Details of a Researcher - Tomita, Masaru

Papers - Tomita, Masaru

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A problem in multivariate analysis of codon usage data and a possible solution

Suzuki H., Saito R., Tomita M.

FEBS Letters 579 ( 28 ) 6499 - 6504 2005.11

ISSN 00145793

Multivariate analyses are often used to identify major trends of variation in synonymous codon usage among genes. These analyses need to be performed on properly normalized codon usage data to avoid biases masking this synonymous variation, i.e., gene length, amino acid usage, and codon degeneracy; however, previous studies have failed to do so. In this paper, we demonstrate that the use of alternative normalized data (called 'relative adaptiveness' in the literature) can avoid all these biases and furthermore, can identify more trends of variation among genes, including GC-ending codon usage, GT-ending codon usage, and gene expression level. © 2005 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

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Dynamic responses of the intracellular metabolite concentrations of the wild type and pykA mutant Escherichia coli against pulse addition of glucose or NH<inf>3</inf> under those limiting continuous cultures

Hoque M., Ushiyama H., Tomita M., Shimizu K.

Biochemical Engineering Journal 26 ( 1 ) 38 - 49 2005.11

ISSN 1369703X

The dynamics of the intracellular metabolite concentrations were investigated for the wild type and pykA gene knockout mutant Escherichia coli in responses to the glucose pulse addition during glucose-limited continuous culture and in responses to the ammonia pulse addition during ammonia-limited continuous culture. For this, we developed a new automated rapid sampling device, which enables us to take samples rapidly within a second. The intracellular concentrations of G6P, F6P, 2PG, PEP, OAA, 6PG, Ribu5P, E4P and NADPH were higher for pykA mutant as compared with the wild type under both limited continuous cultures, and the concentrations of PYR, ATP and acetate were much lower for pykA mutant than those of the wild type. These phenomena reflected the fact that the accumulation of PEP caused the increased flux from PEP to OAA and that the accumulated PEP inhibited pfk, which caused the accumulation of G6P and F6P, which in turn increased the flux toward pentose phosphate (PP) pathway and increased the PP pathway metabolite concentrations. Oxygen uptake rate (OUR) was a little higher for pykA mutant as compared with that of its wild type, while CO2 production rate (CER) shows the reverse trend. OUR and CER were much less for NH3-limited condition than that of NH3-rich condition. The intracellular concentrations of PEP, ATP and PYR decreased rapidly within several seconds, whereas the concentrations of G6P, F6P FBP, 6PG, ADP, NADH and NADPH increased after glucose pulse addition during glucose-limited condition for both wild type and pykA knockout mutant. Initial decrease in PEP concentration was considered to be due to PTS system. The intracellular concentration of NADPH decreased after NH 3 pulse addition under NH3-limited condition for both strains, which is due to the fact that NADPH is utilized through glutamate production under NH3 addition. © 2005 Elsevier B.V. All rights reserved.

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A comprehensive software suite for the analysis of cDNAs

Arakawa K., Suzuki H., Fujishima K., Fujimoto K., Ueda S., Matsui M., Tomita M.

Genomics, Proteomics and Bioinformatics 3 ( 3 ) 179 - 188 2005.08

ISSN 16720229

We have developed a comprehensive software suite for bioinformatics research of cDNAs; it is aimed at rapid characterization of the features of genes and the proteins they code. Methods implemented include the detection of translation initiation and termination signals, statistical analysis of codon usage, comparative study of amino acid composition, comparative modeling of the structures of product proteins, prediction of alternative splice forms, and metabolic pathway reconstruction.

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All systems go: launching cell simulation fueled by integrated experimental biology data

Arita, M; Robert, M; Tomita, M

Current Opinion in Biotechnology 16 ( 3 ) 344-349 - 349 2005.06

Research paper (scientific journal), Joint Work, ISSN 09581669

Biological simulation serves to unify the basic elements of systems biology, namely, model selection, experimentation and model refinement. To select biochemical models for simulation, metabolome analysis can be performed using capillary electrophoresis or liquid chromatography coupled with mass spectrometry. In this manner, selected models can be elaborated with temporal/spatial gene and protein expression data obtained from model organisms such as Escherichia coli. The E. coli single gene deletion mutant library (KO collection) and His-tag/GFP-fusion single open reading frame clone expression library (ASKA) are powerful resources for this task. The integration of parallel experimental datasets into dynamic simulation tools forms the remaining challenge for the systematic analysis and elucidation of biological networks and holds promise for biotechnological applications. © 2005 Elsevier Ltd. All rights reserved.

