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研究人員 ｜ Research Faculty

● Assistant Research Fellow, Institute of Information Science, tion Engineering, National Taiwan University (Oct. 2003- Apr. 2004)
蔡懷寬 Huai-Kuang Tsai Academia Sinica, 2006- ● Ph.D., Department of Computer Science and Information Engineer-
● Assistant Research Fellow, Research Center of Information Technol- ing, National Taiwan University (1998-2003)
ogy Innovation, Academia Sinica, 2006- ● M.S., Department of Computer Science and Information Engineer-
● Assistant Professor, Department of Biological Science and Technol- ing, National Taiwan University (1996-1998)
助研究員 Assistant Research Fellow ogy, National Chiao-Tung University, 2008- ● B.S., Department of Computer Science and Information Engineering,
Ph.D., Computer Science and Information Engineering, National Taiwan University ● Assistant Professor, Department of Computer Science and Engineer- National Taiwan University (1992-1996)
ing, National Ocean University, 2008-
Tel: +886-2-2788-3799 ext. 1718 ● Postdoctoral Fellow, Genome Research Center, Academia Sinica
Fax: +886-2-2782-4814 (May 2004- June 2005)
Email: hktsai@iis.sinica.edu.tw ● Postdoctoral Fellow, Department of Computer Science and Informa-
http://www.iis.sinica.edu.tw/~hktsai

進一步分析這些退化位置序列的特性，我們發現這些具「功能性」的退化位置相對
於其他退化位置，顯著地在演化過程中被保留。我們證實了轉錄因子結合序列中有
部份退化位置對基因調控確實具備影響力，期能賦予基因轉錄調控研究在 DNA 序列 代表著作 Publications
分析上新的觀點與視野。
1. Tsai, H.K., Yang, J.M., and Kao, C.Y. (2001) A genetic algorithm for 15. Tsai, H.K., Yang, J.M., Tsai, Y.F. and Kao, C.Y. (2004) An evolution-
traveling salesman problems, Proceedings of the Genetic and Evolu- ary approach for gene expression patterns, IEEE Trans Inf Technol
研究簡介 Research Description tionary Computation Conference (GECCO), 687-693. Biomed, 8, 69-78.
2. Tsai, H.K., Yang, J.M. and Kao, C.Y. (2002) Solving traveling sales- 16. Tsai, H.K., Yang, J.M., Tsai, Y.F. and Kao, C.Y. (2004) An evolution-
目前普遍認為基因轉錄是受到轉錄因子及其結合位置所調 The transcription of genes is controlled by interaction between transcription fac- man problems by combining global and local search mechanisms, ary algorithm for large traveling salesman problems, IEEE Trans Syst
控，分析轉錄因子的功能與其對應的結合位置將有助於瞭 tors (TFs) and their binding sites (TFBSs) (or cis-regulatory elements). Inferring the Congress of Evolutionary Computation (CEC), 1290-1295. Man Cybern B Cybern, 34, 1718-1729.
解基因轉錄的機制。我們利用染色質免疫沈析晶片資料、 function of a TF and identifying its binding sites are helpful for understanding the 3. Tsai, H.K., Yang, J.M. and Kao, C.Y. (2002) Applying genetic algo- 17. Chan, C.H., Lee, S.A., Kao, C.Y. and Tsai, H.K. (2005) Improving
生物晶片資料以及酵母菌鄰近物種之 DNA 序列，作出 TF- mechanism of transcriptional regulation. In the past years, we develop a TFBS iden- rithms to finding the optimal gene order in displaying the microarray EAX with restricted 2-opt, Proceedings of the 2005 Genetic and Evo-
lutionary Computation (GECCO), 1471-1476.
data, Proceedings of the Genetic and Evolutionary Computation Con-
BSfinder 軟體以辨識轉錄因子之結合位置。對於每個轉錄 tification method, TFBSfinder, which utilizes several data sources, including DNA ference (GECCO), 610-617.
因子，TFBSfinder 先根據生物晶片資料找出可信度很高的調 sequences, phylogenetic information, microarray data and ChIP-chip data. For a TF, 18. Tsai, H.K., Lu, H.H. and Li, W.H. (2005) Statistical methods for iden-
tifying yeast cell cycle transcription factors, Proc Natl Acad Sci U S
控基因與非調控基因 (non-target genes)，然後在相較於那 TFBSfinder rigorously selects a set of reliable target genes and a set of non-target 4. Yang, J.M., Tsai, C.H., Hwang, M.J., Tsai, H.K., Hwang, J.K. and A, 102, 13532-13537.
