1、Genes VIII 基因八OXFORD UNIVERSITY PRESSFirst published 2000,朱玉贤 现代分子生物学，高等教育出版社 孙乃恩 分子遗传学，南京大学出版社。 阎隆飞 分子生物学，中国农业大学出版社， 李振刚 分子遗传学，科学出版社 沈羽非 真核基因表达调控，北京高等教育出版社 Lewin,B, Genes VII , Oxford University Press Turner P.C. et al. Molecular Biology. 科学出版社 Weaver R. Molecular Biology. 科学出版社,参 考 书 目,2005年2月出版 ,
2、198,2004年2月出版 ,260,Outline :Part I 基因 genes Part II 蛋白质 Protein Part III 基因表达 mRNA Part IV DNA Part V 细胞核 nucleus Part VI 细胞 Cells,Chapter 1 Genes are DNA,基因是特殊因子 Genes are particulate factors 1971 核酸的发现 Discovry of nucleic acid染色体是遗传单位 Chromosomes are hereditary units基因位于染色体上Genes lie on chromosome
3、s染色体是基因的线性排列 Chromosomes contain linear arrays of genes突变是基因的物理改变 Mutations are physical changes in genes,1.1 Key events a brief history of genetics,1931 重组通过交换而发生 Recombination is caused by crossing over 1944 DNA是遗传物质 DNA is genetic material 1945 基因编码蛋白质 A gene codes for a protein 1953 DNA是双螺旋 DNA
4、is a double helix 1958 DNA是半保留复制 DNA replicates semiconservatively 1961 遗传密码子是三联体 Genetic code is triplet 1977 真核生物基因是断裂的 DNA can be sequenced 1977 DNA可以测序 Genomes can be sequenced测序细菌基因组 Bacterial genenome sequenced 2001 测序人类基因组 Hunman genenome sequenced,(1) The Early Years of Genetics,A. 1859, Cha
5、rles Darwin and evolutionary theory,1809 -1882 Father of evolutionary theory Published Origin of Species By Means of Natural Selection or the Preservation of Favoured Races in the Struggle for Life in 1859,QuestionHow the Woodpecker Avoids a Headache?,Survival of the Fittest.,Animation,B. 1865, Greg
6、or Mendel and genetics,1822 -1884 Father of genetics Laws of inheritance,What Did Mendel Find?,He discovered different laws and rules that explain factors affecting heredity., Rule of Unit Factors,Each organism has two alleles for each trait Alleles Genes,Law of Independent Assortment 基因的自由组合定律 当具有两
7、对（或更多对）相对性状的亲本进行杂交，在子一代产生配子时，在等位基因分离的同时，非同源染色体上的基因表现为自由组合。,Law of Segregation 基因的分离定律 基因的分离定律的实质是，在减数分裂形成配子时，等位基因随同源染色体的分开而分离，分别进入两个配子中独立地传给后代。,1869, Johann Friedrich Miescher discovered “nuclein核素“.,C.,1889, Richard Altmann named it “nucleic acid“. This substance was found to exist only in the chro
8、mosomes.,1909, “gene“ , genotype, phenotype,D.,E.,Thomas Hunt Morgan (1866-1945) Chromosome likage 1933, Nobel Prize in Physiology or Medicine,1910s, Golden Age of Genetics, Sex determination, genes and their traits are linked to specific loci on chromosomes Mapping - Crossing over will allow us to
9、map position of genes,1943, Oswald Avery, Colin MacLeod, and Maclyn McCarty report evidence that, at least in bacteria, the molecule that carries genetic information is DNA (deoxyribonucleic acid).,Avery,MacLeod,McCarty,G.,F.,1941, One gene, one enzyme 1908年，英国医学生化学家伽罗德-尿黑酸-缺乏尿黑酸氧化酶-尿液发黑。 比德尔 -辐射（如X
10、射线或紫外线）-红色面包霉孢子-突变体 -突变体,H. 1952, DNA - Inherited substanceMartha Chase and Alfred Hershey demonstrated that DNA is the inherited substance. Hershey shares the 1969 Nobel Prize (not with Martha Chase but with Max Delbruck and Salvador Luria).,I,II,III,Animation,Crick,Watson,Wilkins,James Watson, Fra
11、ncis Crick and Maurice Wilkins jointly received the 1962 Nobel Prize for their determination of the structure of DNA.,I. 1953, Unraveling the DNA double helix,Rosalind Franklin and her “Exposure 51”,J. 1967, Cracking the genetic codeHar Khorana, Robert Holley, and Marshall Nirenberg share the 1968 N
12、obel Prize.,(2) The Birth of Biotechnology,A. 1968, Plasmid Stanley Cohen,B. 1970, Restriction enzymes Herb Boyer,C. 1972, Recombinant DNA Paul Berg splices together two blunt-ended fragments of DNA from the SV40 virus and E. coli, creating recombinant DNA.,Berg, Gilbert and Sanger shared the 1980 N
