Amazing genetics?!

Amazing genetics?!

李辉

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Room: S-408

苟德明

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Room: SG-107

1. 21 Sections

2. Each Section contains several topics

3. Each Topic contains a “Key notes”

panel & the main text

Instant notes in Molecular Biology（ Third Edition, by Phil Turner et al.)

赵亚华，分子生物学教程，科学出版社， 2006.9杨歧生，分子生物学，浙江大学出版社 2004朱玉贤，李毅，现代分子生物学高等教育出版社 2004.4沈栩非，方福德，真核基因表达调控，高教出版社， 1994Benjamin Lewin Genes XI, Pearson Prentice Hall, 2008Robert F. Weaver Molecular biology McGRAW.Hill 2005.

References

1. Defining Molecular Biology

分子生物学：从分子水平理解生命活动细胞生物学：从细胞水平理解生命活动遗传学：从遗传角度理解生命活动生物化学：从化学组成角度来理解生物大分子和生物代谢。普通生物学（动物 & 植物） & 微生物学：不同生物类型的特点

分子生物学：从分子水平理解生命活动，主要指遗传信息的传递（复制）、保持（损伤和修复）、基因的表达（转录和翻译）与调控。强调以上各种生命活动（ Biochemical processe

s ）： 1 是什么（ what ，生物学重要性和具体过程）， 2 所涉及的生物大分子（ DNA 、 RNA 、蛋白质 ) 是如何相互作用使之发生的（ how ）。

Molecular biology seeks to explain the relationships between the structure and function of biological molecules and how these relationships contribute to the operation and control of biochemical processes.

Instant Notes in Molecular Biology ---Turner et al.

A Cells and macromolecules

B Protein Structure C Nucleic acids

D Chromosome D’ Gene and genome

E-F Replication & fidelity DNA

RNA

Protein

K-N Transcription & regulation

O RNA processing & degradation

P-Q Translation

Q4 post translational events

遗传信息的保持

与基因表达调控

G-J: DNA cloning

I consider molecular biology to be the study of genes and their activities at the molecular level, including transcription, translation, DNA replication, recombination and translocation.

Molecular Biology (McGraw-Hill) --- Robert Weaver

Part I: Introduction

Part II: Methods in Molecular Biology

Part III: Transcription in Prokaryotes

Part IV: Transcription in Eukaryotes

Part V: Post-transcriptional Events

Part VI: Translation

Part VII: DNA replication,

Recombination, and transposition

Molecular Biology of the Gene, 5/E --- Watson et al. (2004)

Part I: Chemistry and Genetics

Part II: Maintenance of the Genome

Part III: Expression of the Genome

Part IV: Regulation

Part V: Methods

现代分子生物学 --- 朱玉贤、李毅 2/E (2002)

分子生物学是研究核酸、蛋白质等生物大分子的形态、结构特征及其重要性、规律性和相互关系的科学，是人类从分子水平上真正揭示生物世界的奥秘，由被动地适应自然界转向主动地改造和重组自然界的基础学科。

1 、绪论2 、染色体与 DNA

3 、生物信息的传递（上）——从 DNA 到 RNA

4 、生物信息的传递（下）——从 mRNA 到蛋白质5 、分子生物学研究方法6 、基因的表达与调控（上）——原核7 、基因的表达与调控（下）——真核8 、疾病与人类健康（癌症、病毒和基因治疗）9 、基因与发育10 、基因组与比较基因组学

2. Studying Molecular Biology

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分子生物学的研究内容分子生物学的研究内容(( 基础分子生物学教程，赵亚华著基础分子生物学教程，赵亚华著 ))

分子生物学是研究生物学现象的分子基础所有生命科学的范畴。因此对分子生物学研究内容的界定也比较困难。

但是按照狭义分子生物学的定义，可以把现代分子生物学的研究内容概括如下。

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2.1 基因与基因组的结构与功能• 50 年代以前，从细胞染色体水平，属于基因的染

