生物技術對生命科學發展之衝擊 基因體大計畫之效應 張淑芬 Genome 基因體 指生物個體所有遺傳物質 指一套染色體中完整的DNA序列 包括基因和非編碼序列 教授 北醫 醫學科學研究 TEL: 27361661 ext. 3415 E-mail: cmbsfc21@tmu.edu.tw DNA (去氧核糖核酸 ) 的基本要素 (含氮鹼基) - nitrogen base (含氮鹼基) (五碳醣) 腺嘌呤 鳥糞嘌呤 嘌呤 Purines 胸腺嘧啶 胞嘧啶 嘧啶 Pyrimidines DNA is made up of four building blocks 1
DNA 結合的方式及結構 DNA from every organism looks essential the same A T G C The human genome contains about 3 billion nucleotides! DNA is extremely stable DNA is also easy to replicate DNA contains all of the information necessary to make a complete organism High-Quality Reference Sequence ( 參考序列 ) 2
Gene ( 基因 ): - 有遺傳信息的 DNA 序列 - 控制生物性狀的基本單位 - 最終以 RNA/ 蛋白質型式決定生物個體的生命現象 1865 - Genes are particulate factors by Gregor Johann Mendel 1903 - Chromosomes are hereditary units by Thomas Hunt Morgan 1953 - DNA is a double helix 3
HGP: (1990~2001~2003) The original goal of HGP: (1990~2001~2003) - identify all the genes in human DNA (找出所有的基因) 20000 ~25000 genes - determine the sequences chemical base pairs that make up human DNA (定序) 3 billion nucleotides - store this information in databases (保存) the information is publicly available Whose genome is it? Not an exact match for any single person s genome! Researchers used DNA samples from a number of - improve tools for data analysis (分析) - transfer related technologies to the private sector (移轉至業界) - address the ethical, legal, and social issues (ELSI 基因科技的 donors, male and female. Reference Sequence (參考序列) 倫理 法律 社會等人文議題) that may arise from the project. 4
All humans share the same basic set of genes and other DNA regions, this reference sequence represents every person. A T ( 鹼基對數目 ) 基因體上至少有 50% 是重覆序列 ( 不帶有製造蛋白質的遺傳密碼 ) 基因體上 < 2% 的序列是帶有製造蛋白質的遺傳密碼 ( 基因 ) 重覆序列本身沒有遺傳密碼的功能, 但與染色體結構的形成與改變有關 ; 也可提供基因重組的發生點, 重組產生新的基因, 也可能經修飾改變基因原本的功能, 再造新的基因體 telomere 端粒 Cluster of trna genes centromere 著絲點 Protein encoding genes telomere 端粒 Moderately repetitive sequence Highly repetitive sequence Cluster of snrna genes 5
Chromosomeat in metaphase Chromatin in interphase ( 細 胞分裂間期 ) 酵母菌 線蟲 果蠅 Heterochromatin 異染色質 阿拉伯芥 Euchromatin 真染色質 Reference Sequence ( 參考序列 ) 6
78 個基因 Y 染色體 X 退化序列 - 27 個與 X 染色體有關的基因, 在身體各細胞內都會表現 X 轉位序列 - 與 X 染色體長臂的一段序列有 99% 似演化過程染色體之間發生基因位轉所產生只有 2 個基因 ( 基因密度最低 重複序列最多 ) 擴增序列 - 有一大堆不斷重複的 DNA, 存在的基因幾乎只在睪丸細胞才表現 (testis-determining factor, SRY ) 78 個基因 7
X 性聯隱性遺傳病 血友病 色盲 蠶豆症 Current ongoing research topics 8
Each individual has a unique DNA sequence 基因體序列變異 (Genomic Sequence Variation) 任兩個不同人的基因體序列絕大部份都是相同的 (99.9%), 僅有大約千分之一的差異 (1/1300 bases) SNPs (single-base DNA polymorphism) 疾病感受性 (disease susceptibility) correlation of SNPs among individuals with health and disease Disease-susceptibility prediction based on gene sequence variation Cancergenomics 癌基因體學 Toxicogenomics 毒物基因體學 Pharmacogenomics 藥物基因體學 個人化醫療 9
人類基因體之單套型圖譜計劃 20 SNPs / 6,000 bases of DNA Africa (Nigeria), Asia (China), Europe (UK), and the United States Haplotype: 特定染色體區域上的 SNP 組合 Nature / Nurture Current ongoing research topics Gene number, exact locations, coordination of gene expression, and protein synthesis - 功能性基因體學 (functional genomics) 10
Chromosomal structure and organization noncoding DNA types, amount, distribution, information content, and functions Current ongoing research topics All of the cells within an individual contain the exact same genetic information Different sets of genes are turned on in different types of cells 11
