Details of a Researcher - Tomita, Masaru

Papers - Tomita, Masaru

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Correlation between Shine-Dalgarno sequence conservation and codon usage of bacterial genes

Sakai, H., Imamura, C., Osada, Y., Saito, R., Washio, T. and Tomita, M.

Journal of Molecular Evolution 52 ( 2 ) 164-170 - 170 2001

Research paper (scientific journal), Joint Work, ISSN 00222844

In this study, we analyzed the correlation between codon usage bias and Shine-Dalgarno (SD) sequence conservation, using complete genome sequences of nine prokaryotes. For codon usage bias, we adopted the codon adaptation index (CAI), which is based on the codon usage preference of genes encoding ribosomal proteins, elongation factors, heat shock proteins, outer membrane proteins, and RNA polymerase subunit proteins. To compute SD sequence conservation, we used SD motif sequences predicted by Tompa and systematically aligned them with 5′UTR sequences. We found that there exists a clear correlation between the CAI values and SD sequence conservation in the genomes of Escherichia coli, Bacillus subtilis, Haemophilus influenzae, Archaeoglobus fulgidus, Methanobacterium thermoautotrophicum, and Methanococcus jannaschii, and no relationship is found in M. genitalium, M. pneumoniae, and Synechocystis. That is, genes with higher CAI values tend to have more conserved SD sequences than do genes with lower CAI values in these organisms. Some organisms, such as M. thermoautotrophicum, do not clearly show the correlation. The biological significance of these results is discussed in the context of the translation initiation process and translation efficiency.

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The E-CELL Project: Towards Integrative Simulation of Cellular Processes

Hashimoto, K., Takahashi, K., Matsuzaki, Y., Matsushima, R., Saito, K., Yugi, K., Miyoshi, F., Nakano, H., Tanida, S., Saito, Y., Kawase, A., Watanabe, N., Shimizu, T. and Nakayama, Y., Tomita M.

New Generation Computing 18 ( 1 ) 1-12 2001

Joint Work

Preferential usage of some minor codons in bacteria

Ohno, H., Sakai, H., Washio, T. and Tomita, M.

Gene 276 ( 1-2 ) 107-15 - 115 2001

Research paper (scientific journal), Joint Work, ISSN 03781119

In many bacterial species, such as Deinococcus radiodurans, Haemophilus influenzae, and Methanobacterium thermoautotrophicum, some minor codons are preferentially used near the initiation codon. Among these codons, there are some minor codons that have strong preference for the initiation site in the high codon adaptation index (CAI) group (comprising of highly expressed genes) rather than in the low CAI genes group (comprising of low expressing genes). In the present study, codon usage in the initiation site and in the rest of the gene was systematically compared in the 27 complete bacterial genomes and Saccharomyces cerevisiae genome. Furthermore, we classified genes into two groups according to the CAI values and conducted the same analysis for each of the two groups. Our results suggest a role for some minor codons in the initiation site of the regulating translation system in many bacteria. We have summarized codons that are preferentially used in the initiation site and probably play a role in regulating genes expression in these organisms. © 2001 Elsevier Science B.V. All rights reserved.

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Whole cell simulation: A grand challenge of the 21st century

Tomita, M

Trends in Biotechnology 19 ( 6 ) 205-210 - 210 2001

Research paper (scientific journal), Single Work, ISSN 01677799

Study of the cell will never be complete unless its dynamic behavior is understood. The complex behavior of the cell cannot be determined or predicted unless a computer model of the cell is constructed and computer simulation is undertaken. Rapid accumulation of biological data from genome, proteome, transcriptome and metabolome projects can bring us to the point where it is no longer purely speculative to discuss how to construct virtual cells in silico. This article describes attempts to construct whole cell models. The E-CELL project has completed a couple of virtual cell models, and computer simulations have revealed some biological surprises.

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E-cell project: towards computer modeling of the whole cell

Tomita M.

Annals of Biomedical Engineering (Annals of Biomedical Engineering) 28 ( SUPPL. 1 ) 2000.12

ISSN 00906964

The E-CELL System (http://www.e-cell.org) is a genetic software package developed, to model not only metabolic pathways but also other higher-order cellular processes such as protein synthesis and signal transduction. Using the system, we have successfully constructed a virtual cell with 127 genes sufficient for 'self-support'. The gene set was selected from the genome of Mycoplasma genitalium, and the metabolisms include transcription, translation, membrane transport, the glycolysis pathway for energy production, and the phospholipid biosynthesis pathway or membrane structure.