色体遗传学。

• 50 年代之后，从 DNA 分子水平，基因的分子生物学。

• 近 30 年，基因重组技术， DNA 测序技术的应用，使基因的研究进入了反向生物学阶段。

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2.2 DNA 的复制、转录和翻译

• 主要研究的是基因的复制和转录过程中相关酶和蛋白调控因子的相互作用。

• 转录产物 mRNA 的剪切和剪接机制。剪切复合体的组装，激酶的调控等。

• 蛋白质新生肽的折叠与功能等。

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2.3 基因的表达调控的研究

• 基因表达调控的信号传导；

• 基因表达调控的调控元件，转录因子及RNA 的剪接，选择性剪切等。

• 肿瘤细胞中基因的表达和调控。

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2.4 DNA 重组技术

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2.5 结构分子生物学

• 生物大分子的作用前题 : 具有特定的结构；发挥作用的过程中必

定存在着结构和构象的变化。• 必须拥有特定的空间结构（三维结构）• 必定存在着结构和构象的变化。

• 结构分子生物学：就是研究生物大分子特定的空间结构以及结构的运动变化与其生物学功能关系的科学。

• 结构分子生物学在今后仍是生命科学发展的基础学科。

3. Recalling Molecular Biology

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Nobel medal

Half a pound of 23-karal gold.

2. 5 inches across

近半个世纪以来医学，化学中重大突破与成就者

Nobel Prize

分子生物学发展的

里程碑与主要内容

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3.1 DNA 遗传物质的确定和遗传信息传递的认识阶段

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3.1.1 人类对 DNA 和遗传信息的传递的认识阶段

1868 年瑞士化学家米歇尔（ Miesher,F.1844－ 1895 ），首先从脓细胞分离出细胞核，用碱抽提再加入酸，得一种含氮和磷特别丰富的沉淀物质，当时曾叫它为核质。

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1866 Gregor Mendel Austria Scientist , Published the results of his investigations of the “inheritance of factors" in pea plants. Mendel's principles were independently discovered and verified, marking the beginning of modern genetics.

Gregor Mendel

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Live smooth bacteria

Live rough bacteria

Heat-killed smooth bacteria + live rough bacteria

Frederick Griffith (1928)

Transformation in Bacteria

Smooth bacteria with capsule

Rough bacteria with no capsule

Dead mouse has live smooth bacteria

Heat-killed smooth bacteria

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"for his discoveries concerning the role played by the Chromosome in heredity , demonstrated that genes are on the chromosome" Proposed a theory of sex-linked inheritance for the first mutation discovered in the fruit fly, Drosophila, white eye.

Thomas Hunt Morgan

in Physiology or Medicine 1933 Nobel Prize

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1941 George Beadle and Edward Tatum establish that one gene makes one enzyme or protein, and share the The Nobel Prize in Physiology or Medicine 1958

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1944 Oswald Avery, Colin MacLeod, Maclyn McCarty Reported that they had purified the transformingprincipal in Griffith's experiment and that it was DNA.

Oswald T. Avery Colin MacLeod Maclyn McCarty

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1950 年 Erwin Chargaff 提出了 Chargaff 规则T=A C=G

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X~ray photograph of DNA with high quality ( 核塘与磷酸连接成的扭曲绳子，每一节上都有配对的碱基 )

1951. King’s Lab. London University UK

unflattering portrayal of Franklin in his account of the discovery of DNA's structure, entitled "The Double Helix," depicts Franklin as an underling of Maurice Wilkins, when in fact Wilkins and Franklin were peers in the Randall laboratory.

Maurice Wilkins & Rosalind Franklin (37y)

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1952 Alfred Hershey & Martha ChaseUsed phages in which the protein was labeled with35S and the DNA with 32P for the final proof thatDNA is the molecule of heredity.

Martha Chase (1930-2003)

Alfred Hershey(1908-1997)

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Francis Crick (35y)

1951

分子生物学的重要里程碑

James Watson (23y)

丹麦哥本哈根

剑桥大学 Cavendish Lab.

1953 年发表了著名论文

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James Watson (34y)

Francis Crick (46y)

Maurice Wilkins (46y)

DNA Double Helix model 1953

1962

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1958 J. Lederberg (33y)

Phage transduction

The Nobel Prize in Chemistry 1958

"for his work on the structure of proteins, especially that of insulin"

Frederick Sanger

Cambridge University 1918-

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1956年， Kongberg 从 E. coli 中分离纯化了 DNA聚合酶 I这是能在试管中合成 DNA 的第一个核酸酶。 The Nobel Prize in Physiology or Medicine in 1959

Arthur Kornberg

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Francois Jacob (44y)

Jacques Monod (55y)

(French)

Lac. Operon Theory （ 1961 ）

The Nobel Prize in Physiology or Medicine 1965

Concept of mRNA

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1966 年，他们完成了 mRNA 上编码 20 种氨基酸的三联密码子遗传密码的破译工作。

Shared the 1968 Nobel Prize for Physiology or Medicine

Robert Holley H.Gobind Khorana Marshall Nirenberg

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Max Delbruck (63y)