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TheSCO2299gene fromStreptomyces coelicolorA3(2) encodes a bifunctional enzyme consisting of an RNase H domain and an acid phosphatase domain

Ohtani, Naoto Saito, Natsumi Tomita, Masaru Itaya, Mitsuhiro Itoh, Aya

FEBS Journal 272 ( 11 ) 2828-2837 - 2837 2005.06

Research paper (scientific journal), Joint Work, ISSN 1742464X

The SCO2299 gene from Streptomyces coelicolor encodes a single peptide consisting of 497 amino acid residues. Its N-terminal region shows high amino acid sequence similarity to RNase HI, whereas its C-terminal region bears similarity to the CobC protein, which is involved in the synthesis of cobalamin. The SCO2299 gene suppressed a temperature-sensitive growth defect of an Escherichia coli RNase H-deficient strain, and the recombinant SCO2299 protein cleaved an RNA strand of RNA-DNA hybrid in vitro. The N-terminal domain of the SCO2299 protein, when overproduced independently, exhibited RNase H activity at a similar level to the full length protein. On the other hand, the C-terminal domain showed no CobC-like activity but an acid phosphatase activity. The full length protein also exhibited acid phosphatase activity at almost the same level as the C-terminal domain alone. These results indicate that RNase H and acid phosphatase activities of the full length SCO2299 protein depend on its N-terminal and C-terminal domains, respectively. The physiological functions of the SCO2299 gene and the relation between RNase H and acid phosphatase remain to be determined. However, the bifunctional enzyme examined here is a novel style in the Type 1 RNase H family. Additionally, S. coelicolor is the first example of an organism whose genome contains three active RNase H genes. © 2005 FEBS.

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Space in systems biology of signaling pathways--towards intracellular molecular crowding in silico

Takahashi, Kouichi Arjunan, Satya Nanda Vel Tomita, Masaru

Febs Letters 579 ( 8 ) 1783-1788 2005.03

Research paper (scientific journal), Joint Work, ISSN 00145793

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GC-compositional strand bias around transcription start sites in plants and fungi

Fujimori S., Washio T., Tomita M.

BMC Genomics 6 2005.02

ISSN 14712164

Background: A GC-compositional strand bias or GC-skew (=(C-G)/(C+G)), where C and G denote the numbers of cytosine and guanine residues, was recently reported near the transcription start sites (TSS) of Arabidopsis genes. However, it is unclear whether other eukaryotic species have equally prominent GC-skews, and the biological meaning of this trait remains unknown. Results: Our study confirmed a significant GC-skew (C > G) in the TSS of Oryza sativa (rice) genes. The full-length cDNAs and genomic sequences from Arabidopsis and rice were compared using statistical analyses. Despite marked differences in the G+C content around the TSS in the two plants, the degrees of bias were almost identical. Although slight GC-skew peaks, including opposite skews (C < G), were detected around the TSS of genes in human and Drosophila, they were qualitatively and quantitatively different from those identified in plants. However, plant-like GC-skew in regions upstream of the translation initiation sites (TIS) in some fungi was identified following analyses of the expressed sequence tags and/or genomic sequences from other species. On the basis of our dataset, we estimated that >70 and 68% of Arabidopsis and rice genes, respectively, had a strong GC-skew (>0.33) in a 100-bp window (that is, the number of C residues was more than double the number of G residues in a +/-100-bp window around the TSS). The mean GC-skew value in the TSS of highly-expressed genes in Arabidopsis was significantly greater than that of genes with low expression levels. Many of the GC-skew peaks were preferentially located near the TSS, so we examined the potential value of GC-skew as an index for TSS identification. Our results confirm that the GC-skew can be used to assist the TSS prediction in plant genomes. Conclusion: The GC-skew (C > G) around the TSS is strictly conserved between monocot and eudicot plants (ie. angiosperms in general), and a similar skew has been observed in some fungi. Highly-expressed Arabidopsis genes had overall a more marked GC-skew in the TSS compared to genes with low expression levels. We therefore propose that the GC-skew around the TSS in some plants and fungi is related to transcription. It might be caused by mutations during transcription initiation or the frequent use of transcription factor-biding sites having a strand preference. In addition, GC-skew is a good candidate index for TSS prediction in plant genomes, where there is a lack of correlation among CpG islands and genes. © 2005 Fujimori et al; licensee BioMed Central Ltd.

