Information Technoloy for Gene Network Analysis

• Project/Area Number: 15014205
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: MIYANO Satoru The Univeristy of Tokyo, Institute of Medical Science, Professor, 医科学研究所, 教授 (50128104)
• Co-Investigator(Kenkyū-buntansha): IMOTO Seiya Institute of Medical Science, Assistant Professor, 医科学研究所, 助手 (10345027) ; DE Hoon Michiel J.L. 東京大学, 医科学研究所, 科学技術振興特任教員 ; HOON Michiel J.I. de Institute of Medical Science, Assistant Professor ; DE Hoon L.J.Michiel 東京大学, 医科学研究所, 科学技術振興特任教員(常勤形態) ; DEHOON L. J. Michiel 東京大学, 医科学研究所, 科学技術振興特任教員(常勤形態)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥32,000,000 (Direct Cost: ¥32,000,000); Fiscal Year 2004: ¥16,000,000 (Direct Cost: ¥16,000,000); Fiscal Year 2003: ¥16,000,000 (Direct Cost: ¥16,000,000)
• Keywords: gene network / Bayesian network / nonparametric regression / simulation / microarray analysis / Petri net / systems biology / search algorithm

Research Abstract

We developed information technology for estimating gene networks accurately from multiple source of genetic information including microarray gene expression data. We also developed an XML format for describing dynamic models of gene networks. The following results are obtained:
(1)We developed a computational method for estimating gene networks from microarray data obtained from various perturbations such as gene disruptions, gene overexpressions, drug responses, etc. The method combines the Bayesian network approach with nonparametric regression, where genes are regarded as random variables and the nonparametric regression enables us to capture from linear to nonlinear structures between genes. As a criterion for choosing good networks, we introduced the BNRC (Bayesian network and Nonparametric Regression Criterion) score. Naturally, the sole use of microarray data has limitations on gene network estimation. For improving the biological accuracy of estimated gene networks, we have made a general framework by extending this method so that it can employ genome-wide other biological information such as sequence information on promoter regions, protein-protein interactions. Computational experiments were conducted with yeast data and they show that cascades of gene regulations were effectively extracted.
(2)The problem of finding an optimal Bayesian network is known computationally intractable for BNRC, BDe, MDL scores. For example, in order to find an optimal Bayesian network of 20 genes from 100 microarray data, the brute force algorithm employing all computing resources in the world even requires the time exceeding the life time of the solar system. Our recent computational challenge has made possible to search and enumerate optimal and suboptimal Bayesian networks in feasible time on supercomputers. Computational experiments with this search algorithm have provided evidences of the biological rationality of our computational strategy We obtained the following scientific knowledge: (i) Optimal Bayesian networks do not necessarily reflect the most accurate biological knowledge. (ii) Gene・gene relations which appear very frequently in optimal and suboptimal networks are biologically very likely. (iii) BNRC score is much better than BDe and MDL scores for gene network estimation. Furthermore, by putting constraints arising from biological knowledge, a faster algorithm is also developed.
(3)We designed and developed an XML called CSML Version 1.0 (Cell System ML) for describing and simulating dynamic models of gene networks. Based on this, we developed programs which automatical convert pathway models in KEGG and BioCyc to CSML models so that dynamic models can be constructed. Cell Illustrator is used for modeling and simulation of the models which employs CSML for model description. This framework enables us to develope large-scale metabolic pathway models for simulation.

Research Products

• [Journal Article] Superiority of network motifs over optimal networks and an application to the revelation of gene network evolution (2005)
  • Author(s): Ott, S., Hansen, A., Kim, S.-Y., Miyano, S.
  • Journal Title: Bioinformatics 21・2 Pages: 227-238
• [Journal Article] Combining microarrays and biological knowledge for estimating gene networks via Bayesian networks (2004)
  • Author(s): Imoto, S., Higuchi, T., Goto, T., Tashiro, K., Kuhara, S., Miyano, S.
  • Journal Title: Journal of Bioinformatics and Computational Biology 2(1) Pages: 77-98
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Dynamic Bayesian network and nonparametric regression for nonlinear modeling of gene networks from time series gene expression data (2004)
  • Author(s): Kim, S., Imoto, S., Miyano, S.
  • Journal Title: Biosystems 75(1-3) Pages: 57-65
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Functional data analysis of the dynamics of gene regulatory networks (2004)
  • Author(s): Ando, T., Imoto, S., Miyano, S.