13、obel Prize in Chemistry.,D. 1975, DNA sequencing Walter Gilbert, Allan Maxam and Fred Sanger come up with two techniques for determining the gene sequence simultaneously.,E. 1975, Monoclonal antibody technology Cesar Milstein, Georges Kohler and Niels Jeme develop monoclonal antibody technology and
14、won the 1984 Nobel Prize in Medicine.,F. 1978, Human insulin cloned,Cesar Milstein Georges Kohler Niels Jeme,(3) The Revolution of the Biotechnology,A. 1986, PCR Kary Mullis was awarded the 1993 Nobel Prize in chemistry.,B. 1989, HGP begins,C. 1990, First use of gene therapy to human,D. 1994, Brave
15、new foodsThe first transgenic food went to the supermarket.,Dolly,Dolly and Bonnie,E. 1996, First mammal cloned from adult cells,F. 1996, Development of the GeneChip,G. 1997, Three Cloned Mice,H. 1997, First Human Artificial Chromosome,(4) Welcome to the Genomics Era,A. 1998, Race for the Genome,B.
16、1998, Breakthrough of Stem Cell,James Thomson and John Gearhart,C. 1999, Shotgun sequencing鸟枪法,D. 2001, Draft of Human Genome,E. 2001, Cloning,F. 2001-2003, Some cloned animals,G. 2006, Nobel Prize for the Discovery of RNAiAndrew Fire and Craig C. Mello shared the Nobel Prize in Physiology or Medici
17、ne for their work on RNA interference in C. elegans, which they published in 1998.,H. 2006 to now, Advances of Stem Cell 2006: Senate approves a stem cell bill 2006: Human embryonic stem cell lines derivedfrom single blastomeres 2007: Biologists make skin cells work like stem cells 2007: Nobel Prize
18、 in Physiology and Medcine,3. What is Molecular Biology?,The study of DNA is a central part of molecular biology.,Molecular biology is the study of biology at a molecular level. Molecular biology chiefly concerns itself with understanding the interactions between the various systems of a cell, inclu
19、ding the interrelationship of DNA, RNA and protein synthesis and learning how these interactions are regulated.,(1) Central Dogma,4. Contents of Molecular Biology,(2) Contents of Molecular Biology Recombinant DNA Technology Expression and Regulation of Genes Structure and Function of Bio-macromolecu
20、lar Genome, Transcriptome, Proteome, Bioinformatics,Genome (all genes),Transcriptome (all RNAs),Proteome (all proteins),5. Progress and Future of Molecular Biology,Animation,Proportionally more deleterious genetic variation in European than in African populations Nature, 2008, 451, 994-997,More Prog
21、ress,Quantifying the number of deleterious mutations per diploid human genome is of crucial concern to both evolutionary and medical geneticists. Here we combine genome-wide polymorphism data from PCR-based exon resequencing, comparative genomic data across mammalian species, and protein structure p
22、redictions to estimate the number of functionally consequential single-nucleotide polymorphisms (SNPs) carried by each of 15 African American (AA) and 20 European American (EA) individuals. We find that AAs show significantly higher levels of nucleotide heterozygosity than do EAs for all categories
23、of functional SNPs considered, including synonymous, non-synonymous, predicted benign, predicted possibly damaging and predicted probably damaging SNPs. This result is wholly consistent with previous work showing higher overall levels of nucleotide variation in African populations than in Europeans.