Current ongoing research topics Current ongoing research topics 比較基因體學 (comparative genomics) 生物之演化 - 有跡可循! 相近之生物常帶有共同的基因, 相對應的基因有可能具有類似之功能 人類疾病的動物模式 高血壓 紅斑性狼瘡 遺傳性腎炎 糖尿病 動脈粥樣硬化 阿茲海默症 帕金森氏症 脊髓肌肉萎縮症等之動物模式 12
尋找上帝生命語言的錯別字 對症下藥對因下藥 13
(582970 bp) What is life? Can we pare it down to its most basic components? Can we digitize it? Can we regenerate life or create new life out of the digital word? Can the chemistry permit synthesizing active chromosomes? If we make a synthetic chromosome, can we boot it up? 定序 化學合成較大的 DNA 片段 送入大腸桿菌 / 酵母菌中複製量產 定序確認 再次連接 以 DNA recombination 於酵母菌中組合黴漿菌的完整基因體 The ELSI 基因科技的人文律法 倫理 法律及社會意涵研究計畫 Goals are: the ethical, legal, and social issues 倫理 法律及社會意涵研究計畫 14
基因遺傳測試的正確性 生物技術方法使用的適當性, 如何管制 基因及相對產品的擁有權 專力權 保密度的認定, 取得和使用權 我的基因, 你的專利? 基因都是天生, 而非人類的 發明? Donita Should Cooperate with the Police (or should she?) The body of a young woman was found in the locker room of the factory where Donita works. Police say the woman was stabbed. The only clues are some strands of hair clutched in the hand of the victim. The hair is not hers, so police think it belongs to the murderer. According to the factory guards, no outsiders were in the building at the time of the murder. For that reason, police believe the killer is one of the 500 women who work there. But which one? To find out, the police decide to 基因比對 do a mass DNA screening 15
They ask each worker to give a saliva sample. They want to compare the DNA from the hair to each worker s DNA. (If they find a match, chances are they will have the killer) Still, the whole thing makes Donita uncomfortable. She believes that you are innocent until proven guilty, not the other way around. Donita didn t do the crime, and the police have no reason to suspect she did. If you were Donita, what would you do? 嫌犯基因? 證人基因? If Donita cooperates, her DNA print will go into the police s data bank along with prints from all the other factory workers. The prints will be compared to the DNA from the hairs found in the victim s hand. Unless those hairs came from Donita s head, her DNA sample should remove her as a suspect. But her DNA sample may not be removed from the police computer. It may become part of a permanent file. This means that every time the police search their computer to find a match for some DNA evidence found at some crime scene, they will be checking her DNA print. In essence, she will be a permanent suspect. 16
From Donita s point of view, this is a permanent invasion of privacy. the right to be left alone the right to decide for yourself what information others can know about you Whether the police will keep the DNA information they have on her secret from others. How will the police safeguard these files? Will they permit the use of the files for purposes that don t have to do with law enforcement? The effect on Donita may be a feeling of loss of control over personal information. Is there the right to decide what information you learn about yourself? She may learn something by accident that she never expected to find out. Perhaps she will learn that she is the carrier of a gene mutation that could lead to disease. Perhaps she will learn that she doesn t share certain genetic traits with her parents and therefore must be adopted. 早知道 / 不知道? 17