Masao Nagasaki

Tohoku University, Japan

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Publications (121)335.94 Total impact

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    ABSTRACT: Library quantitation is a critical step to obtain high data output in Illumina HiSeq sequencers. Here, we introduce a library quantitation method that utilizes Illumina MiSeq sequencer, designated as quantitative MiSeq (qMiSeq). In this procedure, 96 dual-index libraries including control samples are denatured, pooled in equal volume, and sequenced by MiSeq. We found that relative concentration of each library can be determined based on the observed index ratio and can be used to determine HiSeq run condition for each library. Thus, qMiSeq provides an efficient way to quantitate a large number of libraries at a time.
    Analytical Biochemistry 08/2014; · 2.58 Impact Factor
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    ABSTRACT: Validation of single nucleotide variations in whole-genome sequencing is critical for studying disease-related variations in large populations. A combination of different types of next-generation sequencers for analyzing individual genomes may be an efficient means of validating multiple single nucleotide variations calls simultaneously.
    BMC genomics. 08/2014; 15(1):673.
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    ABSTRACT: Next-generation sequencers (NGSs) have become one of the main tools for current biology. To obtain useful insights from the NGS data, it is essential to control low-quality portions of the data affected by technical errors such as air bubbles in sequencing fluidics.
    BMC genomics. 08/2014; 15(1):664.
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    ABSTRACT: Recently, several biological simulation models of, e.g., gene regulatory networks and metabolic pathways, have been constructed based on existing knowledge of biomolecular reactions, e.g., DNA-protein and protein-protein interactions. However, since these do not always contain all necessary molecules and reactions, their simulation results can be inconsistent with observational data. Therefore, improvements in such simulation models are urgently required. A previously reported method created multiple candidate simulation models by partially modifying existing models. However, this approach was computationally costly and could not handle a large number of candidates that are required to find models whose simulation results are highly consistent with the data. In order to overcome the problem, we focused on the fact that the qualitative dynamics of simulation models are highly similar if they share a certain amount of regulatory structures. This indicates that better fitting candidates tend to share the basic regulatory structure of the best fitting candidate, which can best predict the data among candidates. Thus, instead of evaluating all candidates, we propose an efficient explorative method that can selectively and sequentially evaluate candidates based on the similarity of their regulatory structures. Furthermore, in estimating the parameter values of a candidate, e.g., synthesis and degradation rates of mRNA, for the data, those of the previously evaluated candidates can be utilized. The method is applied here to the pharmacogenomic pathways for corticosterids in rats, using time-series microarray expression data. In the performance test, we succeeded in obtaining more than 80% of consistent solutions within 15% of the computational time as compared to the comprehensive evaluation. Then, we applied this approach to 142 literature-recorded simulation models of corticosteroid-induced genes, and consequently selected 134 newly constructed better models. The method described here was found to be capable of efficiently exploring candidate simulation models and obtaining better models within a short span of time. Furthermore, the results suggest that there may be room for improvement in literature recorded pathways and that they can be systematically updated using biological observational data.
    Bio Systems 06/2014; · 1.27 Impact Factor
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    ABSTRACT: CSML and SBML are XML-based model definition standards which are developed with the aim of creating exchange formats for modeling, visualizing and simulating biological pathways. In this article we report a release of a format convertor for quantitative pathway models, namely CSML2SBML. It translates models encoded by CSML into SBML without loss of structural and kinetic information. The simulation and parameter estimation of the resulting SBML model can be carried out with compliant tool CellDesigner for further analysis. The convertor is based on the standards CSML version 3.0 and SBML Level 2 Version 4. In our experiments, 11 out of 15 pathway models in CSML model repository and 228 models in Macrophage Pathway Knowledgebase (MACPAK) are successfully converted to SBML models. The consistency of the resulting model is validated by libSBML Consistency Check of CellDesigner. Furthermore, the converted SBML model assigned with the kinetic parameters translated from CSML model can reproduce the same dynamics with CellDesigner as CSML one running on Cell Illustrator. CSML2SBML, along with its instructions and examples for use are available at http://csml2sbml.csml.org.