24、 EA individuals, in contrast, have significantly more genotypes homozygous for the derived allele at synonymous and non-synonymous SNPs and for the damaging allele at probably damaging SNPs than AAs do. For SNPs segregating only in one population or the other, the proportion of non-synonymous SNPs i
25、s significantly higher in the EA sample (55.4%) than in the AA sample (47.0%; P 2.3 10-37). We observe a similar proportional excess of SNPs that are inferred to be probably damaging (15.9% in EA; 12.1% in AA; P 3.3 10-11). Using extensive simulations, we show that this excess proportion of segregat
26、ing damaging alleles in Europeans is probably a consequence of a bottleneck that Europeans experienced at about the time of the migration out of Africa.,Lifting the Veil on Traditional Chinese Medicine Science, 2008, 319( 5864): 709 -710,DALIAN, CHINA-Genome, proteome, metabolome herbalome? In the l
27、atest industrial assault on natures biochemical secrets, a Chinese team in this seaside city is about to embark on a 15-year effort to identify the constituents of herbal preparations used as medications for centuries in China. The Herbalome Project is the latest-and most ambitious-attempt to modern
28、ize t raditional Chinese medicine (TCM). The venerable concoctions-as many as 400,000 preparations using 10,000 herbs and animal tinctures-are the treatment of choice and often the only recourse for many in China. In the 1970s, TCM tipped off researchers to qinghaosu, a compound in sweet wormwood wh
29、ose derivatives are potent antimalaria drugs. But TCMs reputation has been blackened by uneven efficacy and harsh side effects, prompting critics to assail it as outmoded folklore. “TCM is not based on science but based on mysticism, magic, and anecdote,“ asserts biochemist Fang Shi-min, who as Chin
30、as self-appointed science cop goes by the name Fang Zhouzi. He calls the Herbalome Project “a waste of research funds.“ Hoping to rebut TCM critics, Herbalome will use high-throughput screening, toxicity testing, and clinical trials to identify active compounds and toxic contaminants in popular reci
31、pes. “We need to ensure that TCM is safe and also show that it is not just qinghaosu,“ says Guo De-an, who leads TCM modernization efforts at the Shanghai Institute of Materia Medica and is not involved in Herbalome. Initial targets are cancer, liver and kidney diseases, and illnesses that are diffi
32、cult for Western medicine to treat, such as diabetes and depression. The Dalian Institute of Chemical Physics (DICP), one of the biggest and best-funded institutes of the Chinese Academy of Sciences, won a $5 million start-up grant to develop purification methods; the Ministry of Science and Technol
33、ogy is reviewing the project with a view to including it as a $70 million initiative in the next 5-year plan to start in 2010. A planning meeting will be held at a Xiangshan Science Conference-Chinas equivalent of a Gordon Research Conference-in Beijing this spring. Several TCM power players have th
34、rown their weight behind the initiative. “Its the right time to start this project,“ says chemist Chen Kai-xian, president of the Shanghai University of Traditional Chinese Medicine. Herbalome should appeal to pharmaceutical firms, as it could identify scores of drug candidates, says Hui Yongzheng,
35、chair of the Shanghai Innovative Research Center of Traditional Chinese Medicine. In many parts of the world, traditional medicine recipes are handed down orally from one generation to the next. But in China, practitioners more than 2000 years ago began to compile formulations in compendia. Although
36、 in major cities Western medicine has largely supplanted TCM, many Chinese still believe in TCMs power as preventive medicine and as a cure for chronic ailments, and rural Chinese depend on it. “For most of us, when we feel unwell, we want to take TCM,“ says chemist Liang Xinmiao of DICP. Since the