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Large-scale prediction of cationic metabolite identity and migration time in capillary electrophoresis mass spectrometry using artificial neural networks

Sugimoto M., Kikuchi S., Arita M., Soga T., Nishioka T., Tomita M.

Analytical Chemistry 77 ( 1 ) 78 - 84 2005.01

ISSN 00032700

We developed a computational technique to assist in the huge-scale identification of charged metabolites. The electrophoretic mobility of metabolites in capillary electrophoresis-mass spectrometry (CE-MS) was predicted from their structure, using an ensemble of artificial neural networks (ANNs). Comparison between relative migration times of 241 various cations measured by CE-MS and predicted by a trained ANN ensemble produced a correlation coefficient of 0.931. When we used our technique to characterize all metabolites listed in the KEGG ligand database, the correct compounds among the top three candidates were predicted in 78.0% of cases. We suggest that this approach can be used for the prediction of the migration time of any cation and that it represents a powerful method for the identification of un characterized CE-MS peaks in metabolome analysis.

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A microarray data-based semi-kinetic method for predicting quantitative dynamics of genetic networks

Yugi K, Nakayama Y, Kojima S, Kitayama T, Tomita M.

BMC Bioinformatics 6 ( 299 ) 2005

Research paper (scientific journal), Joint Work, ISSN 14712105

Background: Elucidating the dynamic behaviour of genetic regulatory networks is one of the most significant challenges in systems biology. However, conventional quantitative predictions have been limited to small networks because publicly available transcriptome data has not been extensively applied to dynamic simulation. Results: We present a microarray data-based semi-kinetic (MASK) method which facilitates the prediction of regulatory dynamics of genetic networks composed of recurrently appearing network motifs with reasonable accuracy. The MASK method allows the determination of model parameters representing the contribution of regulators to transcription rate from time-series microarray data. Using a virtual regulatory network and a Saccharomyces cerevisiae ribosomal protein gene module, we confirmed that a MASK model can predict expression profiles for various conditions as accurately as a conventional kinetic model. Conclusions: We have demonstrated the MASK method for the construction of dynamic simulation models of genetic networks from time-series microarray data, initial mRNA copy number and first-order degradation constants of mRNA. The quantitative accuracy of the MASK models has been confirmed, and the results indicated that this method enables the prediction of quantitative dynamics in genetic networks composed of commonly used network motifs, which cover considerable fraction of the whole network. © 2005 Yugi et al., licensee BioMed Central Ltd.

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Reverse engineering of biochemical equations from time-course data by means of genetic programming

Sugimoto M., Kikuchi S., Tomita M.

Biosystems 80 ( 2 ) 155 - 164 2005

Research paper (scientific journal), Joint Work, ISSN 03032647

Increased research aimed at simulating biological systems requires sophisticated parameter estimation methods. All current approaches, including genetic algorithms, need pre-existing equations to be functional. A generalized approach to predict not only parameters but also biochemical equations from only observable time-course information must be developed and a computational method to generate arbitrary equations without knowledge of biochemical reaction mechanisms must be developed. We present a technique to predict an equation using genetic programming. Our technique can search topology and numerical parameters of mathematical expression simultaneously. To improve the search ability of numeric constants, we added numeric mutation to the conventional procedure. As case studies, we predicted two equations of enzyme-catalyzed reactions regarding adenylate kinase and phosphofructokinase. Our numerical experimental results showed that our approach could obtain correct topology and parameters that were close to the originals. The mean errors between given and simulation-predicted time-courses were 1.6 × 10-5% and 2.0 × 10-3%, respectively. Our equation prediction approach can be applied to identify metabolic reactions from observable time-courses. © 2004 Elsevier Ireland Ltd. All rights reserved.

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In silico diagnosis of inherently inhibited gene expression focusing on initial codon combinations

Ohashi Y., Yamashiro A., Washio T., Ishii N., Ohshima H., Michishita T., Tomita M., Itaya M.

