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1、2000年基因组研究的三个突出方面,前言：2000年基因组研究的三个突出方面,1. 干细胞作为基因组研究的重要选材 Celera Genomics And Geron Corporation Announce Collaboration For Human Pluripotent Stem Cell Genomics June 12, 2000 The objective of the collaboration is to identify and assign function to genes important in early human development, and to ut
2、ilize the information to develop small molecule pharmaceuticals, protein therapeutics, cell and gene therapies, diagnostics, and tools for use in drug discovery and testing. 2. SNP研究的国际大协作 The SNP Consortium Ltd. is a non-profit foundation organized for the purpose of providing public genomic data.
3、Its mission is to develop up to 300,000 SNPs distributed evenly throughout the human genome and to make the information related to these SNPs available to the public without intellectual property restrictions. 856,666 mapped SNPs, is now available. July 11, 2000 Human Genome Project and SNP Consorti
4、um Announce Collaboration 3. DNA芯片的广泛使用,第一部分：干细胞研究进展,一、什么是干细胞？ 干细胞是具有无限期产生各种分化细胞能力的细胞。它是各种干细胞的统称。通常认为干细胞有几个主要特征： 它们是未分化的，但具有分化成各种特定细胞的能力； 它们可无限地分裂产生大量后裔; 其子细胞有两种命运，保持为干细胞或分化为特定细胞。,干细胞分类,Totipotent stem cell: 全能干细胞, 如受精卵 pluripotent stem cell: 多能干细胞，如囊胚中的内囊细胞 multipotent stem cell: 专能干细胞，如造血干细胞,二、怎样得
5、到 pluripotent stem cell?,1998年美国有两个小组分别培养出了人多能( pluripotent )干细胞： James A. Thomson在 Wisconsin大学领导一个研究小组从人胚胎组织中培养出了干细胞株。他们使用的方法是：人卵体外受精后，将胚胎培育到囊胚阶段，提取 inner cell mass细胞，建立细胞株。经测试这些细胞株的细胞表面 marker 和酶活性，证实它们就是胚胎干细胞。用这种方法，每个胚胎可取得1520个细胞用于培养。 John D. Gearhart在 Johns Hopkins大学领导另一个研究小组也从人胚胎组织中建立了干细胞株。他们的方
6、法是：从受精后59周人工流产的胚胎中提取生殖母细胞( primordial germ cell )。由此培养的细胞株，证实具有巨能干细胞的特征。,干细胞培养过程,三：干细胞研究的一些最新成果,1. Dr. Ira Black of the University of Medicine and Dentistry of New Jersey reported the stem cells, treated with growth factors and antioxidants in tissue culture experiments, quickly divided into two cel
7、ls - another stem cell and a nerve cell. Black and his colleagues were able to turn 80 percent of the bone marrow cells taken from rats and humans into nerve cells. 2. The Macklis group in HMS was able to induce stem cells deep in the cerebral cortex of adult mice to replace damaged neurons. The new
8、 neurons grew from already present immature precursor cells into fully formed, connected, and mature replacements.,四：成年个体的干细胞研究,成体干细胞研究是干细胞研究中最激动人心的部分。它可以有效地防止组织排斥，可以避免伦理学、法律系方面的争论。 1. 成体干细胞是否具有胚胎干细胞那样的分化潜力？ 大量的动物实验证明了成体干细胞具有很强的分化能力。如：Recent experiments in mice suggest that when neural stem cells we
9、re placed into the bone marrow, they appeared to produce a variety of blood cell types. Studies with rats have indicated that stem cells found in the bone marrow were able to produce liver cells. 下边的几个最新的研究成果进一步说明包括人在内的高等生物的成体干细胞依然有明确的分化能力。,从成年小白鼠未发育的脑干细胞转变为肌肉细胞 Angelo Vescovi 和 Giulio Cossu, 在 the
10、Institute for Stem Cell Research in Milan 2000 9 20 他们也用成年人志愿者的神经干细胞实现了同样的工作,With A Song In Their Heads - Birth of new brain cells induced in birds,2. 影响成体干细胞应用的某些因素： A. 当前并没有在所以人体组织中发现成体干细胞； B. 成体干细胞含量极少，很难分离与纯化； C. 对某些病人来说，可能： 疾病的进程等不到足量干细胞的培养； 病人自身基因组有遗传缺陷；,五、干细胞的应用价值,人类胚胎干细胞研究的重要性至少表现在以下几个方面： 一、
11、生物学与医学基础研究： 人类干细胞是机体早期发育的极好模型。过去，人类发育生物学研究经常受到很多实际问题和伦理学的限制，因此只有使用动物模型。有了胚胎干细胞就可以直接在人类组织上研究早期发育出现的复杂事件和细胞分化的原初过程。关键是找到特定的因子，它们控制着与发育和分化过程相关的基因的打开和关闭。这一研究也必然为了解非正常细胞分化（如：肿瘤等）的原因提供线索。 二、医疗实践 细胞移植 药物设计,第二部分：干细胞和基因组研究,一、生物学领域两项新进展的结合 国际上很多新闻单位都把基因组和干细胞的研究进展评为2000国际十大科技成果。很快这两项研究就结合在一起了。 “Celeras agreeme
12、nt with Geron is important because we will be using human pluripotent stem cells-the most basic form of human cells that contain a diverse set of genes not expressed in high abundance in other cells-as a source to better understand the human genome,“ said J. Craig Venter, Ph.D., Celeras president an
13、d chief scientific officer. “By combining Celeras high-throughput sequencing facility, computational power, and bioinformatics expertise with Gerons human pluripotent stem cell technology, our goal is to enable the development of new approaches to prevent, diagnose and treat some of our most devasta
