Biomedical subjects

Tal Dagan

Publications and source records attributed to Tal Dagan.

10 recordsLinked to original sources

PubMed2025

SegMantX: A Novel Tool for Detecting DNA Duplications Uncovers Prevalent Duplications in Plasmids.

Segmental duplications play an important role in genome evolution via their contribution to copy-number variation, gene-family diversification, and the emergence of novel functions. The detection of segmental duplications is challenging due to heterogeneous amelioration of sequence similarity among duplicates, which hinders the reconstruction of continuous sequence alignment. Here we introduce SegMantX, a novel approach for the identification of diverged segmental duplications in prokaryote genomes using local alignment chaining. In this approach, local alignments resulting from a preliminary sequence similarity search (e.g. BLASTn) are chained into continuous segments. Evaluating the performance of SegMantX using simulated sequences shows that the tool can detect diverged duplications beyond the sensitivity limits of standard alignment-based methods. Applying SegMantX to 6,784 enterobacterial plasmids, we find that 65% plasmids contain duplicated regions and gene duplications, most of which correspond either to dispersed, noncoding regions or duplicated mobile genetic elements (MGEs; e.g. transposons and insertion sequences). Furthermore, we demonstrate the applicability of SegMantX for the identification of diverged gene transfers between replicons and plasmid hybridization events. Our findings highlight MGEs as drivers of segmental duplications in plasmid evolution, leading to the amplification of their cargo genes, including antibiotic resistance genes. SegMantX provides a powerful framework for reconstructing diverged segmental duplications and other alignment problems.

Plasmids↗

PubMed2005

The "domino theory" of gene death: gradual and mass gene extinction events in three lineages of obligate symbiotic bacterial pathogens.

During the adaptation of an organism to a parasitic lifestyle, various gene functions may be rendered superfluous due to the fact that the host may supply these needs. As a consequence, obligate symbiotic bacterial pathogens tend to undergo reductive genomic evolution through gene death (nonfunctionalization or pseudogenization) and deletion. Here, we examine the evolutionary sequence of gene-death events during the process of genome miniaturization in three bacterial species that have experienced extensive genome reduction: Mycobacterium leprae, Shigella flexneri, and Salmonella typhi. We infer that in all three lineages, the distribution of functional categories is similar in pseudogenes and genes but different from that of absent genes. Based on an analysis of evolutionary distances, we propose a two-step "domino effect" model for reductive genome evolution. The process starts with a gradual gene-by-gene-death sequence of events. Eventually, a crucial gene within a complex pathway or network is rendered nonfunctional triggering a "mass gene extinction" of the dependent genes. In contrast to published reports according to which genes belonging to certain functional categories are prone to nonfunctionalization more frequently and earlier than genes belonging to other functional categories, we could discern no characteristic regularity in the temporal order of function loss.

Bacteria↗

PubMed2005

GC composition of the human genome: in search of isochores.

The isochore theory, proposed nearly three decades ago, depicts the mammalian genome as a mosaic of long, fairly homogeneous genomic regions that are characterized by their guanine and cytosine (GC) content. The human genome, for instance, was claimed to consist of five distinct isochore families: L1, L2, H1, H2, and H3, with GC contents of <37%, 37%-42%, 42%-47%, 47%-52%, and >52%, respectively. In this paper, we address the question of the validity of the isochore theory through a rigorous sequence-based analysis of the human genome. Toward this end, we adopt a set of six attributes that are generally claimed to characterize isochores and statistically test their veracity against the available draft sequence of the complete human genome. By the selection criteria used in this study: distinctiveness, homogeneity, and minimal length of 300 kb, we identify 1,857 genomic segments that warrant the label "isochore." These putative isochores are nonuniformly scattered throughout the genome and cover about 41% of the human genome. We found that a four-family model of putative isochores is the most parsimonious multi-Gaussian model that can be fitted to the empirical data. These families, however, are GC poor, with mean GC contents of 35%, 38%, 41%, and 48% and do not resemble the five isochore families in the literature. Moreover, due to large overlaps among the families, it is impossible to classify genomic segments into isochore families reliably, according to compositional properties alone. These findings undermine the utility of the isochore theory and seem to indicate that the theory may have reached the limits of its usefulness as a description of genomic compositional structures.