Kao, C.Y. (2002) GEM: a Gaussian Evolutionary Method for predict-
些非調控基因下，尋找在其調控基因的啟動子中出現頻率 genes (as a background set) to find overrepresented and conserved motifs in tar- ing protein side-chain conformations, Protein Sci, 11, 1897-1907.
get genes. A new metric for measuring the degree of conservation at a binding site
高，且在相近物種間也被保存的 DNA 片段，將這些片段作 19. Zhao, E., Liu, H.L., Tsai, C.H., Tsai, H.K., Chan, C.H. and Kao, C.Y.
across species and methods for clustering motifs and for inferring position weight 5. Tsai, Y.F., Tsai, H.K. and Shieh, C.L. (2002) Hazard zone mapping of (2005) Cysteine separations profiles on protein sequences infer di-
群聚並找出具代表性的位置加權矩陣。此外，轉錄因子結 matrices are proposed. Besides, TFBSs are usually degenerate. We further propose debris flow, The Chinese Journal of Mechanics, part B, 18, 91-102. (in sulfide connectivity, Bioinformatics, 21, 1415-1420.
合位置常存有退化位置，亦即容許不同的核苷酸出現在該位 a method for discovering gapped motifs. A gapped transcription factor-binding Chinese) 20. Tsai, H.K., Huang, Grace T., Chou, M.Y., Lu, Henry, H.S. and Li,
置上。我們進一步尋找具非連續序列特徵之結合位置。所謂 site (TFBS) contains one or more highly degenerate positions. Discovering gapped 6. Chuang, H.Y., Tsai, H.K., Tsai, Y.F. and Kao, C.Y. (2003) Ranking W.H. (2006) Method for identifying transcription factor binding sites
的非連續性序列特徵指的是所找到的序列特徵其中包含連續 motifs is difficult, because allowing highly degenerate positions in a motif greatly genes for discriminability on microarray data, J Inf Sci Eng, 19, 953- in yeast, Bioinformatics, 22, 1675-1681.
的退化位置，這樣的序列特徵很難尋找，因為具高退化性的 enlarges the search space and complicates the discovery process. These obstacles 966. (corresponding author) 21. Tsai, H.K.*, Chou, M.Y., Shih, C. H., Huang, Grace T. W., Chang, T.
位置大量增加在尋找答案過程中的搜尋空間。我們利用序列 were surmounted by the following a pattern mining technique and position concur- 7. Tsai, H.K., Yang, J.M., Tsai, Y.F. and Kao, C.Y. (2003) Heterogene- H. and Li, W.H. (2007) MYBS: A comprehensive web server for min-
特徵探勘技術以及位置的同現性來加強辨識位置的可信度。 rences. Empirical tests on known TFBSs show that the new method is highly accu- ous selection genetic algorithms for traveling salesman problems, Eng ing transcription factor binding sites in yeast, Nucleic Acids Research,
我們將此方法應用於已知其結合位置的酵母菌轉錄因子，跟 rate in identifying gapped motifs, outperforming current methods, and it also works Optimiz, 35, 297-311. 35, W221-W226.
其他方法相比，此方法不僅對非連續序列之結合位置具有高 well on non-gapped motifs, achieving high sensitivity and specificity for predicting 8. Tsai, C.H., Tsai, H.K., Chen, S.C. and Kao, C.Y. (2004) Disulfide con- 22. Tsai, H.K., Su, Cindy, P.C., Lu, M.J., Shih, C.H., and Wang, Daryi.
正確率，對一般結合位置的結果也相當好，具有相當高的信 experimentally verified TFBSs. In addition, we constructed a user-friendly interac- nectivity prediction using support vector machine and novel features, (2007) Co-expression of adjacent genes in yeast cannot be simply at-
tributed to shared regulatory system, BMC Genomics, 8:352.
度與效度。此外，我們建立了一方便使用者查詢的平台- 叫 tive platform for dynamic binding site mapping using ChIP-chip data and phyloge- The 2004 International Conference on Mathematics and Engineering
Techniques in Medicine and Biological Sciences (METMBS), 391-
MYBS，可以動態運用資料找到所需的結合位置。MYBS 可讓 netic footprinting as two filters. Based MYBS, we further investigated the impact of 395. 23. Chen, C.Y., Tsai, H.K., Hsu, C.M., Chen, M.J. May, Hung, H.G.,
DNA binding position variants on yeast gene expression. Although the prevailing Huang, G.T., and Li, W.H. (2008) Discovering gapped binding sites
使用者設定選擇不同的染色質免疫沈析晶片資料以及演化足
assumption is that nucleotide variants at such positions are functionally equivalent, 9. Chiu, H.S., Chuang, H.Y., Tsai, H.K., Huang, T.W. and Kao, C.Y. of yeast transcription factors, Proc Natl Acad Sci U S A, 105, 2527-
跡資料以觀察特定基因之轉錄因子的結合位置。利用該資料 there is increasing evidence that such variants play a role in regulation of gene ex- (2004) Discovering Statistically Significant Clusters by Using Ge- 2532.