  • Journal Title: Proc. Knowledge Exploration in Life Science Informatics KELSI2004. Lecture Notes in Artificial Intelligence 3303 Pages: 69-83
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Bayesian network and radial basis function network regression for nonlinear modeling of genetic network (2004)
  • Author(s): Ando, T., Imoto, S., Miyano, S.
  • Journal Title: Proc. Third International Conference on Information 3 Pages: 561-564
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Using protein-protein interactions for refining gene networks estimated from microarray data by Bayesian networks (2004)
  • Author(s): Nariai, N., Kim, S., Imoto, S., Miyano S.
  • Journal Title: Pacific Symposium on Biocomputing 9 Pages: 336-347
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Finding optimal models for small gene networks (2004)
  • Author(s): Ott, S., Imoto, S., Miyano, S.
  • Journal Title: Pacific Symposium on Biocomputing 9 Pages: 557-567
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Predicting gene regulation by sigma factors in Bacillus subtilis from genome-wide data (2004)
  • Author(s): De Hoon, M.J.L., Makita, Y., Imoto, S., Kobayashi, K., Ogasawara, N., Nakai, K., Miyano, S.
  • Journal Title: Bioinformatics 20 (Suppl.1)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] An 0(N^2) algorithm for discovering optimal Boolean pattern pairs (2004)
  • Author(s): Bannai, H., Hyyro, H., Shinohara, A., Takeda, M., Nakai, K., Miyano, S.
  • Journal Title: IEEE/ACM Transactions on Computational Biology and Bioinformatics 1 Pages: 159-170
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Efficiently finding regulatory elements using correlation with gene expression (2004)
  • Author(s): Bannai, H., Inenaga, S., Shinohara, A., Takeda, M., Miyano, S.
  • Journal Title: J. Bioinformatics and Computational Biology 2(2) Pages: 273-288
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Predicting the operon structure of Bacillus subtilis using operon length, intergene distance, and gene expression information (2004)
  • Author(s): De Hoon, M.J., Imoto, S., Kobayashi, K., Ogasawara, N., Miyano, S.
  • Journal Title: Pacific Symposium on Biocomputing 9 Pages: 276-287
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Open source clustering software (2004)
  • Author(s): De Hoon, M.J.L., Imoto, S., Nolan, J., Miyano, S.
  • Journal Title: Bioinformatics 20(9) Pages: 1453-1454
  • NAID: 130003997165
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A versatile Petri net based architecture for modeling and simulation of complex biological processes (2004)
  • Author(s): Nagasaki, M., Doi, A., Matsuno, H., Miyano, S.
  • Journal Title: Genome Informatics 15(1) Pages: 180-197
  • NAID: 120003184321
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Integrating biopathway databases for large-scale modeling and simulation. Proc (2004)
  • Author(s): Nagasaki, M., Doi, A., Matsuno, H., Miyano, S.
  • Journal Title: Second Asia-Pacific Bicinformatics Conference (APBC2004) Conferences in Research and Practice in Information Technology (Y. P. Chen, ed). 29 Pages: 43-52
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] XML pathway file conversion between Genomic Object Net and SBML (2004)
  • Author(s): Nakano, M., Noda, R., Kitakaze, H., Matsuno, H., Miyano, S.
  • Journal Title: Proc. The Third International Conference on Information 3 Pages: 585-588
  • NAID: 130003997270
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Combining microarrays and biological knowledge for estimating gene networks via Bayesian networks (2004)
  • Author(s): Imoto, S.., Higuchi, T., Goto, T., Tashiro, K., Kuhara, S., Miyano, S.
  • Journal Title: Journal of Bioinformatics and Computational Biology. 2(1) Pages: 77-98
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Dynamic Bayesian network and nonparametric regression for nonlinear modeling of gene networks from time series gene expression data (2004)
  • Author(s): Kim, S., Imoto, S., Miyano, S.
  • Journal Title: Biosystems. 75(1-3) Pages: 57-65
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional data analysis of the dynamics of gene regulatory networks (2004)
  • Author(s): Ando, T., Imoto, S., Miyano, S.
  • Journal Title: Proc. Knowledge Exploration in Life Science Informatics KELSI2004. Lecture Notes in Artificial Intelligence. 3303 Pages: 69-83
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Bayesian network and radial basis function network regression for nonlinear modeling of genetic network (2004)
  • Author(s): Ando, T., Imoto, S., Miyano, S.