Base Composition↗

PubMed2004

The comparative method rules! Codon volatility cannot detect positive Darwinian selection using a single genome sequence.

All established methods for detecting positive selection at the molecular level rely on comparisons between nucleotide sequences. An exceptional method that purports to detect selection on the basis of a single genomic sequence has recently been proposed. This method uses a measure called "codon volatility," defined for each codon as the ratio between the number of nonsynonymous codons that differ from the codon under study at a single nucleotide position and the number of sense codons that differ from the codon under study at a single nucleotide position. Here, we examine various properties of codon volatility and its derivatives and use simulation of evolutionary processes to determine whether they can be used to detect selective pressures. Codons for only four amino acids (glycine, leucine, arginine, and serine) show any variation in codon volatility. Thus, codon volatility is mainly a proxy for amino acid usage, rather than for codon usage, with 65% of all synonymous changes and 27% of all nonsynonymous changes being undetectable by this measure. Genes identified by the volatility method as being subject to positive selection tend to have idiosyncratic amino acid compositions (e.g., they are glycine rich or arginine poor). An additional property of codon volatility is the near zero variance of its mean expectation, which translates into overestimated statistical significance estimates, especially in the absence of corrections for multiple comparisons. A comparison with measures of selection inferred through comparative methodology reveals no relationship between the results of the two methods. Finally, we show that codon volatility can increase in the absence of positive Darwinian selection; that is, increased codon volatility is not indicative of positive selection.

Animals↗

PubMed2004

Minimal conditions for exonization of intronic sequences: 5' splice site formation in alu exons.

Alu exonization, which is an evolutionary pathway that creates primate-specific transcriptomic diversity, is a powerful tool for studying alternative-splicing regulation. Through bioinformatic analyses combined with experimental methodology, we identified the mutational changes needed to create functional 5' splice sites in Alu. We revealed a complex mechanism by which the sequence composition of the 5' splice site and its base pairing with the small nuclear RNA U1 govern alternative splicing. We show that in Alu-derived GC introns the strength of the base pairing between U1 snRNA and the 5' splice site controls the skipping/inclusion ratio of alternative splicing. Based on these findings, we identified 7810 Alus within the human genome that are prone to exonization. Mutations in these Alus may cause genetic disorders or contribute to human-specific protein diversity.

5' Untranslated Regions↗

PubMed2004

AluGene: a database of Alu elements incorporated within protein-coding genes.

Alu elements are short interspersed elements (SINEs) approximately 300 nucleotides in length. More than 1 million Alus are found in the human genome. Despite their being genetically functionless, recent findings suggest that Alu elements may have a broad evolutionary impact by affecting gene structures, protein sequences, splicing motifs and expression patterns. Because of these effects, compiling a genomic database of Alu sequences that reside within protein-coding genes seemed a useful enterprise. Presently, such data are limited since the structural and positional information on genes and Alu sequences are scattered throughout incompatible and unconnected databases. AluGene (http://Alugene.tau.ac.il/) provides easy access to a complete Alu map of the human genome, as well as Alu-associated information. The Alu elements are annotated with respect to coding region and exon/intron location. This design facilitates queries on Alu sequences, locations, as well as motifs and compositional properties via a one-stop search page.

Alu Elements↗

PubMed2004

The suprameatal approach: an alternative surgical approach to cochlear implantation.

The suprameatal approach is an alternative method for performing cochlear implantation developed in the Sheba Medical Center in 1999. This technique eliminates the need for mastoidectomy and posterior tympanotomy. The middle ear is entered through a retroauricular tympanotomy flap, and the electrode is introduced into the cochlea via a tunnel drilled in the suprameatal region superior to Henle's spine. The suprameatal approach is a simple and safe technique that does not endanger the facial nerve nor the chorda tympani. A wide exposure of the promontory enables exact determination of scala tympani and smooth introduction of the electrodes into the cochlea. This technique may also be used in malformed or ossified cochlea. Until now 140 patients were operated in our department and an additional 48 patients were operated on in the department of Otorhinolaryngology at the University of Vienna employing the suprameatal approach technique.

Adult↗

PubMed2004

Quality of life of well-differentiated thyroid carcinoma patients.

