Download - 人类基因组计划的进展和内容 Human Genome Project HGP
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人类基因组计划的进展和内容Human Genome Project HGP
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Sequence the 3 billion base pairs of humanDNA and identify the 100,000 genescontained in the human genome• 测定人类染色体DNA上的 30亿个核苷酸的排列顺序• 确定染色体上的大约 10万个基因
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人类的染色体组
成
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基因和染色体的关系
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HGP 的基本任务
• 遗传图谱:基因连锁图
• 物理图谱: 人类基因组的不同载体 DNA 克隆片 段重叠群图,大片段
限制性内切酶切点图, DNA 片段(探针)或一段特异 DNA 序列( STS )的路标图,以及基因组中广泛存在的特征性序列等的标记图,人类基因组的细胞遗传学图,最终在分子水平上与序列图的统一。
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• 序列图谱: 30 亿个核苷酸组成的人类基因组的序列图• 基因图谱: 人类基因组中鉴别出占据 2-5% 长度的
全部基因的位置、结构与功能
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人类基因组计划大事记• 一九九○年十月
誉为生命科学「阿波罗登月计划」的国际人类基因组计划启动。• 一九九八年五月
一批科学家在美国罗克威尔组建塞莱拉遗传公司,目标是投入三亿美元,到二○○一年绘制出完整的人体基因组图谱,与国际人类基因组计划展开竞争。十月二十三日美国国家人类基因组研究所在美国《科学》杂志上发表声明说,人类基因组计划的全部基因测序工作将比原计划提前两年,即在二○○三年完成。
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• 1999年九月中国获准加入人类基因组计划,负责测定人类基因组全部序列的百分之一,也就是三号染色体上的三千万个硷基对。中国是继美、英、日、德、法之後第六个国际人类基因组计划参与国,也是参与这一计划的唯一发展中国家。十二月一日国际人类基因组计划联合研究小组宣布,他们完整地破译出人体第二十二对染色体的遗传密码,这是人类首次成功地完成人体染色体基因完整序列的测定。2000 年四月底中国科学家按照国际人类基因组计划的部署,完成了百分之一人类基因组的工作框架图。2000六月二十六日科学家公布人类基因组工作草图。
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不同的生物基因组序列大小比较
Human 3.0 x 109
Mouse 3.0 x 109
Worm 1.0 x 108
Drosophila 1.1 x 108
Yeast 1.2 x 107
Bacteria 1.0 - 5.0 x 106
Dictyostellium 3.4 x 107
BCM-BCM-HGSCHGSC
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基因组测序
鸟枪法测序的原理及过程
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全基因组鸟枪法测序的主要步骤
第一,建立高度随机、插入片段大小为 2kb 左的基因组文库。第二,高效、大规模的末端测序。对文库中每一个克隆,进行两端测序。第三,序列集合。 TIGR 发展了新的软件,修改了序列集合规则以最大限度地排除错误的连锁匹配。第四,填补缺口。
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高等真核生物(如人类)基因组中有大量重复序列,导致判断失误
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对鸟枪法的改进(1) Clone contig 法。首先用稀有内切酶把待测基因组降解为数百 kb 以上的片段,再
分别测序。(2) 靶标鸟枪法 (direted shotgun) 。首先根据染色体上已知基因和标记的位置来确
定部分 DNA 片段的相对位置,再逐步缩小各片段之间的缺口。
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Regional mapping
已知基因位置
由已知基因向两端未知区域分别测序
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Regional mapping
片段之间还存在未知缺口序列
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Minimal tiling path selected for sequencing.
Regional mapping
缺口片段逐渐减少,最后完成拼接
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>20 kbp
~300 bp
Molecular weightmarker every
5th laneRestriction fragmentfingerprinting
- BAC clones are grown
in 96-well format
- Hind III digest
- 1% agarose
限制性酶切指纹图谱
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Contig assembly
Clone A B C D E F G
FPC* Overlap identification by
restriction pattern similarities Facilitated contig assembly
*Sanger Centre C. Soderlund, I Longden and R. Mott
*
*
*
*
*
*
All restriction fragments withina clone selected for the tilingpath must be verified by theirpresence in overlapping clones. : vector fragments
: insert fragments
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BCM-BCM-HGSCHGSC
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Shotgun Sequencing I :RANDOM PHASE
Bac Clone: Bac Clone: 100-200 kb100-200 kb
Sheared DNA: Sheared DNA: 1.0-2.0 kb1.0-2.0 kb
SequencingSequencingTemplates: Templates:
RandomRandomReadsReads
BCM-BCM-HGSCHGSC
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Shotgun Sequencing II:ASSEMBLY
ConsensusConsensusSequenceSequence
GapGap
Low Base Low Base QualityQuality
SingleSingleStrandedStrandedRegionRegion
Mis-AssemblyMis-Assembly
((InvertedInverted))
BCM-BCM-HGSCHGSC
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ConsensusConsensusSequenceSequence
GapGap
Low Base Low Base QualityQuality
SingleSingleStrandedStrandedRegionRegion
Mis-AssemblyMis-Assembly
((InvertedInverted))
BCM-BCM-HGSCHGSC
Shotgun Sequencing III: FINISHING
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ConsensusConsensusSequenceSequence
GapGap
SingleSingleStrandedStrandedRegionRegion
Mis-AssemblyMis-Assembly
((InvertedInverted))
BCM-BCM-HGSCHGSC
Shotgun Sequencing III: FINISHING
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ConsensusConsensusSequenceSequence
GapGap
Mis-AssemblyMis-Assembly
((InvertedInverted))
BCM-BCM-HGSCHGSC
Shotgun Sequencing III: FINISHING
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ConsensusConsensusMis-AssemblyMis-Assembly
((InvertedInverted))
BCM-BCM-HGSCHGSC
Shotgun Sequencing III: FINISHING
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BCM-BCM-HGSCHGSC
Shotgun Sequencing III: FINISHING
High Accuracy Sequence:High Accuracy Sequence:< 1 error/ 10,000 bases< 1 error/ 10,000 bases
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Whole Genome Shotgun Sequencing
Whole Genome: Whole Genome: 3,000 Mb3,000 Mb
Sheared DNA: Sheared DNA: 1.0-2.0 kb1.0-2.0 kb
SequencingSequencingTemplates: Templates:
RandomRandomReadsReads
BCM-BCM-HGSCHGSC
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Whole Genome Shotgun Sequencing:Assembly
ConsensusConsensusSequenceSequence
GapGap
Low Base Low Base QualityQuality
SingleSingleStrandedStrandedRegionRegion
Mis-AssemblyMis-Assembly
((InvertedInverted))
BCM-BCM-HGSCHGSC
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Whole Genome Shotgun Sequencing:Assembly
ConsensusConsensusSequenceSequence
GapGap
Low Base Low Base QualityQuality
BCM-BCM-HGSCHGSC
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BCM-BCM-HGSCHGSC
基因图谱
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人类基因组计划
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