真核生物體基因轉錄調控因子之預測系統

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黃憲達(Hsien-Da Huang) 查詢紙本館藏

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資訊工程學系

論文名稱

真核生物體基因轉錄調控因子之預測系統
(A Predictive System for Transcriptional Regulatory Sites in Eukaryotic Genomes)

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摘要(中)

研究基因的調控機制，是一項探討真核生物體基因體運作的重要工作。由於大量基因表現(Gene Expression)資料的取得，使得可以運用電腦計算的方式來探索基因(Gene)的調控機制。一般來說，在生物體內的有著相同表現現象的某一群基因，有很大的機會被同一組的轉錄因子(Transcription Factors)來調控(Regulation)。透過電腦計算的方式可以用來預測轉錄因子所黏結(Binding)的黏結子(Binding Sites)是可行的。而傳統的研究分析方法，是繁瑣的、不方便的和費時的。本研究的目的即是設計及實作一自動化之整合性的基因轉錄因子黏結子(Transcription Factor Binding Sites)預測系統，簡稱為RgS-Miner。RgS-Miner預測系統的功能為輸入一群基因，此預測系統便會針對這群基因的調控區(Upstream)進行分析，透過具有統計基礎的電腦運算方法，預測可能共同調控(Co-regulation)這群基因的基因轉錄因子黏結子。此系統更運用資料探勘(Data Mining)的方法，找尋基因轉錄因子黏結子之間出現的關連分析(Occurrence Association)。系統並提供網頁介面供使用者直接查詢、使用及分析，圖形化的使用介面提供使用者更容易了解預測結果。在與其它的系統比較之後，我們的系統確實提供生物學家更方便的工具，可以用來分析真核生物基因體的基因調控機制。

摘要(英)

The availability of genome-wide gene expression data provides a unique set of genes from which can be to decipher the mechanisms underlying the common transcriptional response. The identification of transcription factor binding sites provides valuable information on gene expression and regulation. Recently, the biological information and analyzing methods are available for the analysis of gene expression and transcriptional regulatory sequences. However, users should make elaborate the complicated analysis processes to query the data from different databases, followed by analyzing the gene upstreams by different prediction tools, and finally convert among different data formats. Beyond methods for the prediction of transcriptional regulatory site, new automated and integrated methods for gene upstream sequence analysis at a higher level are needed. Since the identification of regulatory sites requires a large set of biological databases, methods for an efficient and integrated data management are also crucial. In this dissertation, we proposed a predictive system, designated RgS-Miner, which is capable of predicting transcriptional regulatory sites in eukaryotes and detecting co-occurrence of these regulatory sites by inputting a group of genes, i.e., a set of genes that are considered potentially with the common regulatory mechanisms. The system integrates several regulatory site detection methods, such as known site matching, over-presented oligonucleotide detection, and DNA motif discovery. Three case studies in yeast and human genomes are studies in the proposed system. Besides, the system successfully constructs a biological data warehouse to integrate a variety of heterogeneous biological databases. By comparison to other systems, our system is a useful tool in the analyses of transcriptional regulatory sites when users investigate on the regulation of gene expression.

關鍵字(中)

★ 基因表現
★ 生物資訊
★ 轉錄因子

關鍵字(英)

★ gene expression
★ Transcription factor
★ data mining

論文目次

摘要 V
ABSTRACT VI
誌謝 VII
TABLE OF CONTENTS VIII
LIST OF FIGURES XI
LIST OF TABLES XIII
CHAPTER 1 INTRODUCTION 1
1.1 BACKGROUND 2
1.2 MOTIVATION 13
1.3 PROBLEM STATEMENTS 14
1.3.1 Management of a Variety of Heterogeneous Biological Data 14
1.3.2 Detection of Co-regulated Genes Based on Gene Expression Analysis 14
1.3.3 A Predictive System for Transcriptional Regulatory Sequences 14
1.4 RESEARCH GOALS 15
1.5 RELATED WORKS 16
1.6 ORGANIZATION OF THIS DISSERTATION 34
CHAPTER 2 DATABASE MANAGEMENT FOR HETEROGENEOUS BIOLOGICAL INFORMATION 35
2.1 MOTIVATION AND THE SPECIFIC AIMS 35
2.2 THE BIOLOGICAL DATA WAREHOUSE 35
2.2.1 The External Data Sources 37
2.2.2 The Internal Data Model 37
2.2.3 The Integrator and the Wrapper/Monitor 38
2.2.4 Implementation 38
2.3 REPETITIVE SEQUENCES DATABASE (RSDB) 41
2.3.1 System Architecture 41
2.3.2 RSDB Functionalities 43
2.3.3 Relationship between Repeats and Genes 44
2.3.4 Statistics in RSDB 44
2.3.5 Using RSDB Information in the Analysis of Regulatory Sequences 47
2.4 SUMMARY 47
CHAPTER 3 DETECTION OF CO-REGULATED GENES BASED ON GENE EXPRESSION ANALYSIS 48
3.1 OVERVIEW 48
3.2 MOTIVATION AND AIMS 49
3.3 GENE EXPRESSION ANALYSIS FOR CDNA LIBRARIES 50
3.3.1 Materials 50
3.3.2 Approach: Detection of Differentially Expressed Gene 52
3.3.3 Results 53
3.4 SUMMARY 55
CHAPTER 4 A PREDICTIVE SYSTEM FOR TRANSCRIPTIONAL REGULATORY SITES IN EUKARYOTIC GENOMES 56
4.1 INTRODUCTION 56
4.2 METHODS 58
4.2.1 Overview of RgS-Miner 58
4.2.2 Information Flow in RgS-Miner 60
4.2.3 Index of Whole Genome Sequences: i-Human, i-Mouse, and i-Yeast 62
4.2.4 Preprocessing 63
4.2.5 Regulatory Site Prediction 63
4.2.6 Filtering Redundant Regulatory Motifs 68
4.2.7 Site Co-occurrence Detection 69
4.2.8 Statistical Considerations of Site Co-occurrence 71
4.2.9 Output Formats 73
4.2.10 User Profile and History Page 74
4.3 RESULTS 76
4.3.1 Data Input Pages 76
4.3.2 Output Formats 76
4.3.3 User Profiles and History Pages 83
4.4 SUMMARY 85
CHAPTER 5 CASE STUDIES 86
5.1 CASE STUDYⅠ: FUNCTIONALLY RELATED GENES IN SACCHAROMYCES CEREVISIAE 86
5.2 CASE STUDYⅡ: TISSUE-SPECIFIC DIFFERENTIALLY EXPRESSED GENES IN HOMO SAPIENS 92
5.3 CASE STUDYⅢ: KNOWN CELL-CYCLE REGULATED GENES IN HOMO SAPIENS 97
CHAPTER 6 DISCUSSIONS 104
6.1 CHARACTERISTICS OF RGS-MINER 104
6.2 A COMPARISON TO OTHER SYSTEMS 105
6.3 LIMITATIONS AND FUTURE WORKS 107
CHAPTER 7 CONCLUSION 108
BIBLIOGRAPHY 109
WEB SITE REFERENCES 115

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指導教授

洪炯宗(Jorng-Tzong Horng)

審核日期

2003-7-9

推文