The thyroid gland is the second most common site for malignancy in the head and neck region. Quality of life (QOL) of thyroid cancer patients has not been studied directly. The QOL of long-term thyroid carcinoma patients was investigated. A standardized set of questions based on the University of Washington QOL questionnaire for head and neck cancer with specific domains associated with thyroid disease was created. This questionnaire was mailed to patients who underwent total thyroidectomy for well-differentiated cancer in the department of Otolaryngology--Head and Neck surgery at the Chaim Sheba Medical Centre in Israel between the years 1994-2000. Seventy-eight patients undergoing total thyroidectomy were identified. Forty-eight patients were excluded and 20 out of the 30 remaining patients responded to the questionnaires. Six were male and 14 female, 12 were under the age of 45 (these 12 patients were staged as stage 1). Eleven patients underwent neck dissection. General health and QOL were significantly better for the younger age group and so was the calcium balance score. General health and QOL were significantly better for patients undergoing neck dissection. The overall QOL score was 3.8 conforming with 'good' in the questionnaire. Surgery and initial radioiodine treatment scored 6.75 and 6.9 respectively in the distressing scale (0-10 range: 10 = most distressing). The highest distress was encountered during withdrawal from thyroid hormone. Women rated the importance of proper replacement therapy significantly higher than men. Global low scores were found for employment and for effective L-thyroxine replacement therapy. Overall, QOL in these patients was good although lower than expected when compared with other forms of cancer. Age and gender-related differences were noted. Better QOL in neck dissection patients is probably associated with age under 45 years. High distress scores for hormone withdrawal during periodical imaging correspond with former reports and supports use of Thyrogen. Better hormone balance is warranted for this group.

Adolescent↗

PubMed2003

pANT: a method for the pairwise assessment of nonfunctionalization times of processed pseudogenes.

We present a method for pairwise Assessment of Nonfunctionalization Times (pANT) in processed pseudogenes. Contrary to existing methods for estimating nonfunctionalization times, pANT utilizes previously calculated probabilities of nucleotide substitution as explicit rate measurements, rather than assume that the substitution rates are the same for all nucleotides. Thus, the method allows a more accurate computation of the time that has elapsed since the nonfunctionalization of a pseudogene. Whereas existing methods require the sequence of an orthologous functional gene, which is not always at hand, pANT only uses the pairwise alignment of the gene/pseudogene pair, thus expanding the range of problems that can be tackled. To estimate evolutionary times in nonfunctional sequences, pANT measures the differences in the pairwise alignment of a gene and its paralogous processed pseudogene, using only the first and second codon positions. It assumes that, because of functional constraints, these positions in the sequence of the functional homolog have not changed since the time of nonfunctionalization of the pseudogene. Hence, the sequence of the gene may be used as the ancestor of the pseudogene. We show that the method's reliance on a detailed substitution matrix, which is derived separately for each species, makes it more accurate than existing methods. We applied pANT to the case of the unitary alpha-1,3-galactosyltransferase human pseudogene and found that our estimate of the nonfunctionalization time was in agreement with that obtained by taxonomic and paleontological considerations pertaining to the divergence between platyrrhines (New World monkeys) and cattarhines (Old World monkeys).

Animals↗

PubMed2002

Ratios of radical to conservative amino acid replacement are affected by mutational and compositional factors and may not be indicative of positive Darwinian selection.

The ratio of radical to conservative amino acid replacements is frequently used to infer positive Darwinian selection. This method is based on the assumption that radical replacements are more likely than conservative replacements to improve the function of a protein. Therefore, if positive selection plays a major role in the evolution of a protein, one would expect the radical-conservative ratio to exceed the expectation under neutrality. Here, we investigate the possibility that factors unrelated to selection, i.e., transition-transversion ratio, codon usage, genetic code, and amino acid composition, influence the radical-conservative replacement ratio. All factors that have been studied were found to affect the radical-conservative replacement ratio. In particular, amino acid composition and transition-transversion ratio are shown to have the most profound effects. Because none of the studied factors had anything to do with selection (positive or otherwise) and also because all of them (singly or in combination) affected a measure that was supposed to be indicative of positive selection, we conclude that selectional inferences based on radical-conservative replacement ratios should be treated with suspicion.

Amino Acid Substitution↗