Characteristic Sequence Pattern in the 5-to 20-bp Upstream Region of Primate Alu Elements

Toda, Y., Saito, R. and Tomita, M.

Journal of Molecular Evolution 50 ( 3 ) 232-237 - 237 2000

Research paper (scientific journal), Joint Work, ISSN 00222844

We conducted comprehensive sequence analysis of 5' flanking regions of primate Alu elements. Information contents were computed and frequencies of 1024 pentanucleotides were measured to approximate the location of a characteristic sequence and to specify its pattern(s), which may be involved in the integration of Alu elements into their host genomes. A large number of samples was used, the wide region of the 5' end of Alu elements was analyzed, and comparisons were made among different subfamilies. Through our analyses, 'TTTTAAAAA' or '(T)(ms)(A)(n)' can be stated as a candidate for the characteristic sequence pattern, which resides around the region 5 to 20 base pairs upstream of the 5' end of Alu elements. This characteristic sequence pattern was more prominent in the sequences of younger Alus, which is a strong indication that the sequence pattern has a role at the time of Alu integration.

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The orientation bias of Chi sequences is a general tendency of G-rich oligomers

Uno R., Nakayama Y., Arakawa K., Tomita M.

Gene 36 ( 1-2 ) 207-215 - 215 2000

Research paper (scientific journal), Joint Work, ISSN 03781119

The Chi sequences are specific oligomers that stimulate DNA repair by homologous recombination, and are different sequences in each organism. Approximately 75% of the copies of the Chi sequence (5′-GCTGGTGG-3′) of Escherichia coli reside on the leading strand, and this orientation bias is often believed to be a consequence of the biological role of Chi sequences as the signal sequence of RecBCD pathway in DNA replication. However, our computer analysis found that many G-rich oligomers also show this asymmetric orientation pattern. The shift in the Chi orientation bias appears around the replication origin and terminus, but these locations are also coincident with the shift points in GC content or GC skew. We conducted the same analysis with the genome of Bacillus subtilis, and found that in addition to Chi, other G-rich oligomers show similar asymmetric orientation patterns, whose shift points were coincident with those of the GC skew. However, the genome of Haemophilus influenzae Rd, whose GC skew is not so pronounced, does not clearly show asymmetric orientation patterns of Chi or other G-rich oligomers. These results lead us to suggest that the uneven distribution of the Chi orientation between the two strands of the double helix is mostly due to the uneven distribution of G content (GC skew) and that the replication-related function of Chi sequences is not the primary factor responsible for the evolutionary pressure causing the orientation bias. © 2000 Elsevier Science B.V.

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Computer Simulation of Human erythrocyte Using the E-CELL Simulation System

Yoichi Nakayama, Ryo Matsushima, Hisako Nakano, Akiko Kawase, Kouichi Takahashi and Masaru Tomita

BRIDGING THE GAP BETWEEN WEQUENCE & FUNCTION 1999.09

Joint Work

ApA dinucleotide periodicity in prokaryote, eukaryote, and organelle genomes

Tomita M., Wada M., Kawashima Y.

Journal of Molecular Evolution 49 ( 2 ) 182 - 192 1999.08

ISSN 00222844

Computer analyses of various genome sequences revealed the existence of certain periodical patterns of adenine-adenine dinucleotides (ApA). For each genome sequence of 13 eubacteria, 3 archaebacteria, 10 eukaryotes, 60 mitochondria, and 9 chloroplasts, we counted frequencies of ApA dinucleotides at each downstream position within 50 bp from every ApA. We found that the complete genomes of all three archaebacteria have clear ApA periodicities of about 10 bps. On the other hand, all of the 13 eubacteria we analyzed were found to have an ApA periodicity of about 11 bp. Similar periodicities exist in the 10 eukaryotes, although higher organisms such as primates tend to have weaker periodic patterns. None of the mitochondria and chroloplasts we analyzed showed an evident periodic pattern.

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Analysis of base-pairing potentials between 16S rRNA and 5' UTR for translation initiation in various prokaryotes

Osada, Y., Saito, R. and Tomita, M.