    Bio Systems 05/2014; · 1.27 Impact Factor
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    ABSTRACT: Heterozygous GATA-2 germline mutations are associated with overlapping clinical manifestations termed GATA-2 deficiency, characterized by immunodeficiency and predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, there is considerable clinical heterogeneity among patients, and the molecular basis for the evolution of immunodeficiency into MDS/AML remains unknown. Thus, we conducted whole-genome sequencing on a patient with a germline GATA-2 heterozygous mutation (c. 988 C > T; p. R330X), who had a history suggestive of immunodeficiency and evolved into MDS/AML. Analysis was conducted with DNA samples from leukocytes for immunodeficiency, bone marrow mononuclear cells for MDS and bone marrow-derived mesenchymal stem cells. Whereas we did not identify a candidate genomic deletion that may contribute to the evolution into MDS, a total of 280 MDS-specific nonsynonymous single nucleotide variants were identified. By narrowing down with the single nucleotide polymorphism database, the functional missense database, and NCBI information, we finally identified three candidate mutations for EZH2, HECW2 and GATA-1, which may contribute to the evolution of the disease.
    Annals of Hematology 04/2014; · 2.87 Impact Factor
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    ABSTRACT: CSML and SBML are XML-based model definition standards which are developed with the aim of creating exchange formats for modeling, visualizing and simulating biological pathways. In this article we report a release of a format convertor for quantitative pathway models, namely CSML2SBML. It translates models encoded by CSML into SBML without loss of structural and kinetic information. The simulation and parameter estimation of the resulting SBML model can be carried out with compliant tool CellDesigner for further analysis. The convertor is based on the standards CSML version 3.0 and SBML Level 2 Version 4. In our experiments, 11 out of 15 pathway models in CSML model repository and 228 models in Macrophage Pathway Knowledgebase (MACPAK) are successfully converted to SBML models. The consistency of the resulting model is validated by libSBML Consistency Check of CellDesigner. Furthermore, the converted SBML model assigned with the kinetic parameters translated from CSML model can reproduce the same dynamics with CellDesigner as CSML one running on Cell Illustrator. CSML2SBML, along with its instructions and examples for use are available at http://csml2sbml.csml.org
    Biosystems. 01/2014;
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    ABSTRACT: Comprehensive understanding of gene regulatory networks (GRNs) is a major challenge in the field of systems biology. Currently, there are two main approaches in GRN analysis using time-course observation data, namely an ordinary differential equation (ODE)-based approach and a statistical model-based approach. The ODE-based approach can generate complex dynamics of GRNs according to biologically validated nonlinear models. However, it cannot be applied to ten or more genes to simultaneously estimate system dynamics and regulatory relationships due to the computational difficulties. The statistical model-based approach uses highly abstract models to simply describe biological systems and to infer relationships among several hundreds of genes from the data. However, the high abstraction generates false regulations that are not permitted biologically. Thus, when dealing with several tens of genes of which the relationships are partially known, a method that can infer regulatory relationships based on a model with low abstraction and that can emulate the dynamics of ODE-based models while incorporating prior knowledge is urgently required. To accomplish this, we propose a method for inference of GRNs using a state space representation of a vector auto-regressive (VAR) model with L1 regularization. This method can estimate the dynamic behavior of genes based on linear time-series modeling constructed from an ODE-based model and can infer the regulatory structure among several tens of genes maximizing prediction ability for the observational data. Furthermore, the method is capable of incorporating various types of existing biological knowledge, e.g., drug kinetics and literature-recorded pathways. The effectiveness of the proposed method is shown through a comparison of simulation studies with several previous methods. For an application example, we evaluated mRNA expression profiles over time upon corticosteroid stimulation in rats, thus incorporating corticosteroid kinetics/dynamics, literature-recorded pathways and transcription factor (TF) information.