Gene 347 ( 1 ) 11 - 19 2005

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

The translation start site, immediately downstream from the start codon, is a dominant factor for gene expression in Escherichia coli. At present, no method exists to improve the expression level of cloned genes, since it remains difficult to find the best codon combination within the region. We determined the expression parameters that correspond to all sense codons within the first four codons using GFPuv which encodes a derivative of green fluorescent protein. Using a genetic algorithm (GA)-based computer program, these parameters were incorporated in a simple, static model for the prediction of translation efficiency, and optimized to the expression level for 137 randomly isolated GFPuv genes. The calculated initial translation index (ITI), also proven for the DsRed2 gene that encodes a red fluorescent protein, should provide a solution to overcome the gene expression problem in cloned genes whose expression is often inherently blocked at the translation process. The proposed method facilitates heterologous protein production in E. coli, the most commonly used host in biological and industrial fields. © 2004 Published by Elsevier B.V.

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Computational analysis suggests that alternative first exons are involved in tissue-specific transcription in rice ( Oryza sativa)

Kitagawa, Noriyuki ; Washio, Takanori ; Kosugi, Shunichi ; Yamashita, Tomoya ; Higashi, Kenji ; Yanagawa, Hiroshi ; Higo, Kenichi ; Satoh, Koji ; Ohtomo, Yasuhiro ; Sunako, Tomomi ; Murakami, Kazuo ; Matsubara, Kenichi ; Kawai, Jun ; Carninci, Piero ; Hayashizaki, Yoshihide ; Kikuchi, Shoshi ; Tomita, Masaru

Bioinformatics 21 ( 9 ) 1758-1763 - 1763 2005

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

Motivation: Transcription start site selection and alternative splicing greatly contribute to diversifying gene expression. Recent studies have revealed the existence of alternative first exons, but most have involved mammalian genes, and as yet the regulation of usage of alternative first exons has not been clarified, especially in plants. Results: We systematically identified putative alternative first exon transcripts in rice, verified the candidates using RT-PCR, and searched for the promoter elements that might regulate the alternative first exons. As a result, we detected a number of unreported alternative first exons, some of which are regulated in a tissue-specific manner. © The Author 2005. Published by Oxford University Press. All rights reserved.

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Hybrid dynamic/static method for large-scale simulation of metabolism

Yugi, K., Nakayama, Y., Kinoshita, A., and Tomita, M.

Theoretical Biology and Medical Modeling 2 ( 42 ) 2005

Research paper (scientific journal), Joint Work, ISSN 17424682

Background: Many computer studies have employed either dynamic simulation or metabolic flux analysis (MFA) to predict the behaviour of biochemical pathways. Dynamic simulation determines the time evolution of pathway properties in response to environmental changes, whereas MFA provides only a snapshot of pathway properties within a particular set of environmental conditions. However, owing to the large amount of kinetic data required for dynamic simulation, MFA, which requires less information, has been used to manipulate large-scale pathways to determine metabolic outcomes. Results: Here we describe a simulation method based on cooperation between kinetics-based dynamic models and MFA-based static models. This hybrid method enables quasi-dynamic simulations of large-scale metabolic pathways, while drastically reducing the number of kinetics assays needed for dynamic simulations. The dynamic behaviour of metabolic pathways predicted by our method is almost identical to that determined by dynamic kinetic simulation. Conclusion: The discrepancies between the dynamic and the hybrid models were sufficiently small to prove that an MFA-based static module is capable of performing dynamic simulations as accurately as kinetic models. Our hybrid method reduces the number of biochemical experiments required for dynamic models of large-scale metabolic pathways by replacing suitable enzyme reactions with a static module. © 2005 Yugi et al; licensee BioMed Central Ltd.

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KEGG-based pathway visualization tool for complex omics data

Arakawa, K., Kono, N., Yamada, Y. and Tomita, M.

In Silico Biology 5 ( 0039 ) 419 - 423 2005

Research paper (scientific journal), Joint Work, ISSN 13866338

Pathway-level visualization of omics data provides an essential means for systems biology, to capture the systematic properties of the inner activities of cells. Here we describe a web-based resource consisting of a web-application for the visualization of complex omics data onto KEGG pathways to overview all entities in the context of cellular pathways, and databases created with the software to visualize a series of microarray data. The web-application accepts transcriptome, proteome, metabolome, or the combination of these data as input, and because of this scalability it is advantageous for the visualization of cell simulation results. The web server can be accessed at http://www.g-language.org/data/marray/. © 2005 IOS Press. All rights reserved.