Bioinformatics 15 ( 7-8 ) 578-581 - 581 1999

Research paper (scientific journal), Joint Work, ISSN 13674803

Motivation: It is well accepted that the 3' end of 16S rRNA is directly involved in prokaryotic translation initiation by pairing with the Shine-Dalgarno (SD) sequence, which is located in the ribosome-binding site of mRNA. According to Shine and Dalgarno, Escherichia coli's 5' UTR has the pattern of 'AGGAGG' (SD sequence), which is complementary to the 3' end sequence of 16S rRNA. In this work, we systematically calculated free-energy values of the base pairing between the 3' end of 16S rRNA and the 5' UTR of mRNA, in order to analyze the base-pairing potentials in various prokaryotes. The free-energy values were then plotted over distances from the start codon to visualize the free-energy pattern of 5' UTRs. Results: The average free-energy values fell sharply before the start codon in E. coli, which is consistent with the model that the 3' end of 16S rRNA base pairs with the SD sequence. Haemophilus influenzae, Bacillus subtilis and Helicobacter pylori show a similar pattern, suggesting that the organisms have basically the same mechanism of translation initiation as E. coli. Other eubacteria, such as Synechocystis PCC6803, Mycoplasma genitalium, Mycoplasma pneumoniae and Borrelia burgdorferi also show decreases in their free-energy values, although they are less evident. We also did the same analysis with a eukaryote genome as a control; no fall in free-energy values was observed between the 3' end of 18S rRNA and 5' UTRs of Saccharomyces cerevisiae, suggesting that this organism does not base pair in translation initiation. The three archaebacteria A. fulgidus, M. jannaschii and M. thermoautotrophicum show patterns similar to eubacteria, but not to S. cerevisiae, indicating that archaebacteria are closer to eubacteria than to eukaryotes with respect to the mechanism of translation initiation. From these observations, it appears that the shape of the curve produced by the algorithm can be used to predict the mechanism of translation initiation. Availability: The C programs used in our analysis are available upon request.

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Computer analyses of complete genomes suggest that some archaebacteria employ both eukaryotic and eubacterial mechanisms in translation initiation.

Saito, R. and Tomita, M.

Gene 238 ( 1 ) 79-83 - 83 1999

Research paper (scientific journal), Joint Work, ISSN 03781119

The translation initiation mechanism of archaebacteria is still not clearly understood. Our previous work showed that ATG triplets before start codons have been strongly depleted in eukaryotic genomes, presumably because ribosome of eukaryotes scans mRNA from the 5' to 3' direction to find proper start codons. Extra ATG triplets before start codons would confuse the process and thus they have been negatively selected in eukaryotic genomes. In eubacterial genomes, on the other hand, ribosome binds to the Shine-Dalgarno (SD) sequence at once without mRNA scanning, and the characteristic patterns of ATG triplet depletion were not observed (Saito, R., Tomita, M., 1999. On negative selection against ATG triplets near start codons in eukaryotic and procaryotic genomes. J. Mol. Evol. 48, 213-217). The ATG triplet analysis on archaebacterial genomes revealed that Methanococcus jannaschii and Pyrococcus horikoshii show patterns similar to eukaryotes, implying that these species employ scanning of mRNA from the 5' to 3' direction in the process of translation initiation. On the other hand, our earlier study found that these archaea have SD-like sequences, which are complementary to the 3' end sequence of 16S rRNA, as in eubacterial translation initiation (Osada, Y., Saito, R., Tomita, M. Analysis of base-pairing potentials between 16S rRNA and 5' UTR for translation initiation in various procaryotes. Bioinformatics, in press). These two results combined lead us to conclude that these archaea probably use a hybrid mechanism; their ribosome scans mRNAs from the 5' to 3' direction and then 16S rRNA binds to the SD-like sequence of the 5' UTR. (C) 1999 Elsevier Science B.V. All rights reserved.

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E-CELL: Software environment for whole cell simulation

Tomita, M., Hashimoto, K., Takahashi, K., Shimizu, T., Matsuzaki, Y., Miyoshi, F., Saito, K., Tanida, S., Yugi, K., Venter, J.,C., Hutchison, C.,A .,3rd.

