oligonucleotides in a probeset may match sequences within more than one gene, potentially leading to misinterpretations. Moreover, a gene is often represented by more than one probeset, and analyzing probe matches at the mRNA level can help one deduce whether these probesets are derived from the same or different splice variants. RESULTS: The GeneAnnot system comprehensively documents the many-to-many relationship between oligonucleotide array probesets and annotated genes in GeneCards. It performs pairwise alignments between the probe sequences and gene transcripts, and assigns sensitivity and specificity scores to each probeset/gene pair. AVAILABILITY: http://genecards.weizmann.ac.il/geneannot/ SUPPLEMENTARY INFORMATION: Program description and statistics http://genecards.weizmann.ac.il/geneannot/DOC/index.html

Algorithms↗
PubMed2004

Loss of olfactory receptor genes coincides with the acquisition of full trichromatic vision in primates.

Olfactory receptor (OR) genes constitute the molecular basis for the sense of smell and are encoded by the largest gene family in mammalian genomes. Previous studies suggested that the proportion of pseudogenes in the OR gene family is significantly larger in humans than in other apes and significantly larger in apes than in the mouse. To investigate the process of degeneration of the olfactory repertoire in primates, we estimated the proportion of OR pseudogenes in 19 primate species by surveying randomly chosen subsets of 100 OR genes from each species. We find that apes, Old World monkeys and one New World monkey, the howler monkey, have a significantly higher proportion of OR pseudogenes than do other New World monkeys or the lemur (a prosimian). Strikingly, the howler monkey is also the only New World monkey to possess full trichromatic vision, along with Old World monkeys and apes. Our findings suggest that the deterioration of the olfactory repertoire occurred concomitant with the acquisition of full trichromatic color vision in primates.

Alouatta↗
PubMed2004

Probability rule for chiral recognition.

Molecular Chirality is of central interest in biological studies because enantiomeric compounds, while indistinguishable by most inanimate systems, show profoundly different properties in biochemical environments. Enantioselective separation methods, based on the differential recognition of two optical isomers by a chiral selector, have been amply documented. Also, great effort has been directed towards a theoretical understanding of the fundamental mechanisms underlying the chiral recognition process. Here we report a comprehensive data examination of enantio separation measurements for over 72000 chiral selector-select and pairs from the chiral selection compendium CHIRBASE. The distribution of alpha = k'(D)/k'(L) values was found to follow a power law, equivalent to an exponential decay for chiral differential free energies. This observation is experimentally relevant in terms of the number of different individual or combinatorial selectors that need to be screened in order to observe alpha values higher than a preset minimum. A string model for enantiorecognition (SMED) formalism is proposed to account for this observation on the basis of an extended Ogston three-point interaction model. Partially overlapping molecular interaction domains are analyzed in terms of a string complementarity model for ligand-receptor complementarity. The results suggest that chiral selection statistics may be interpreted in terms of more general concepts related to biomolecular recognition.

Algorithms↗
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↗
PubMed2004

Prospects of a computational origin of life endeavor.

While the last century brought an exquisite understanding of the molecular basis of life, very little is known about the detailed chemical mechanisms that afforded the emergence of life on early earth. There is a broad agreement that the problem lies in the realm of chemistry, and likely resides in the formation and mutual interactions of carbon-based molecules in aqueous medium. Yet, present-day experimental approaches can only capture the synthesis and behavior of a few molecule types at a time. On the other hand, experimental simulations of prebiotic syntheses, as well as chemical analyses of carbonaceous meteorites, suggest that the early prebiotic hydrosphere contained many thousands of different compounds. The present paper explores the idea that given the limitations of test-tube approaches with regards to such a 'random chemistry' scenario, an alternative mode of analysis should be pursued. It is argued that as computational tools for the reconstruction of molecular interactions improve rapidly, it may soon become possible to perform adequate computer-based simulations of prebiotic evolution. We thus propose to launch a computational origin of life endeavor (http://ool.weizmann.ac.il/CORE), involving computer simulations of realistic complex prebiotic chemical networks. In the present paper we provide specific examples, based on a novel algorithmic approach, which constitutes a hybrid of molecular dynamics and stochastic chemistry. As one potential solution for the immense hardware requirements dictated by this approach, we have begun to implement an idle CPU harvesting scheme, under the title ool@home.

Computational Biology↗
PubMed2004

Prediction of the odorant binding site of olfactory receptor proteins by human-mouse comparisons.