  • Journal Title: Proc. Third International Conference on Information. Pages: 561-564
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Using protein-protein interactions for refining gene networks estimated from microarray data by Bayesian networks (2004)
  • Author(s): Nariai, N., Kim, S., Imoto, S., Miyano, S.
  • Journal Title: Pacific Symposium on Biocomputing. 9 Pages: 336-347
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Finding optimal models for small gene networks (2004)
  • Author(s): Ott, S., Imoto, S., Miyano, S.
  • Journal Title: Pacific Symposium on Biocomputing. 9 Pages: 557-567
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Predicting gene regulation by sigma factors in Bacillus subtilis from genome-wide data (2004)
  • Author(s): De Hoon, M.J.L., Makita, Y., Imoto, S., Kobayashi, K., Ogasawara, N., Nakai, K., Miyano, S.
  • Journal Title: Bioinformatics. 20 (Supp1.1)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] An 0(N'2) algorithm for discovering optimal Boolean pattern pairs (2004)
  • Author(s): Bannai, H., Hyyro, H., Shinohara, A., Takeda, M., Nakai, K., Miyano, S.
  • Journal Title: IEEE/ACM Transactions on Computational Biology and Bioinformatics. 1(4) Pages: 159-170
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Efficiently finding regulatory elements using correlation with gene expression (2004)
  • Author(s): Bannai, H., Inenaga, S., Shinohara, A., Takeda, M., Miyano, S.
  • Journal Title: J. Bioinformatics and Computational Biology. 2(2) Pages: 273-288
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Predicting the operon structure of Bacillus subtilis using operon length, intergene distance, and gene expression information (2004)
  • Author(s): De Hoon, M.J., Imoto, S., Kobayashi, K., Ogasawara, N., Miyano, S.
  • Journal Title: Pacific Symposium on Biocomputing. 9 Pages: 276-287
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Open source clustering software (2004)
  • Author(s): De Hoon, M.J.L., Imoto, S., Nolan, J., Miyano, S.
  • Journal Title: Bioinformatics. 20(9) Pages: 1453-1454
  • NAID: 130003997165
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A versatile Petri net based architecture for modeling and simulation of complex biological processes (2004)
  • Author(s): Nagasaki, M., Doi, A., Matsuno, H., Miyano, S.
  • Journal Title: Genome Informatics. 15(1) Pages: 180-197
  • NAID: 120003184321
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Integrating biopathway databases for large-scale modeling and simulation (2004)
  • Author(s): Nagasaki, M., Doi, A., Matsuno, H., Miyano, S.
  • Journal Title: Proc. Second Asia-Pacific Bioinformatics Conference (APBC2004) (Y.P. Chen, ed). Conferences in Research and Practice in Information Technology. 29 Pages: 43-52
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] XML pathway file conversion between Genomic Object Net and SBML (2004)
  • Author(s): Nakano, M., Noda, R., Kitakaze, H., Matsuno, H., Miyano, S.
  • Journal Title: Proc. The Third International Conference on Information. Pages: 585-588
  • NAID: 130003997270
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional data analysis of the dynamics of gene regulatory networks (2004)
  • Author(s): Ando, T., Imoto, S., Miyano, S.
  • Journal Title: Lecture Notes in Artificial Intelligence 3303 Pages: 69-83
• [Journal Article] Combining microarrays and biological knowledge for estimating gene networks via Bayesian networks (2004)
  • Author(s): Imoto, S., Higuchi, T., Goto, T., Tashiro, K., Kuhara, S., Miyano, S.
  • Journal Title: J.Bioinformatics and Computational Biology 2・1 Pages: 77-98
• [Journal Article] A versatile Petri net based architecture for modeling and simulation of complex biological processes (2004)
  • Author(s): Nagasaki, M., Doi, A., Matsuno, H., Miyano, S.
  • Journal Title: Genome Informatics 15・1 Pages: 180-197
  • NAID: 120003184321
• [Journal Article] Integrating biopathway databases for large-scale modeling and simulation (2004)
  • Author(s): Nagasaki, M., Doi, A., Matsuno, H., Miyano, S.