37、Mao Zedong era, the government has strongly supported TCM, in part because it was too expensive to offer Western medicine to the masses. It remains taboo for Chinese media to label TCM as pseudoscience. “Criticizing TCM is unthinkable to many Chinese and almost like committing a traitorous act,“ say
38、s Fang. Proponents insist that TCM has much to offer. But for every claimed TCM success, there are reports of adverse effects from natural toxins and contaminants such as pesticides. Dosages are hard to pin down, as preparations vary in potency according to where and when herbs are harvested. Qualit
39、y can vary from manufacturer to manufacturer and from batch to batch. “Thats why many people dont trust TCM,“ says Guo. In the modernization drive, quality control is a paramount concern. Herbalome intends to take modernization to a whole new level. The initiative is the brainchild of Liang, who bel
40、ieves many TCM recipes are effective. “The problem is, we dont know why it works,“ he says. The main hurdle is the complexity of the preparations. As an example, Liang shows a chromatograph of Hong Hua, or “red flower,“ a preparation applied externally for muscle pain. In many samples chemists deal
41、with, one peak usually represents one compound, Liang says. But for Hong Hua, each peak is many compounds, and fractionating these yields more multicompound peaks like nested matryoshka dolls. Hong Hua is composed of at least 10,000 compounds, says Liang: “We know only 100.“ Faced with such complexi
42、ty, “we must invent new methodologies,“ says Liang. “This is the battleground of the Herbalome project.“ For starters, his 45-person team at DICP is developing new separation media. Herbs will be parsed into “multi-components“: groups of similar constituents. To determine which substances are benefi
43、cial or toxic, his group plans to devise Herbalome chips in which arrays of compounds are screened for their binding to key peptides. The expanded Herbalome project would involve researchers at many institutes in China and abroad. Herbalome has potential pitfalls. One is a concern that Western compa
44、nies will develop blockbuster drugs-and walk away with the spoils-by modifying compounds identified by the project. To counter this possibility, says Guo, “were encouraging scientists not to rush to publish and do structure modifications to identify drug candidates first.“ Teams would then apply for
45、 patents on groups of similar structures. Not all practitioners embrace TCMs demystification. “Some are afraid that the traditions will be lost,“ says Chen. But Hui says that modernization is necessary “to reconcile the knowledge-oriented, deductive process of Western medicine with the experience-or
46、iented, inductive process of TCM.“ Fang has a different take: “Can you marry astrology and astronomy, alchemy and chemistry? It never works.“ Hui insists that TCM can coexist wi th Western medicine. Liang hopes his Herbalome project will prove Hui right. With reporting by Li Jiao in Beijing.,The Ass
47、ociation Between Physical Activity in Leisure Time and Leukocyte Telomere Length Archives of Internal Medicine, 2008, 168(2):154-158,Complete Chemical Synthesis, Assembly, and Cloning of a Mycoplasma genitalium Genome Science, Published Online January 24, 2008,每个生物体的基因组决定了该生物体的遗传特性，基因组拥有很长的核苷酸序列，能提供
48、构建机体所需的信息。,任何有机体的基因组都蕴藏着一套完整的遗传信息。基因组在结构上可分成若干功能不同的基因。每条基因是核酸中代表一种蛋白质的序列。,Seminar report,2 weeks for prepare, 1 report/1 person Select one English paper within the f0llowing fields given, prepare for a ppt report in Chinese, and hand in the files including report in Chinese and selected paper, then
49、discuss extensively about the topics each other on the class. Address in Chinese the followings in your report : Main scientific question the paper was trying to answer (Given usually in the abstract ); what the main background of the paper was (Given usually in the introduction ); Experimental approaches taken and main techniques used; Major results and conclusions, focused on tables and figures; What points were intersted to you of the paper; Your ideas to further the research.,