Bioinformatics 15 ( 1 ) 72 - 84 1999

Research paper (scientific journal), Joint Work, ISSN 13674803

Motivation: Genome sequencing projects and further systematic functional analyses of complete gene sets are producing an unprecedented mass of molecular information for a wide range of model organisms. This provides us with a detailed account of the cell with which we may begin to build models for simulating intracellular molecular processes to predict the dynamic behaviour of living cells. Previous work in biochemical and genetic simulation has isolated well-characterized pathways for detailed analysis, but methods for building integrative models of the cell that incorporate gene regulation, metabolism and signaling have not been established. We, therefore, were motivated to develop a software environment for building such integrative models based on gene sets, and running simulations to conduct experiments in silico. Results: E-CELL, a modeling and simulation environment for biochemical and genetic processes, has been developed. The E-CELL system allows a user to define functions of proteins, protein-protein interactions, protein-DNA interactions, regulation of gene expression and other features of cellular metabolism, as a set of reaction rules. E-CELL simulates cell behavior by numerically integrating the differential equations described implicitly in these reaction rules. The user can observe, through a computer display, dynamic changes in concentrations of proteins, protein complexes and other chemical compounds in the cell. Using this software, we constructed a model of a hypothetical cell with only 127 genes sufficient for transcription, translation, energy production and phospholipid synthesis. Most of the genes are taken from Mycoplasma genitalium, the organism having the smallest known chromosome, whose complete 580 kb genome sequence was determined at TIGR in 1995. We discuss future applications of the E-CELL system with special respect to genome engineering. Availability: The E-CELL software is available upon request. Supplementary information: The complete list of rules of the developed cell model with kinetic parameters can be obtained via our web site at: http://e-cell.org/. Contact: mt@@@sfc.keio.ac.jp.

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Comparative study of overlapping genes in the genomes of Mycoplasma genitalium and Mycoplasma pneumoniae

Fukuda, Y., Washio, T. and Tomita, M.

Nucleic Acids Research 27 ( 8 ) 1847-1853 - 1853 1999

Research paper (scientific journal), Joint Work, ISSN 03051048

Overlapping genes are defined, in this paper, as a pair of adjacent genes whose coding regions are partly overlapping. We systematically analyzed all overlapping genes in the genomes of two closely related species: Mycoplasma genitalium and Mycoplasma pneumoniae. Careful comparisons were made for homologous genes that are overlapped in one species but not in the other. This comparative analysis allows us to propose a model of how overlapping genes emerged in the course of evolution. It was found that overlapping genes were generated primarily due to the loss of a stop codon in either gene, in many cases, the absence of which resulted in elongation of the 3' end of the gene's coding region. More specifically, the loss of the stop codon took place as a result of the following events: deletion of the stop codon (64.4%), point mutation at the stop codon (4.4%), and frame shift at the end of the coding region (6.7%). Overlapping genes, in a sense, can be thought of as the results of evolutionary pressure to minimize genome size. However, our analysis indicates that many overlapping genes, at least in the genomes of M. genitalium and M. pneumoniae, are due to incidental elongation of the coding regions.

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Sequence patterns observed in 5' flanking regions of primate Alu elements

Toda, Y., Saito, R. and Tomita, M.

Annals of the New York Academy of Sciences 18 369-374 - 374 1999

Research paper (scientific journal), Joint Work, ISSN 00778923

Retrotransposons have generally been known to integrate randomly into host genomes. Jurka, however, showed some consensus sequence patterns at insertion sites of some mammalian retrotransposons and proposed enzymatic involvement that mediates integration. Jurka used about 400 complete human Alu and rodent ID sequences which retain full length with identical flanking sequences at both ends. In our study, more than 25,000 Alu sequences longer than 250 bp were used for comprehensive analysis to identify any consensus sequence(s) preceding the 5' end of Alu elements. 'Entropy' at each nucleotide position within 500 bases of the 5' Alu end was computed. Significant drop of entropy was observed between position -20 and -10 of the 5' end of Alu, suggesting the existence of certain consensus sequence(s) in the region. Frequencies of all possible triplets (total of 64) were measured in the same region. Observation that frequencies of triplets 'aaa,' 'taa,' and 'tta' in the 5' flanking sequences were high is consistent with Jurka. However, frequencies of triplets 'att' and 'aca' were also significantly high, which are not the primary candidates for nick site in Jurka.

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On negative selection against ATG triplets near start codons in eukaryotic and prokaryotic genomes

Saito R, Tomita M

Journal of Molecular Evolution 26 ( 23 ) 5456-5463 - 217 1998.12

Research paper (scientific journal), Joint Work, ISSN 0022-2844

The frequencies of ATG triplets in the genomes of various species were systematically analyzed, and the frequency of ATG triplets was significantly low around start codons in both prokaryotic and eukaryotic genomes. In eukaryotes, however, the frequency decrease before the start codon is much more evident than that after the start codon. In prokaryotes, on the other hand, the ATG frequency pattern around the start codon is less evident, and - more importantly - symmetric. We also computed average distances between a start codon and its nearest upstream-located ATG triplet and found a general tendency for the average distances to be longer in higher organisms.

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Analysis of complete genomes suggests that many prokaryotes do not rely on hairpin formation in transcription termination

Washio T., Sasayama J., Tomita M.