Shared the 1969 Nobel Prize for Phage group ， Phage infection cycle and DNA as genetic material

Alfred Hershey (61y)

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3.2 重组 DNA 技术的建立和发展

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• DNA 连接酶是 1967 年• Gellert M (NIH ， Maryland) ,

• Olivera B.M. (Stanford school of Medicine, CA)

• Weiss B. ( Harvard Medical School)

• 三个实验室同时发现的。它是一种封闭 DNA 链上切口的酶，借助 ATP 或 NAD 水解提供的能量催化 DNA 链的 5'-P 与另一 DNA 链的 3'-OH 生成磷酸二酯键。

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The Nobel Prize in Physiology or Medicine 1978 （ 1970 ）

"for the discovery of restriction enzymes and their application to problems of molecular genetics"

Werner Arber

Biozentrum der Universität Switzerland1929-

Daniel Nathans

Johns Hopkins University School of Medicine Baltimore, USA1928 - 1999

Hamilton O. Smith

Johns Hopkins University School of Medicine Baltimore, USA 1931 -

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1975. Howard Temin (41y)David Baltimore (37y)

Reverse transcription （引发癌症的内因）

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• 1972 Paul Berg & Herb Boyer Produced the first recombinant DNA molecules.

They Shared the 1980 Nobel Prize in Chemistry "for his fundamental studies of the biochemistry of nucleic acids, with particular regard to recombinant-DNA",

Paul Berg Herb Boyer

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Walter Gilbert 1932 - Biological Laboratories Cambridge, MA,

“for their contributions concerning the determination of base sequences in nucleic acids in 1975-1977"

Frederick Sanger 1918 - MRC Laboratory of Molecular Biology Cambridge, Great Britain

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3.3 重组 DNA 技术的应用和分子生物学迅速发展阶段

1-48


“for her discovery of DNA transposable element”

genes are transposable -- they can move around -- on and between chromosomes.

Barbara McClintock 1902-1992 Cold Spring Harbor Laboratory in

New York.

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"for their discovery of catalytic properties of RNA Ribozyme"

Sidney Altman Yale University New Haven, CT, USA 1939 -

Thomas R. CechUniversity of Colorado Boulder, CO, USA 1947-

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• 1985 Kary B. Mullis Published a paper describing the polymerase chain reaction (PCR), the most sensitive assay for DNA yet devised

The Nobel Prize in Chemistry 1993 "for his invention of the polymerase chain reaction (PCR) method"

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The Nobel Prize in Physiology or Medicine 1993 “for their discovery of split genes In 1978”

Richard J. Roberts Phillip A. Sharp

1-52

discovered Genetic control of early development in Drosophila

Edward B. ewis Christiane Nüsslein-Volhard

Eric F. Wieschaus


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• 1996 Patrick O. Brown, Professor of Stanford University presented the 'gene chip' containing 6116 different gene specific sequences of the yeast genome. This is of great benefit in mapping the genomes.

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• 1996 Ian Wilmut at Scotland's Roslin Institute presented "Dolly", a sheep cloned from the cell of an adult mammary gland.

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Wilmut and his co-workers completed their feat by transferring the nuclei from various types of sheep cells into unfertilized sheep eggs from which the natural nuclei had been removed by microsurgery. Once the transfer was complete, the recipient eggs contained a complete set of genes, just as they would if they had been fertilized by sperm. The eggs were then cultured for a period before being implanted into sheep that carried them to term, one of which culminated in a successful birth. The resulting lamb was, as expected, an exact genetic copy, or clone, of the sheep that provided the transferred nucleus, not of those that provided the egg.

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Stanley B. Prusiner University of California,School of Medicine USA 1942 -

"for his discovery of Prions - a new biological principle of infection in 1984"


1-58

discovered key regulators of the cell cycle

Leland H. Hartwell identified CDC28-gene

R. Timothy(Tim) Huntdiscovered cyclins

Sir Paul M. Nursediscovered the gene cdc2


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“for their discoveries concerning genetic regulation of organ development and programmed cell death”in 2002

John E. Sulston

showed that specific cells undergo programmed cell death, identified the first mutation of a gene participating in the cell death process.