Metabolome Analysis and Metabolic Simulation

Ishii N., Soga T., Nishioka T. and Tomita M.

Metabolomics 1 ( 1 ) 29-37 - 37 2005

Research paper (scientific journal), Joint Work, ISSN 15733882

For many decades microorganisms have been used for industrial purposes; traditional fermentations such as brewing and production of food additives, aroma molecules, organic acids and pharmaceutical-like antibiotics or recombinant proteins are instances of the industrial microorganism utilization. Therefore, microorganism modeling and simulation have been required for engineering purposes, because of demands for design, optimization and quality control of large-scale fermentation plants. Modeling has recently become more highly developed, aided by the deciphering of microorganism genomes, the completion of metabolic databases, the development of analytical methodologies and improvements in the performance of computers. This paper reviews past and recent metabolic simulation of microorganisms, and also discusses the metabolome analytical techniques and the construction of large-scale microorganism models which are now being developed in our group. © 2005 Springer Science+Business Media, Inc.

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Dynamic simulation of red blood cell metabolism and its application to the analysis of a pathological condition

Nakayama Y., Kinoshita A., Tomita M.

Theoretical Biology and Medical Modeling 2 ( 18 ) 2005

Research paper (scientific journal), Joint Work, ISSN 17424682

Background: Cell simulation, which aims to predict the complex and dynamic behavior of living cells, is becoming a valuable tool. In silico models of human red blood cell (RBC) metabolism have been developed by several laboratories. An RBC model using the E-Cell simulation system has been developed. This prototype model consists of three major metabolic pathways, namely, the glycolytic pathway, the pentose phosphate pathway and the nucleotide metabolic pathway. Like the previous model by Joshi and Palsson, it also models physical effects such as osmotic balance. This model was used here to reconstruct the pathology arising from hereditary glucose-6-phosphate dehydrogenase (G6PD) deficiency, which is the most common deficiency in human RBC. Results: Since the prototype model could not reproduce the state of G6PD deficiency, the model was modified to include a pathway for de novo glutathione synthesis and a glutathione disulfide (GSSG) export system. The de novo glutathione (GSH) synthesis pathway was found to compensate partially for the lowered GSH concentrations resulting from G6PD deficiency, with the result that GSSG could be maintained at a very low concentration due to the active export system. Conclusion: The results of the simulation were consistent with the estimated situation of real G6PD-deficient cells. These results suggest that the de novo glutathione synthesis pathway and the GSSG export system play an important role in alleviating the consequences of G6PD deficiency. © 2005 Nakayama et al; licensee BioMed Central Ltd.

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Cleavage of double-stranded RNA by RNase HI from a thermoacidophilic archaeon, Sulfolobus tokodaii 7

Ohtani N., Yanagawa H., Tomita M., Itaya M.

Nucleic Acids Research 32 ( 19 ) 5809 - 5819 2004.12

ISSN 03051048

ST0753, the orthologous gene of Type 1 RNase H found in a thermoacidophilic archaeon, Sulfolobus tokodaii, was analyzed. The recombinant ST0753 protein exhibited RNase H activity in both in vivo and in vitro assays. The protein expressed in an RNase H-deficient mutant Escherichia coli strain functioned to suppress the temperature-sensitive phenotype associated with the lack of RNase H. The in vitro characteristics of the gene's RNase H activity were similar to those of Halobacterium RNase HI, the first archaeal Type 1 RNase H to be characterized. Surprisingly, the S.tokodaii RNase HI cleaved not only the RNA strand of an RNA/DNA hybrid but also an RNA strand of an RNA/RNA duplex in the presence of Mn2+ or Co2+. The result of gel filtration column chromatography showed this double-stranded RNA-dependent RNase (dsRNase) activity was coincident with S.tokodaii RNase HI. A site-directed mutagenesis study of essential amino acids for RNase H activity indicated that this activity also affected dsRNase activity. A single amino acid replacement of Asp-125 by Asn resulted in loss of dsRNase activity but not RNase H activity, suggesting that amino acid residues required for dsRNase activity seemed slightly different from those of RNase H activity. Some reverse transcriptases from retroelements can cleave double-stranded RNA, and this activity requires the RNase H domain. Similarities in primary structure and biochemical characteristics between S.tokodaii RNase HI and reverse transcriptases imply that the S.tokodaii enzyme might be derived from the RNase H domain of reverse transcriptase. © Oxford University Press 2004; all rights reserved.