Nucleic Acids Research 26 ( 23 ) 5456 - 5463 1998.12

ISSN 03051048

Free energy values of mRNA tertiary structures around stop codons were systematically calculated to surmise the hairpin-forming potential for all genes in each of the 16 complete prokaryote genomes. Instead of trying to detect each individual hairpin, we averaged the free energy values around the stop codons over the entire genome to predict how extensively the organism relies on hairpin formation in the process of transcription termination. The free energy values of Escherichia coli K-12 shows a sharp drop, as expected, at 30 bp downstream of the stop codon, presumably due to hairpin-forming sequences. Similar drops are observed for Haemophilus influenzae Rd, Bacillus subtilis and Chlamydia trachomatis, suggesting that these organisms also form hairpins at their transcription termination sites. On the other hand, 12 other prokaryotes - Mycoplasma genitalium, Mycoplasma pneumoniae, Synechocystis PCC6803, Helicobacter pylori, Borrelia burgdorferi, Methanococcus jannaschii, Archaeoglobus fulgidus, Methanobacterium thermoautotrophicum, Aquifex aeolicus, Pyrococcus horikoshii, Mycobacterium tuberculosis and Treponema pallidum - show no apparent decrease in free energy value at the corresponding regions. This result suggests that these prokaryotes, or at least some of them, may never form hairpins at their transcription termination sites.

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Alu elements as an aid in deciphering genome rearrangements

Toda, Y. and Tomita, M.

Gene 205 ( 1-2 ) 173 - 176 1997

Research paper (scientific journal), Joint Work, ISSN 03781119

Genomic rearrangements result in genomic duplications that lead to the generation of more complex genomes. Some attempts have been made to trace duplication histories of different loci using Alu elements because of their large population in primate genomes. In this short report, using the human growth hormone locus as an example, we demonstrate the usefulness of Alu repetitive elements in computer sequence analyses when tracing duplication histories. Information on subfamily classification, direction, arrangements, Poly(A) tails and direct repeats can aid our understanding of genome rearrangements.

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CpG distribution patterns in methylated and nonmethylated species

Shimizu, T., Takahashi, K. and Tomita, M.

Gene 205 ( 1-2 ) 103-107 - 107 1997

Research paper (scientific journal), Joint Work, ISSN 03781119

To characterize the extent of DNA methylation and its possible biological roles in a wide variety of organisms, we have analyzed gene sequences extracted from the GenBank database. Sequences of both methylated and non-methylated species were used for comparative analysis. The local CpG dinucleotide distribution near the 5' ends of genes as well as the degree of overall CpG suppression/depletion in the entire gene region were examined in all complete gene sequences for each species. We show that the distribution patterns of CpG near the 5' region of genes differ among vertebrates, invertebrates, plants and bacteria. CpG island-like peaks in CpG O/E (observed/expected ratio) were observed not only in methylated species, but also in non-methylated species. In methylated non-vertebrates, overall CpG O/E values were lower, and peaks in the CpG profile of 5' regions were larger than in non-methylated species. We discuss the implications of such biases with respect to DNA methylation.

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Introns and reading frames: Correlation between splicing sites and their codon positions

Tomita, M., Shimizu, N. and Brutlag, D.L.

Molecular Biology and Evolution 13 ( 9 ) 1219-1223 - 1223 1996

Research paper (scientific journal), Joint Work, ISSN 07374038

Computer analyses of the entire GenBank database were conducted to examine correlation between splicing sites and codon positions in reading frames. Intron insertion patterns (i.e., splicing site locations with respect to codon positions) have been analyzed for all of the 64 codons of all the eukaryote taxonomic groups: primates, rodents, mammals, vertebrates, invertebrates, and plants. We found that reading frames are interrupted by an intron at a codon boundary (as opposed to the middle of a codon) significantly more often than expected. This observation is consistent with the exon shuffling hypothesis, because exons that end at codon boundaries can be concatenated without causing a frame shift and thus are evolutionarily advantageous. On the other hand, when introns interrupt at the middles of codons, they exist in between the first and second bases much more frequently than between the second and third bases, despite the fact that boundaries between the first and second bases of codons are generally far more important than those between the second and third bases. The reason for this is not clear and yet to be explained. We also show that the length of an exon is a multiple of 3 more frequently than expected. Furthermore, the total length of two consecutive exons is also more frequently a multiple of 3. All the observations above are consistent with results recently published by Long, Rosenberg, and Gilbert (1995).

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72-82 1989

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