14、ting diseases such as heart disease, Parkinsons disease, and cancer.“,二、干细胞是功能基因组研究的最佳选材 1. 是各种不同组织和细胞类型的共同的源; 2. 可代表个体发育的各个阶段; 3. 是人体材料但很少涉及伦理学和法律学问题； 4. 具有重要的应用价值。,第三部分：SNP研究,DOE在一篇介绍SNP文章中写到： Why does one man live to celebrate his hundredth birthday with a glass of wine in one hand and a cigar in
15、 the other while another succumbs in midlife to cancer or heart disease? And why may one womans breast cancer be effectively eradicated while anothers shows no significant response to the same treatment? The explanations may reside in the cumulative effect of a small number of differences in DNA bas
16、e sequence called single-nucleotide polymorphisms (SNPs), which underlie individual responses to environment, disease, and medical treatments. SNPs are the most common type of sequence variation. SNP研究是基因组领域理论成果走向应用的关键步骤。是联系基因型和表现型之间关系的桥梁。,HUMAN GENETIC DIVERSITY: The Ultimate Human Genetic Database
17、 Any two individuals differ in about 3 x 106 bases (0.1%). The population is now about 6 x 109. A catalog of all sequence differences would require 18 x 1015 entries. This catalog may be needed to find the rarest or most complex disease genes.,Statistics for the January 2001 Release Mapping Summary
18、by Chromosome (The SNP Consortiums database ) The 856,666 SNPs (cumulative) in this data release were mapped to chromosomes as follows: Chrom SNPs Chrom SNPs 1 68197 12 36916 2 75001 13 36309 3 61512 14 29687 4 62127 15 25219 5 57435 16 22889 6 52611 17 19005 7 42070 18 27215 8 41216 19 11337 9 4043
19、6 20 16660 10 39695 21 11264 11 47031 22 12017 X 17848 Y 607 Unassigned 2362,dbSNP Summary(NCBI) Total Number of Submitted SNP(ss) by organism: rat: 1 chimpanzee: 2 plasmodium: 4 mouse: 445 human: 2840695 Reference SNP(rs) by organism: rat: 1 chimpanzee: 2 plasmodium: 4 mouse: 49 human: 1652865 SNP研
20、究中存在的主要问题： 真实SNP的鉴定,Major databases * The SNP Consortium * dbSNP - A Database of Single Nucleotide Polymorphisms * HGBASE - human genic bi-allelic sequences - SNPs * The Human Gene Mutation Database - HGMD (Cardiff) * Single Nucleotide Polymorphisms in the Human Genome * Human SNP Database * ALFRED
21、- Allele Frequency Database * Mutation Database Website * Universal Mutation Database * Protein Mutation Database Specific gene locus databases * The Androgen Receptor Mutations Database * Antithrombin Mutation Database Homepage * Asthma Gene Database * Breast Cancer Mutation Data Base (BIC) * BCGD
22、- The Breast Cancer Gene Database * BIOMDB - Database of mutations causing tetrahydrobiopterin deficiencies * Blood Group Antigen Mutation Database * BTKbase - agammaglobulinemia XLA-causing mutations * The European CD40L Defect Database (CD40Lbase) * Database of Human Type I and Type III Collagen M
23、utations,* Emery-Dreifuss Muscular Dystrophy Mutation Database * Factor VII Mutation Database * GPCRmut, The G Protein-Coupled Receptors mutant database * GPCRDB: Information system for G protein-coupled receptors (GPCRs) * GRAP Mutant Database (GPCRs, Family A) * Haemophilia B Mutation Database * H
24、AMSTeRS - Haemophilia A Mutation, Search, Test and Resource Site * Human HPRT database * Hypertrophic Cardiomyopathy mutation database * LDLR Mutation Database * Long QT syndrome database * Marfan Database * MutRes - List of Mutation Resources * Neuronal Ceroid Lipofuscinoses (NCL) Mutations * PAH G
25、enes and alleles (PAHDB) * Human p53 database * p53 gene mutations * Somatic p53 mutations in human tumors and cell lines. * Database of germline p53 mutations * p53link - P53 database integration * PAX2 * PAX6 mutation database * Schindler Disease * VHL Mutation Database * VMD2 Mutation Database *
26、von Willebrand Factor (vWF) Database * WS-associated WRN mutations,第五部分：DNA芯片数据分析,芯片数据分析中存在的问题： 尽管现在无处不谈芯片、无处不以使用芯片为应用高技术，但到目前为止，可以说DNA芯片分析中的根本问题尚未解决。 问题举例： 1.数据标准化问题； 2.基因表达谱中的关联分析。,Run-Sheng Chen 陈润生 Bioinformatics Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, P. R. China 中国科学院生物物理研究所 北京朝阳区大屯路15号 E-mail : Tel: 86-10-64888543 Fax: 86-10-64871293,