庫，我們進一步探討轉錄因子結合位置的序列組成與其調控 pression. We therefore propose a method for studying the relationship between the netic Algorithms in Gene Expression Data”, The 2004 International 24. Chang, Y.L., Tsai, H.K.+, Kao, C.Y., Chen, Y.C., and Yang, J.M.
基因表現情形之間的關聯性。雖然目前學界普遍認為這些核 Conference on Mathematics and Engineering Techniques in Medicine (2008) Evolutionary conservation of DNA-contact residues in DNA-
expression of target genes and nucleotide variants in TFBS motifs at a genome-wide and Biological Sciences (METMBS), 243-249.
苷酸的差異並不會對基因調控產生影響力，但近年來揭露其 scale in Saccharomyces cerevisiae, especially the combinatorial effects of variants at binding domains, BMC Bioinformatics, 9, S3.
對基因表現調控重要性的研究與證據卻與日俱增。因此我們 two positions. Our analysis shows that nucleotide variations in more than one-third 10. Huang, Y.C., Chao, Y.C., Lin, S.B., Tsai, H.K. and Kao C.Y. (2004) 25. Sung, H.M., Wang, T.Y., Wang, D., Huang, Y.S., Wu, J.P., Tsai, H.K.,
針對酵母菌中轉錄因子結合序列的退化位置與調控基因的表 of variable positions and in 20% of dependent position pairs are highly correlated to A Tool to Determine the Specificity of Antisense Oligonucleotide, Tzeng, J., Huang, C.J., Lee, Y.C., Yang, P. et al. (2009) Roles of Trans
The 2004 International Conference on Mathematics and Engineer-
現之間的關聯性進行分析。我們發現在酵母菌已知的可信轉 gene expression. We define such positions as functional. However, some positions ing Techniques in Medicine and Biological Sciences (METMBS), 447- and Cis Variation in Yeast Intra-species Evolution of Gene Expres-
錄因子結合位置上，有超過三分之一的退化位置與約五分之 are only functional as dependent pairs, but not individually. In addition, a significant 449. sion. Mol Biol Evol, 26, 2533-2538.
一的退化位置對具「功能性」，表示退化位置的出現確實與 proportion of the functional positions have been well conserved across all yeast- 11. Chuang, H.Y., Tsai, H.K. and Kao, C.Y. (2004) Optimal designs for 26. Tsai, H.K., Huang, P.Y., Kao, C.Y. and Wang, Daryi (2009) Co-ex-
基因表現有顯著的關聯性，且有些退化位置需要同時有另一 related species studied. Our analysis supports the importance of nucleotide variants microarray experiments, The 7 International Symposium on Parallel pression of Neighboring Genes in the Zebrafish (Danio rerio) Ge-
th
nome, International Journal of Molecular Sciences, 10, 3658-3670.
個退化位置的發生，形成退化位置對才具有調控的影響力。 at variable positions of TFBSs in gene regulation. Architectures, Algorithms, and Networks (I-SPAN), 619-624.
27. Swamy, B. S. K., Cho, C.Y., Chiang, S., Tsai, Z. T.Y., and Tsai, H.K.*
12. Huang Y.C., Chuang H.Y., Tsai, H.K., Chang C.F. and Kao C.Y.
(2004) Designing multiple-use primer set for multiplex PCR by using (2009) Impact of DNA binding position variants on yeast gene expres-
compact GAs, Lecture Notes in Computer Science, 3242, 511-523. sion, Nucleic Acids Research, 37, 6991-7001.
*corresponding author; +equally contributed
13. Tsai, Y.F., Tsai, H.K. and Kao, C.Y. (2004) Clustering analysis of de-
bris flow streams, International Journal of Sediment Research, 19,
37-46. (corresponding author)
14. Tsai, H.K., Yang, J.M., Tsai, Y.F. and Kao, C.Y. (2004) Some issues
of designing genetic algorithms for traveling salesman problems, Soft
Comput, 8, 689-697.
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