第八章 人類基因之應用

1. 第八章 人類基因之應用 • 人類基因體解碼定序的重要發現（2001） • DNA為多型性(polymorphism) • SNPs, single nucleotide polymorphisms：單一核苷酸多型性 • 同一段DNA序列，不同的人某單一核苷酸的鹼基不一樣 • 造成人與人之間的差異性？ • 300個鹼基會有一個，人類大約有1000萬個SNPs • 基因大約有23500，3000個假基因 • 蛋白質種類超過十萬 • RNA分子會自行斷裂與接合重組

2. http://www.genome.gov/

4. Human genome is 3.08 Gb. • The euchromatic genome is thus 2.88 Gb • Interrupted by 341 gaps • 33 gaps (total, 198 megabases (Mb) reflect heterochromatin (which was not targeted by the HGP) • 308 gaps (total, 28 Mb) are euchromatin • Human genes: 20,000-25,000 (contains 22,287 gene loci), 34,214 transcript (coding exons total 34 Mb, 1.2% of euchromatic genome; untranslated region, 21Mb, 0.7% ofeuchromatic genome) • 19,599 protein-coding genes • 2,188 DNA segments that are predicted to be protein-coding genes

6. accuracy of 99.999 %, which translates to an error rate of only 1 base per 100,000 base pairs • 2004 : 2001 • Gap: 341 : 147,821 • Continuity: 38,500 kb : 81 kb • Segmental duplications (cover 5.3%), A number of human diseases are known to be associated with mutations in segmentally duplicated regions

7. 藍色：人類基因體中重複性片段在不同染色體中的分佈藍色：人類基因體中重複性片段在不同染色體中的分佈 紅色：人類基因體目前定序的空缺部分(gap) The heterochromatic regions all tend to be highly polymorphic in length in the human population.

8. 圖：各染色體重複性片段所佔的百分比圖 藍色：HGP的結果 金色：散彈槍定序的結果

9. Protein-coding genes do not include known non-coding RNAs, such as transfer RNAs, ribosomal RNAs, small nucleolar RNAs (snoRNAs) and microRNAs • The most problematic cases would be genes that have very short open reading frames (100 amino acids), consist of single exons or evolve very rapidly. • the predictions tend to have fewer exons per transcript than known genes (4.7 versus ,9.7) and to encode shorter open reading frames (847 versus,1,487 amino acids).

10. 全基因體散彈槍定序的侷限性

17. Key challenges that lie ahead include: • systematic identification of all genetic polymorphisms carried in the human population, to facilitate the study of their association with disease; this will require comprehensive study of hundreds to thousands of human genomes. • Systematic identification of all functional elements in the human genome, including genes, proteins, regulatory controls and structure elements; this will require comparative analysis with many additional mammalian genomes and systematic application of diverse experimental techniques. • Systematic identification of all the ‘modules’ in which genes and proteins function together; this will require comprehensive study and improved interpretation of expression, localization and interaction in a temporal and spatial context.

20. www.gdb.org • 人類染色體基因圖譜 • NCBI →human genome resources • The GDB human genome database insulin

21. 察看染色體圖譜上的相對位置

24. 查詢與疾病有關基因 • NCBI → OMIM (Online Mendelian Inheritance in Man) • 以色列魏茲曼學院GeneCards http://www.genecards.org/index.shtml

26. High blood pressure

28. 按下連結有更多相關資訊與染色體圖

30. 癌症基因資料庫 • NCBI → Cancer Genome Anatomy Project • 查詢EST資料庫 • 免疫有關資料庫 • 主要組織相容複合體MHC, major histocompatibility complex • 單一核苷酸多型性資料查詢 • 此變異可能與疾病、藥物感受性、遺傳…….都有相關 • NCBI →

31. Lung cancer

36. 個人基因體定序的瓶頸 • HGP計畫花費3億美金 • 第一位個人基因體定序-華生 • 2007.5.29 454生命科學公司454 Life Sciences • 花費100萬美金 • 近程目標降至10萬美金 • 終極目標降至1000美元

38. 藥物基因體學 • 完成人類基因體後稱後基因體時代， 針對個體基因差異量身訂做藥物 • 藥物反應與遺傳因子的相關性 • 重要性 • 個體差異 • 舊瓶新裝(療效低的藥物獲得重生) • 提高療效 降低副作用 • 單一核苷酸多型性：SNP single nucleotide polymorphism • 降低病患用藥風險性、達成個體化醫療

39. 第九章 有關演化與分類工具之應用 • 以樹狀分佈圖來闡明不同生物之間的親緣關係 • 核苷酸片段 • 胺基酸序列 • 利用ClustalW分析比對序列，再以treeview軟體輸出 • 正確作法為 • 演化樹相關網站 • Tree of Life web project： http://tolweb.org/tree/ • Species2000：http://www.species2000.org