Olfactory receptors (ORs) are a large family of proteins involved in the recognition and discrimination of numerous odorants. These receptors belong to the G-protein coupled receptor (GPCR) hyperfamily, for which little structural data are available. In this study we predict the binding site residues of OR proteins by analyzing a set of 1441 OR protein sequences from mouse and human. The central insight utilized is that functional contact residues would be conserved among pairs of orthologous receptors, but considerably less conserved among paralogous pairs. Using judiciously selected subsets of 218 ortholog pairs and 518 paralog pairs, we have identified 22 sequence positions that are both highly conserved among the putative orthologs and variable among paralogs. These residues are disposed on transmembrane helices 2 to 7, and on the second extracellular loop of the receptor. Strikingly, although the prediction makes no assumption about the location of the binding site, these amino acid positions are clustered around a pocket in a structural homology model of ORs, mostly facing the inner lumen. We propose that the identified positions constitute the odorant binding site. This conclusion is supported by the observation that all but one of the predicted binding site residues correspond to ligand-contact positions in other rhodopsin-like GPCRs.

Amino Acid Sequence↗
PubMed2003

Natural selection on the olfactory receptor gene family in humans and chimpanzees.

The olfactory receptor (OR) genes constitute the largest gene family in mammalian genomes. Humans have >1,000 OR genes, of which only approximately 40% have an intact coding region and are therefore putatively functional. In contrast, the fraction of intact OR genes in the genomes of the great apes is significantly greater (68%-72%), suggesting that selective pressures on the OR repertoire vary among these species. We have examined the evolutionary forces that shaped the OR gene family in humans and chimpanzees by resequencing 20 OR genes in 16 humans, 16 chimpanzees, and one orangutan. We compared the variation at the OR genes with that at intergenic regions. In both humans and chimpanzees, OR pseudogenes seem to evolve neutrally. In chimpanzees, patterns of variability are consistent with purifying selection acting on intact OR genes, whereas, in humans, there is suggestive evidence for positive selection acting on intact OR genes. These observations are likely due to differences in lifestyle, between humans and great apes, that have led to distinct sensory needs.

Animals↗
PubMed2003

Human specific loss of olfactory receptor genes.

Olfactory receptor (OR) genes constitute the basis for the sense of smell and are encoded by the largest mammalian gene superfamily of >1,000 genes. In humans, >60% of these are pseudogenes. In contrast, the mouse OR repertoire, although of roughly equal size, contains only approximately 20% pseudogenes. We asked whether the high fraction of nonfunctional OR genes is specific to humans or is a common feature of all primates. To this end, we have compared the sequences of 50 human OR coding regions, regardless of their functional annotations, to those of their putative orthologs in chimpanzees, gorillas, orangutans, and rhesus macaques. We found that humans have accumulated mutations that disrupt OR coding regions roughly 4-fold faster than any other species sampled. As a consequence, the fraction of OR pseudogenes in humans is almost twice as high as in the non-human primates, suggesting a human-specific process of OR gene disruption, likely due to a reduced chemosensory dependence relative to apes.

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↗
PubMed2003

Different noses for different people.

Of more than 1,000 human olfactory receptor genes, more than half seem to be pseudogenes. We investigated whether the most recent of these disruptions might still segregate with the intact form by genotyping 51 candidate genes in 189 ethnically diverse humans. The results show an unprecedented prevalence of segregating pseudogenes, identifying one of the most pronounced cases of functional population diversity in the human genome.

Animals↗
PubMed2003

CATSPER2, a human autosomal nonsyndromic male infertility gene.

In the course of positional cloning of the Congenital Dyserythropoietic Anemia type I (CDAI) [MIM 224120] gene on 15q15.1-15.3, we examined a family of French origin, in which the propositus suffered from asthenoteratozoospermia and nonsyndromic deafness in addition to CDAI. Two of his brothers had a similar phenotype. All three siblings were homozygous carriers of the CDA1 mutation as well as of a distally located approximately 70 kb deletion of the proximal copy of a 106 kb tandem repeat on chromosome 15q15. These repeats encode four genes whose distal copies may be considered pseudogenes. Lack of functional stereocilin and CATSPER2 (a voltage-gate cation channel expressed specifically in spermatozoa) may explain the observed deafness and male infertility phenotypes. To the best of our knowledge, the involvement of CATSPER2 in asthenoteratozoospermia is the first description of a human autosomal gene defect associated with nonsyndromic male infertility.

Anemia, Dyserythropoietic, Congenital↗
PubMed2003

GeneAnnot: interfacing GeneCards with high-throughput gene expression compendia.

The interpretation of microarray expression results often includes extensive efforts to identify and annotate the gene representatives immobilised on the arrays. In this paper we describe the usage of our automatic GeneAnnot system, which links between Affymetrix arrays and the rich human gene annotations available in GeneCards. We explain GeneCards search options and results display; elaborate on the presentation of expression information in GeneCards, including both our whole-genome GeneNote project and external expression resources; describe the various parameters and displays used by GeneAnnot to assess the annotation quality and probeset specificity; and show how to search GeneAnnot and GeneNote websites directly.

Data Interpretation, Statistical↗