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Comparative Analysis of Physical Maps of Four Bacillus subtilis (natto) Genomes

Qiu, Dongru Fujita, Kyoko Sakuma, Yuko Tanaka, Teruo Ohashi, Yoshiaki Ohshima, Hideyuki Tomita, Masaru Itaya, Mitsuhiro

Applied & Environmental Microbiology 70 ( 10 ) 6247-6256 - 6256 2004.10

Research paper (scientific journal), Joint Work, ISSN 00992240

The complete SfiI and I-CeuI physical maps of four Bacillus subtilis (natto) strains, which were previously isolated as natto (fermented soybean) starters, were constructed to elucidate the genome structure. Not only the similarity in genome size and organization but also the microheterogeneity of the gene context was revealed. No large-scale genome rearrangements among the four strains were indicated by mapping of the genes, including 10 rRNA operons (rrn) and relevant genes required for natto production, to the loci corresponding to those of the B. subtilis strain Marburg 168. However, restriction fragment length polymorphism and the presence or absence of strain-specific DNA sequences, such as the prophages SPβ, skin element, and PBSX, as well as the insertion element IS4Bsu1, could be used to identify one of these strains as a Marburg type and the other three strains as natto types. The genome structure and gene heterogeneity were also consistent with the type of indigenous plasmids harbored by the strains.

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Computational comparative analyses of alternative splicing regulation using full-length cDNA of various eukaryotes.

Itoh H, Washio T, Tomita M.

RNA 10 ( 7 ) 1005-1018 - 1018 2004.07

Research paper (scientific journal), Joint Work, ISSN 13558382

We previously reported a computational approach to infer alternative splicing patterns from Mus musculus full-length cDNA clones and microarray data. Although we predicted a large number of unreported splice variants, the general mechanisms regulating alternative splicing were yet unknown. In the present study, we compared alternative exons and constitutive exons in terms of splice-site strength and frequency of potential regulatory sequences. These regulatory features were further compared among five different species: Homo sapiens, M. musculus, Arabidopsis thaliana, Oryza sativa, and Drosophila melanogaster. Solid statistical validations of our comparative analyses indicated that alternative exons have (1) weaker splice sites and (2) more potential regulatory sequences than constitutive exons. Based on our observations, we propose a combinatorial model of alternative splicing mechanisms, which suggests that alternative exons contain weak splice sites regulated alternatively by potential regulatory sequences on the exons.

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A new role for expressed pseudogenes as ncRNA: Regulation of mRNA stability of is homologous coding gene

Yano Y., Saito R., Yoshida N., Yoshiki A., Wynshaw-Boris A., Tomita M., Hirotsune S.

Journal of Molecular Medicine 82 ( 7 ) 414 - 422 2004.07

ISSN 09462716

We have earlier generated a mutant mouse in a course of making a transgenic line that exhibited interesting heterozygote phenotypes, which exhibited failure to thrive, severe bone deformities, and polycystic kidneys. This mutant mouse provided a clue to uncover a unique role of expressed pseudogenes. In this mutant the transgene was integrated into the vicinity of the expressing pseudogene of Makorin1 called Makorin1-p1. This insertion reduced transcription of the Makorin1-p1, resulting in destabilization of the Makorin1 mRNA in trans via a cis-acting RNA decay element within the 5′ region of Makorin1 that is homologous between Makorin1 and Makorin1-p1. These findings demonstrate a novel and specific regulatory role of an expressed pseudogene as well as functional significance for noncoding RNAs. Next, we developed an original algorithm to determine how many pseudogenes are expressed. Based on our examination 2-3% of human processed pseudogenes are expressed using the most strict criteria. Interestingly, the mouse has a much smaller proportion of expressed pseudogenes (0.5-1%). Pseudogenes are functionally less constrained, and have accumulated more mutations than translated genes. If they have some functions in gene regulation, this property would allow more rapid functional diversification than protein-coding genes. In addition, some genetic phenomena that exhibit incomplete penetrance might be attributed to "mutation" or "variation" of pseudogenes. © Springer-Verlag 2004.

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