    PLoS ONE 01/2014; 9(8):e105942. · 3.53 Impact Factor
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    ABSTRACT: Recently, several biological simulation models of, e.g., gene regulatory networks and metabolic pathways, have been constructed based on existing knowledge of biomolecular reactions, e.g., DNA–protein and protein–protein interactions. However, since these do not always contain all necessary molecules and reactions, their simulation results can be inconsistent with observational data. Therefore, improvements in such simulation models are urgently required. A previously reported method created multiple candidate simulation models by partially modifying existing models. However, this approach was computationally costly and could not handle a large number of candidates that are required to find models whose simulation results are highly consistent with the data. In order to overcome the problem, we focused on the fact that the qualitative dynamics of simulation models are highly similar if they share a certain amount of regulatory structures. This indicates that better fitting candidates tend to share the basic regulatory structure of the best fitting candidate, which can best predict the data among candidates. Thus, instead of evaluating all candidates, we propose an efficient explorative method that can selectively and sequentially evaluate candidates based on the similarity of their regulatory structures. Furthermore, in estimating the parameter values of a candidate, e.g., synthesis and degradation rates of mRNA, for the data, those of the previously evaluated candidates can be utilized. The method is applied here to the pharmacogenomic pathways for corticosteroids in rats, using time-series microarray expression data. In the performance test, we succeeded in obtaining more than 80% of consistent solutions within 15% of the computational time as compared to the comprehensive evaluation. Then, we applied this approach to 142 literature-recorded simulation models of corticosteroid-induced genes, and consequently selected 134 newly constructed better models. The method described here was found to be capable of efficiently exploring candidate simulation models and obtaining better models within a short span of time. Furthermore, the results suggest that there may be room for improvement in literature recorded pathways and that they can be systematically updated using biological observational data.
    Biosystems. 01/2014;
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    ABSTRACT: Variant calling from genome-wide sequencing data is essential for the analysis of disease-causing mutations and elucidation of disease mechanisms. However, variant calling in low coverage regions is difficult due to sequence read errors and mapping errors. Hence, variant calling approaches that are robust to low coverage data are demanded. We propose a new variant calling approach that considers pedigree information and haplotyping based on sequence reads spanning two or more heterozygous positions termed phase informative reads. In our approach, genotyping and haplotyping by the assignment of each read to a haplotype based on phase informative reads are simultaneously performed. Therefore, positions with low evidence for heterozygosity are rescued by phase informative reads, and such rescued positions contribute to haplotyping in a synergistic way. In addition, pedigree information supports more accurate haplotyping as well as genotyping, especially in low coverage regions. Although heterozygous positions are useful for haplotyping, homozygous positions are not informative and weaken the information from heterozygous positions as majority of positions are homozygous. Thus, we introduce latent variables that determine zygosity at each position in order to filter out homozygous positions for haplotyping. In performance evaluation with a parent-offspring trio sequencing data, our approach outperforms existing approaches in accuracy on the agreement with SNP array genotyping results. Also, performance analysis considering distance between variants showed that the use of phase informative reads is effective for accurate variant calling, and further performance improvement is expected with longer sequencing data. nagasaki@megabank.tohoku.ac.jp.
    Bioinformatics 09/2013; · 5.47 Impact Factor
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    ABSTRACT: Cohesin is a multimeric protein complex that is involved in the cohesion of sister chromatids, post-replicative DNA repair and transcriptional regulation. Here we report recurrent mutations and deletions involving multiple components of the cohesin complex, including STAG2, RAD21, SMC1A and SMC3, in different myeloid neoplasms. These mutations and deletions were mostly mutually exclusive and occurred in 12.1% (19/157) of acute myeloid leukemia, 8.0% (18/224) of myelodysplastic syndromes, 10.2% (9/88) of chronic myelomonocytic leukemia, 6.3% (4/64) of chronic myelogenous leukemia and 1.3% (1/77) of classical myeloproliferative neoplasms. Cohesin-mutated leukemic cells showed reduced amounts of chromatin-bound cohesin components, suggesting a substantial loss of cohesin binding sites on chromatin. The growth of leukemic cell lines harboring a mutation in RAD21 (Kasumi-1 cells) or having severely reduced expression of RAD21 and STAG2 (MOLM-13 cells) was suppressed by forced expression of wild-type RAD21 and wild-type RAD21 and STAG2, respectively. These findings suggest a role for compromised cohesin functions in myeloid leukemogenesis.
