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生物資訊 (Bioinformatics)
蔡懷寬
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Please tell me Why you are here? Make a definition of bioinformatics
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Introduction What is bioinformatics? Why bioinformatics?
The past, current, and future in bioinformatics
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什麼是生物資訊學？ 它是一個跨領域的學門： 終極目標：了解生物特性及生命本質 重要的子領域： 大量資料的分析演算法及統計方法
結合生物、資訊科學、數學、物理及化學等領域 終極目標：了解生物特性及生命本質 重要的子領域： 大量資料的分析演算法及統計方法 各種生物序列, 結構, 功能及演化的分析與解釋 管理及使用各種型態資訊的軟體工具
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為什麼需要生物資訊學？
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REVOLUTION IN BIO-MEDICAL RESEARCH
CLASSICAL APPROACH HIGH-THROUGHPUT APPROACH Northern Hybridization Western Hybridization Southern Hybridization RFPD Differential Display Subtraction Library Real-Time PCR Microarray 2-Dimensional Protein Electrophoresis Serial Analysis of Gene Expression Expression Sequence Tags EXPERIMENT DRIVEN Hypothesis Experiment INFORMATION DRIVEN Experiment Hypothesis
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為什麼需要生物資訊學？ 生物相關資料的累積迅速，資料量非常大，亟需電腦協助分析
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The GeneBank Data (9/25/2002) Year Base Pairs Sequences 1982 680338
606 1983 2427 1984 4175 1985 5700 1986 9978 1987 14584 1988 20579 1989 28791 1990 39533 1991 55627 1992 78608 1993 143492 1994 215273 1995 555694 1996 1997 1998 1999 2000 2001
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Protein DataBank Data (9/25/2002)
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為什麼需要生物資訊學？ 生物相關資料的累積迅速，資料量非常大，亟需電腦協助分析
提供實驗設計更宏觀的看法，從以往個別基因的研究，邁向整個基因組的研究 透過資料挖掘來了解基因功能及蛋白質結構 更進一步了解演化歷史及物種間的演化關係
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人類基因組解讀計畫
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基因組(genome) All the genetic material in the chromosomes of a particular organism Its size is generally given as its total number of base pairs.
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基因組的大小 Human: 3000 million bases Mouse: 3000 million bases
Drosophila (fruit fly): 165 million bases Nematode (roundworm): 100 million bases Yeast (fungus): 14 million bases E. coli (bacteria) million bases
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人類基因組解讀計畫 簡稱為HGP (Human Genome Project) 主要目標有：
identify all the genes in human DNA, determine the sequences of the 3 billion chemical bases that make up human DNA store this information in databases develop tools for data analysis transfer related technologies to the private sector address the ethical, legal, and social issues (ELSI) that may arise from the project
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Human Genome
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HGP的沿革與進展 HGP從1990年起開始進行 HGP是由美國及英國所主導的一項全球性計畫
2000年六月與Celera私人公司共同宣布人類基因組的初稿已完成
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HGP的沿革與進展(續) 2001年2月: Initial sequencing and analysis of the human genome (Nature, Vol. 409, 15 Feb. 2001, by International Human Genome Sequencing Consortium) The sequence of the human genome (Science, Vol. 291, 16 Feb. 2001, by J. C. Venter, et al.)
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Biology moves into the silicon stage
in vivo in vitro in silico
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從HGP來看整個生物資訊界的脈動
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Before HGP String analysis Pair-wise, multiple sequence alignment
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Sequence Analysis Alignment
Pair-wise alignment SURVIVE SURVIVE SURIUE SUR- IUE Multiple sequence alignment RPCVCPVLRQAAQ s RPCVC_ P__VLRQAAQ a1 RPCACCPVLRQVVQ s2 RPCACCP__VLRQVVQ a2 KPCLCPRQLRQV s3 KPCLC_ P RQLRQV_ _ a3 KPCCPRQAAQ s4 KPC_C_ P____ RQAAQ a4 S A
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Before HGP String alignment Linkage analysis
Pair-wise, multiple alignment Linkage analysis
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Linkage Analysis
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Before HGP String alignment Linkage analysis Phylogenetic tree
Pair-wise, multiple alignment Linkage analysis Phylogenetic tree
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Phylogenetic Tree
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Phylogenetic Tree
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Before HGP String alignment Linkage analysis Phylogenetic tree
Pair-wise, multiple alignment Linkage analysis Phylogenetic tree Protein structure prediction …
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Protein Structure Prediction
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During HGP Sequencing Physical mapping Fragment assembly
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Sequencing Strategies (1)
Map-Based Assembly: Create a detailed complete fragment map Time-consuming and expensive Provides scaffold for assembly Original strategy of Human Genome Project
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Sequencing Strategies (2)
Shotgun: Quick, highly redundant – requires 7-9X coverage for sequencing reads of bp. This means that for the Human Genome of 3 billion bp, billion bases need to be sequence to provide adequate fragment overlap. Computationally intensive Troubles with repetitive DNA Original strategy of Celera Genomics
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Shotgun Sequencing: Assembly of Random Sequence Fragments
To sequence a Bacterial Artificial Chromosome ( Kb), millions of copies are sheared randomly, inserted into plasmids, and then sequenced. If enough fragments are sequenced, it will be possible to reconstruct the BAC based on overlapping fragments.