Sydney Brenner

established C. elegans as a novel experimental model organism

H. Robert Horvitz

discovered and characterized key genes controlling cell death in C. elegans

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The Nobel Prize in Chemistry 2003 "for discoveries concerning channels in cell membranes"

Peter Agre Johns Hopkins University School of Medicine Baltimore, MD, USA

Rockefeller University New York, NY, USA; Howard Hughes Medical Institute b. 1949

Roderick MacKinnon Johns Hopkins University School of Medicine Baltimore, MD, USA

Rockefeller University New York, NY, USA; Howard Hughes Medical Institute b. 1956

"for the discovery of water channels"

"for structural and mechanistic studies of ion channels"

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Howard Hughes Medical Institute, Columbia University, New York, NY, USA

Linda B.Buck Richard Axel Fred Hutchinson Cancer Research Center Seattle, WA, USA

b. 1947

瑞典卡罗林斯卡医学院和瑞典皇家科学院宣布了 2004 年度诺贝尔医学生理学奖的归属。美国科学家 Richard Axel和 Linda B.Buck 因为在气味受体和嗅觉系统的研究贡献而一同分享了今年的生理学医学奖。 (2004)

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"for their discovery of RNA interference - gene silencing by double-stranded RNA“(2006)

Andrew Z. Fire Stanford University School of Medicine Stanford, CA, USA

Craig C. Mello University of Massachusetts Medical School

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"for their discoveries of principles for introducing specific gene modifications in mice by the use of

embryonic stem cells“ (2007)

• Mario R. Capecchi• University of Utah

Salt Lake City, UT, USA; Howard Hughes Medical Institute 1937-(in Italy)

• Sir Martin J. Evans• United Kingdom

Cardiff University Cardiff, United Kingdom1941-

• Oliver Smithies • University of North Carolina at

Chapel Hill Chapel Hill, NC,

1925-(in United Kingdom)

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"for his discovery of human papilloma viruses causing

cervical cancer"

• Harald zur Hausen

• Germany German Cancer Research Centre Heidelberg, Germany

1936-

"for their discovery of human immunodeficiency virus“ (2008)

• Françoise Barré-Sinoussi

• France

Regulation of Retroviral Infections Unit, Virology Department, Institut Pasteur

Paris, France

1947-

• Luc Antoine Montagnier • France World Foundation for

AIDS Research and Prevention Paris, France 1936-

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"for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase“(2009)

Elizabeth H. Blackburn

Carol W. Greider

Jack W. Szostak

University of California

San Francisco, CA, USA

1948

Johns Hopkins University School

of Medicine Baltimore, MD,

USA

1961

Harvard Medical School; Massachusetts General

Hospital Boston, MA, USA; Howard Hughes Medical Institute

1952

2010 and 2011??

4. Future of Molecular Biology

21 世纪生命科学发展的趋势

• 对生命现象的认识从单基因水平向全基因组整体水平发展

• 现代生命科学研究的理论与技术从较长期的积累走向应用

21 世纪生命科学发展的趋势

•人类基因组计划推动了基因组工业的兴起。•人类基因组计划的实施带动了新学科的产生和发展。基因组（ Genomics ）、基因组学（ Genomic

s ）及功能基因组学（ Functional genomics ）蛋白组（ Proteome ）及蛋白组学（ Proteomics ）生物信息学（ Bioinformatics ）

• 分子生物学技术的进展DNA 芯片技术的发展基因表达连续分析技术噬菌体表面展示技术分子标记技术研究酵母双杂交技术RNAi 技术的研究

• 基因工程研究进展转基因植物转基因动物克隆动物基因治疗生物制药产业的发展

• 免疫分子生物学• 发育分子生物学• 神经分子生物学• 癌基因的分子生物学• AISD病毒的分子生物学• 环境生物学的应用

生物大分子的高级三维结构与功能的统一生物大分子之间的互作 → 基因的社会学 (Nature 杂志增设 Natural developing biology 分册 )

基因表达，基因互作器官发生胚胎形成个体发育

结构生物学（ Structural Biology ）

分子发育生物学（ Molecular Developing Biology ）

个体细胞分子

还原论

整体论细胞中的定位细胞分化

分子细胞生物学

(Molecular Cell Biology)

Genomics

Structural genomics

Functional genomics

Structural genomics• 基因组的全序列• 高密度的分子标记图谱• 高精度的物理图谱• 转录水平上的表达图谱• 大规模的蛋白质构型模拟

Functional genomics 利用结构基因组提供的信息

大规模地分析基因的功能

不仅提供基因功能的简单列表

最终要阐释基因

如何工作细胞组织个体

计算计语言

分辨，提取，分析，比较，预测生物信息

生物大分子的结构与功能信息

生物信息学(Bioinformatics)

应用生物学发展生物技术

诊断试剂治疗药物

植物品种畜用制品

食品加工环境工程

废物处理生物塑料

民用制品再生能源

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Amazing genetics?!