    Nature Genetics 08/2013; · 35.21 Impact Factor
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    ABSTRACT: Many human genes express multiple transcript isoforms through alternative splicing, which greatly increases diversity of protein function. Although RNA sequencing (RNA-Seq) technologies have been widely used in measuring amounts of transcribed mRNA, accurate estimation of transcript isoform abundances from RNA-Seq data is challenging, because reads often map to more than one transcript isoforms or paralogs whose sequences are very similar to each other. We propose a statistical method to estimate transcript isoform abundances from RNA-Seq data. Our method can handle gapped alignments of reads against reference sequences so that it allows insertion or deletion errors within reads. The proposed meth-od optimizes the number of transcript isoforms by variational Bayes-ian inference through an iterative procedure, and its convergence is guaranteed under a stopping criterion. On simulated data sets, our method outperformed the comparable quantification methods in inferring transcript isoform abundances, and at the same time its rate of convergence was faster than that of the expectation maximi-zation (EM) algorithm. We also applied our method to RNA-Seq data of human cell line samples, and showed that our prediction result was more consistent among technical replicates than those of other methods. An implementation of our method is available at http://github.com/nariai/tigar CONTACT: nariai@megabank.tohoku.ac.jp SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    Bioinformatics 07/2013; · 5.47 Impact Factor
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    ABSTRACT: The derivation of induced pluripotent stem (iPS) cells from individuals of genetic disorders offers new opportunities for basic research into these diseases and the development of therapeutic compounds. Severe congenital neutropenia (SCN) is a serious disorder characterized by severe neutropenia at birth. SCN is associated with heterozygous mutations in the neutrophil elastase [elastase, neutrophil-expressed (ELANE)] gene, but the mechanisms that disrupt neutrophil development have not yet been clarified because of the current lack of an appropriate disease model. Here, we generated iPS cells from an individual with SCN (SCN-iPS cells). Granulopoiesis from SCN-iPS cells revealed neutrophil maturation arrest and little sensitivity to granulocyte-colony stimulating factor, reflecting a disease status of SCN. Molecular analysis of the granulopoiesis from the SCN-iPS cells vs. control iPS cells showed reduced expression of genes related to the wingless-type mmtv integration site family, member 3a (Wnt3a)/β-catenin pathway [e.g., lymphoid enhancer-binding factor 1], whereas Wnt3a administration induced elevation lymphoid enhancer-binding factor 1-expression and the maturation of SCN-iPS cell-derived neutrophils. These results indicate that SCN-iPS cells provide a useful disease model for SCN, and the activation of the Wnt3a/β-catenin pathway may offer a novel therapy for SCN with ELANE mutation.
    Proceedings of the National Academy of Sciences 02/2013; · 9.81 Impact Factor
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    ABSTRACT: Structural variations (SVs), such as insertions, deletions, inversions, and duplications, are a common feature in human genomes, and a number of studies have reported that such SVs are associated with human diseases. Although the progress of next generation sequencing (NGS) technologies has led to the discovery of a large number of SVs, accurate and genome-wide detection of SVs remains challenging. Thus far, various calling algorithms based on NGS data have been proposed. However, their strategies are diverse and there is no tool able to detect a full range of SVs accurately. We focused on evaluating the performance of existing deletion calling algorithms for various spanning ranges from low- to high-coverage simulation data. The simulation data was generated from a whole genome sequence with artificial SVs constructed based on the distribution of variants obtained from the 1000 Genomes Project. From the simulation analysis, deletion calls of various deletion sizes were obtained with each caller, and it was found that the performance was quite different according to the type of algorithms and targeting deletion size. Based on these results, we propose an integrated structural variant calling pipeline (iSVP) that combines existing methods with a newly devised filtering and merging processes. It achieved highly accurate deletion calling with >90% precision and >90% recall on the 30× read data for a broad range of size. We applied iSVP to the whole-genome sequence data of a CEU HapMap sample, and detected a large number of deletions, including notable peaks around 300 bp and 6,000 bp, which corresponded to Alus and long interspersed nuclear elements, respectively. In addition, many of the predicted deletions were highly consistent with experimentally validated ones by other studies. We present iSVP, a new deletion calling pipeline to obtain a genome-wide landscape of deletions in a highly accurate manner. From simulation and real data analysis, we show that iSVP is broadly applicable to human whole-genome sequencing data, which will elucidate relationships between SVs across genomes and associated diseases or biological functions.