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During HGP Sequencing Gene Prediction Physical mapping
Fragment assembly Gene Prediction
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During HGP Sequencing Gene Prediction … Physical mapping
Fragment assembly Gene Prediction …
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After HGP (Post Genomic)
Microarray
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Microarray
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After HGP (Post Genomic)
Microarray Regulatory network
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Regulatory Network Simplified representation of the NF- B network.
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After HGP (Post Genomic)
Microarray Regulatory network Proteomics …
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生物資訊學的相關課題
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生物資訊相關主題(1) 定序(sequencing)
基因組的DNA序列很長，但卻扭曲在小小的細胞內，目前仍然沒有方法可以一次將整個序列讀出來 現階段的方法都是將基因組序列切成很多的小段，然後藉由重疊的區域將整個基因組序列再組合回來
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生物資訊相關主題(2) 序列分析(sequence analysis) 藉由序列分析的結果，來探索序列的功能
這是基因組學(genomics)分析的基礎 DNA序列間的比較 蛋白質序列間的比較 長序列的比較 相似序列的比較 多重序列比較 SNP (Single nucleotide polymorphism) Haplotypes
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生物資訊相關主題(3) 找尋基因(gene finding) 給定一個基因組序列，決定各個基因的位置
由於目前尚未完全理解DNA語言，所以並沒有百分之一百正確的方法可以直接從基因組序列決定出所有的基因出現位置 現階段的方法，很多都是用已知的基因所歸納出來的規則來做判斷
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生物資訊相關主題(4) 生物資訊資料庫(bioinformatics database)
生物序列相關的資訊累積很快，資料庫已成為生物資訊應用上最重要的工具 資料庫就是一堆資料的儲存庫，它的存放方式，通常會規劃得讓電腦可以快速搜尋及擷取資料。而資料庫管理系統則可讓使用者設計所需要的資料庫，以及操作資料庫所需的修訂、存取及搜尋功能。
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生物資訊相關主題(5) 蛋白質結構的預測(protein structure prediction) 蛋白質的功能很多是由它的結構所決定的
X-ray及NMR是目前決定蛋白質結構常用的方式 如何從蛋白質的一維序列推測它的三維結構，是一個很難但很重要的研究課題
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生物資訊相關主題(6) 蛋白體學(proteomics)
methodological developments in protein separation and characterization advances in bioinformatics, and novel applications of proteomics in all areas of the life sciences and industry. (These endeavours give new insights into protein functions, interactions and pathways.)
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生物資訊相關主題(7) 演化樹的建構(evolutionary tree construction) 演化樹的建構可協助了解演化過程及歷史
有的方法根據特徵(character)保留的狀況表來決定演化樹 有個方法根據物種間的距離來決定演化樹 大部分的演化樹建構問題都是NP-Complete (換句話說，都是很難的計算問題)
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生物資訊相關主題(8) 其他課題： RNA二維結構預測(RNA secondary structures)
比較基因組學(comparative genomics) 基因網路(genetic networks) 微陣列晶片(microarrays 或稱基因晶片) 分子計算機(molecular computers)
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生物資訊的相關文獻
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Bioinformatics and Computational Biology-Related Journals:
Bioinformatics (期刊原名為CABIOS) Bulletin of Mathematical Biology Computers and Biomedical Research Genome Research Genomics Journal of Computational Biology Journal of Molecular Biology Nature Science
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Bioinformatics and Computational Biology-Related Conferences:
the first IEEE Computer Society Bioinformatics Conference (CSB 2002, CA, USA) Intelligent Systems for Molecular Biology (ISMB 2003, Brisbane, Australia) Pacific Symposium on Biocomputing (PSB 2003, Kauai, Hawaii, USA) The Seventh Annual International Conference on Research in Computational Molecular Biology (RECOMB 2003, Berlin, Germany)
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Bioinformatics and Computational Biology-Related Books:
Calculating the Secrets of Life: Applications of the Mathematical Sciences in Molecular Biology, by Eric S. Lander and Michael S. Waterman (1995) Introduction to Computational Biology: Maps, Sequences, and Genomes, by Michael S. Waterman (1995) Introduction to Computational Molecular Biology, by Joao Carlos Setubal and Joao Meidanis (1996) Algorithms on Strings, Trees, and Sequences: Computer Science and Computational Biology, by Dan Gusfield (1997) Computational Molecular Biology: An Algorithmic Approach, by Pavel Pevzner (2000) Introduction to Bioinformatics, by Arthur M. Lesk (2002)
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生物資訊學相關網頁 MIT Biology Hypertextbook
很不錯的on-line生物學 The International Society for Computational Biology: National Center for Biotechnology Information (NCBI, NIH): (NCBI, EBI 及 DDBJ是目前生物序列的三大集散中心， 它們互相傳遞資料) European Bioinformatics Institute (EBI): DNA Data Bank of Japan (DDBJ):
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生命科學與資訊科學的互動 就某方面而言，這種互動很類似物理與數學間的互動：
因為要解釋某些大量生物資料的信息，帶動了新的資訊分析方法及工具的製作 新的資訊理論及工具的產生，也為未來的生物學研究，舖設了新的途徑。
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跨領域合作 真理只有一個 眼光要放遠 文化背景不同 研究步驟不同 Credits 隔行如隔山
分生的應用常迫在眉睫；而資訊理論的開發卻常曠日費時且充滿不確定性 Theory & Practice 真理只有一個 眼光要放遠
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