  • Journal Title: Research and Practice in Information Technology 29 Pages: 43-52
• [Journal Article] Bayesian network and nonparametric heteroscedastic regression for nonlinear modeling of genetic network (2003)
  • Author(s): Imoto, S., Kim, S., Goto, T., Aburatani, S., Tashiro, K., Kuhara, S., Miyano, S.
  • Journal Title: Journal of Bioinformatics and Computational Biology 1(2) Pages: 231-252
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inferring gene networks from time series microarray data using dynamic Bayesian networks (2003)
  • Author(s): Kim, S., Imoto, S., Miyano, S.
  • Journal Title: Briefings in Bioinformatics 4(3) Pages: 228-235
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inferring gene regulatory networks from time-ordered gene expression data of Bacillus subtilis using differential equations (2003)
  • Author(s): De Hoon, M., Imoto, S., Kobayashi, K., Ogasawara, N., Miyano, S.
  • Journal Title: Pacific Symposium on Biocomputing 8 Pages: 17-28
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Estimating gene networks from gene expression data by combining Bayesian network model with promoter element detection (2003)
  • Author(s): Tamada, Y., Kim, S., Bannai, H., Imoto, S., Tashiro, K., Kuhara, S., Miyano, S.
  • Journal Title: Bioinformatics 19 (Suppl. 2)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Finding optimal gene networks using biological constraints (2003)
  • Author(s): Ott, S., Miyano, S.
  • Journal Title: Genome Informatics 14 Pages: 124-133
  • NAID: 130003811824
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Bayesian network and nonparametric heteroscedastic regression for nonlinear modeling of genetic network (2003)
  • Author(s): Imoto, S., Kim, S., Goto, T., Aburatani, S., Tashiro, K., Kuhara, S., Miyano, S.
  • Journal Title: Journal of Bioinformatics and Computational Biology. 1(2) Pages: 231-252
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inferring gene networks from time series microarray data using dynamic Bayesian networks (2003)
  • Author(s): Kim, S., Imoto, S., Miyano, S.
  • Journal Title: Briefings in Bioinformatics. 4(3) Pages: 228-235
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inferring gene regulatory networks from time-ordered gene expression data of Bacillus subtilis using differential equations (2003)
  • Author(s): De Hoon, M., Imoto, S., Kobayashi, K., Ogasawara, N., Miyano, S.
  • Journal Title: Pacific Symposium on Biocomputing. 8 Pages: 17-28
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Estimating gene networks from gene expression data by combining Bayesian network model with promoter element detection (2003)
  • Author(s): Tamada, Y., Kim, S., Bannai, H., Imoto, S., Tashiro, K., Kuhara, S., Miyano, S.
  • Journal Title: Bioinformatics. 19(Supp1.2)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Finding optimal gene networks using biological constraints (2003)
  • Author(s): Ott, S., Miyano, S.
  • Journal Title: Genome Informatics. 14 Pages: 124-133
  • NAID: 130003811824
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kim, S., Imoto, S., Miyano, S.: "Inferring gene networks from time series microarray data using dynamic Bayesian networks"Briefings in Bioinformatics. 4巻3号. 228-235 (2003)
• [Publications] Tamada, Y., Kim, S., Bannai, H., Imoto, S., Tashiro, K., Kuhara, S., Miyano, S.: "Estimating gene networks from gene expression data by combining Bayesian network model with promoter element detection"Bioinformatics. 19巻Suppl.2. ii227-ii236 (2003)
• [Publications] Ott, S., Miyano, S.: "Finding optimal gene networks using biological constraints"Genome Informatics. 14巻. 124-133 (2003)
• [Publications] Nagasaki, M., Doi, A., Matsuno, H., Miyano, S.: "Genomic Object Net : I. a platform for modeling and simulating biopathways"Applied Bioinformatics. 2巻3号. 181-184 (2003)
• [Publications] Imoto, S., Kim, S., Goto, T., Aburatani, S., Tashiro K., Kuhara, S., Miyano, S.: "Bayesian network and nonparametric heteroscedastic regression for nonlinear modeling of genetic network"Journal of Bioinformatics and Computational Biology. 1巻2号. 231-252 (2003)
• [Publications] Imoto, S., Savoie, C.J., Aburatani, S., Kim, S., Tashiro, K., Kuhara, S., Miyano, S.: "Use of gene networks for identifying and validating drug targets"Journal of Bioinformatics and Computational Biology. 1巻3号. 459-474 (2003)