    BMC Systems Biology 01/2013; 7 Suppl 6:S8. · 2.98 Impact Factor
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    ABSTRACT: Using quantitative PCR-based miRNA arrays, we comprehensively analyzed the expression profiles of miRNAs in human and mouse embryonic stem (ES), induced pluripotent stem (iPS), and somatic cells. Immature pluripotent cells were purified using SSEA-1 or SSEA-4 and were used for miRNA profiling. Hierarchical clustering and consensus clustering by nonnegative matrix factorization showed two major clusters, human ES/iPS cells and other cell groups, as previously reported. Principal components analysis (PCA) to identify miRNAs that segregate in these two groups identified miR-187, 299-3p, 499-5p, 628-5p, and 888 as new miRNAs that specifically characterize human ES/iPS cells. Detailed direct comparisons of miRNA expression levels in human ES and iPS cells showed that several miRNAs included in the chromosome 19 miRNA cluster were more strongly expressed in iPS cells than in ES cells. Similar analysis was conducted with mouse ES/iPS cells and somatic cells, and several miRNAs that had not been reported to be expressed in mouse ES/iPS cells were suggested to be ES/iPS cell-specific miRNAs by PCA. Comparison of the average expression levels of miRNAs in ES/iPS cells in humans and mice showed quite similar expression patterns of human/mouse miRNAs. However, several mouse- or human-specific miRNAs are ranked as high expressers. Time course tracing of miRNA levels during embryoid body formation revealed drastic and different patterns of changes in their levels. In summary, our miRNA expression profiling encompassing human and mouse ES and iPS cells gave various perspectives in understanding the miRNA core regulatory networks regulating pluripotent cells characteristics.
    PLoS ONE 01/2013; 8(9):e73532. · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: Structural variations (SVs) in genomes are commonly observed even in healthy individuals and play key roles in biological functions. To understand their functional impact or to infer molecular mechanisms of SVs, they have to be characterized with the maximum resolution. However, high-resolution analysis is a difficult task because it requires investigation of the complex structures involved in an enormous number of alignments of next-generation sequencing (NGS) reads and genome sequences that contain errors. RESULTS: We propose a new method called ChopSticks that improves the resolution of SV detection for homozygous deletions even when the depth of coverage is low. Conventional methods based on read pairs use only discordant pairs to localize the positions of deletions, where a discordant pair is a read pair whose alignment has an aberrant strand or distance. In contrast, our method exploits concordant reads as well. We theoretically proved that when the depth of coverage approaches zero or infinity, the expected resolution of our method is asymptotically equal to that of methods based only on discordant pairs under double coverage. To confirm the effectiveness of ChopSticks, we conducted computational experiments against both simulated NGS reads and real NGS sequences. The resolution of deletion calls by other methods was significantly improved, thus demonstrating the usefulness of ChopSticks. CONCLUSIONS: ChopSticks can generate high-resolution deletion calls of homozygous deletions using information independent of other methods, and it is therefore useful to examine the functional impact of SVs or to infer SV generation mechanisms.
    BMC Bioinformatics 10/2012; 13(1):279. · 3.02 Impact Factor
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    ABSTRACT: XiP (eXtensible integrative Pipeline) is a flexible, editable and modular environment with a user-friendly interface that does not require previous advanced programming skills to run, construct and edit workflows. XiP allows the construction of workflows by linking components written in both R and Java, the analysis of high-throughput data in grid engine systems and also the development of customized pipelines that can be encapsulated in a package and distributed. XiP already comes with several ready to use pipeline flows for the most common genomic and transcriptomic analysis and ≈300 computational components. AVAILABILITY: XiP is open source, freely available under the Lesser General Public License (LGPL) and can be downloaded from http://xip.hgc.jp. CONTACT: nagasaki@megabank.tohoku.ac.jp.
    Bioinformatics 10/2012; · 5.47 Impact Factor
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    ABSTRACT: Neural stem cells (NSCs) are considered to be the cell of origin of glioblastoma multiforme (GBM). However, the genetic alterations that transform NSCs into glioma-initiating cells remain elusive. Using a unique transposon mutagenesis strategy that mutagenizes NSCs in culture, followed by additional rounds of mutagenesis to generate tumors in vivo, we have identified genes and signaling pathways that can transform NSCs into glioma-initiating cells. Mobilization of Sleeping Beauty transposons in NSCs induced the immortalization of astroglial-like cells, which were then able to generate tumors with characteristics of the mesenchymal subtype of GBM on transplantation, consistent with a potential astroglial origin for mesenchymal GBM. Sequence analysis of transposon insertion sites from tumors and immortalized cells identified more than 200 frequently mutated genes, including human GBM-associated genes, such as Met and Nf1, and made it possible to discriminate between genes that function during astroglial immortalization vs. later stages of tumor development. We also functionally validated five GBM candidate genes using a previously undescribed high-throughput method. Finally, we show that even clonally related tumors derived from the same immortalized line have acquired distinct combinations of genetic alterations during tumor development, suggesting that tumor formation in this model system involves competition among genetically variant cells, which is similar to the Darwinian evolutionary processes now thought to generate many human cancers. This mutagenesis strategy is faster and simpler than conventional transposon screens and can potentially be applied to any tissue stem/progenitor cells that can be grown and differentiated in vitro.
    Proceedings of the National Academy of Sciences 10/2012; · 9.81 Impact Factor
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    ABSTRACT: Epidemiological studies have suggested that the encounter with commensal microorganisms during the neonatal period is essential for normal development of the host immune system. Basic research involving gnotobiotic mice has demonstrated that colonization at the age of 5 weeks is too late to reconstitute normal immune function. In this study, we examined the transcriptome profiles of the large intestine (LI), small intestine (SI), liver (LIV), and spleen (SPL) of 3 bacterial colonization models-specific pathogen-free mice (SPF), ex-germ-free mice with bacterial reconstitution at the time of delivery (0WexGF), and ex-germ-free mice with bacterial reconstitution at 5 weeks of age (5WexGF)-and compared them with those of germ-free (GF) mice. Hundreds of genes were affected in all tissues in each of the colonized models; however, a gene set enrichment analysis method, MetaGene Profiler (MGP), demonstrated that the specific changes of Gene Ontology (GO) categories occurred predominantly in 0WexGF LI, SPF SI, and 5WexGF SPL, respectively. MGP analysis on signal pathways revealed prominent changes in toll-like receptor (TLR)- and type 1 interferon (IFN)-signaling in LI of 0WexGF and SPF mice, but not 5WexGF mice, while 5WexGF mice showed specific changes in chemokine signaling. RT-PCR analysis of TLR-related genes showed that the expression of interferon regulatory factor 3 (Irf3), a crucial rate-limiting transcription factor in the induction of type 1 IFN, prominently decreased in 0WexGF and SPF mice but not in 5WexGF and GF mice. The present study provides important new information regarding the molecular mechanisms of the so-called "hygiene hypothesis".
    BMC Genomics 07/2012; 13:335. · 4.40 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. We sequenced and analyzed the whole genomes of 27 HCCs, 25 of which were associated with hepatitis B or C virus infections, including two sets of multicentric tumors. Although no common somatic mutations were identified in the multicentric tumor pairs, their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared etiological backgrounds may have strongly influenced their somatic mutation patterns. Statistical and functional analyses yielded a list of recurrently mutated genes. Multiple chromatin regulators, including ARID1A, ARID1B, ARID2, MLL and MLL3, were mutated in ∼50% of the tumors. Hepatitis B virus genome integration in the TERT locus was frequently observed in a high clonal proportion. Our whole-genome sequencing analysis of HCCs identified the influence of etiological background on somatic mutation patterns and subsequent carcinogenesis, as well as recurrent mutations in chromatin regulators in HCCs.
    Nature Genetics 05/2012; 44(7):760-4. · 35.21 Impact Factor

Publication Stats

1k Citations
335.94 Total Impact Points

Institutions

  • 2012–2014
    • Tohoku University
      Japan
    • Osaka Prefecture University
      • Department of Mathematical Sciences
      Sakai, Osaka-fu, Japan
  • 1998–2011
    • The University of Tokyo
      • • Institute of Medical Science
      • • Center for Human Genome
      • • Department of Information Science
      Tokyo, Tokyo-to, Japan
  • 2009
    • Cambridge College
      Cambridge, Massachusetts, United States
  • 2008–2009
    • The Institute of Statistical Mathematics
      Edo, Tōkyō, Japan
  • 2002–2004
    • Yamaguchi University
      • • Faculty of Science
      • • Graduate School of Science and Engineering
      Yamaguchi-shi, Yamaguchi-ken, Japan