基因组学与人类基因组计划.ppt

遗传学遗传学李伟李伟2015-9-22遗传学概念遗传学（Genetics）研究生物的遗传与变异的科学；研究基因的结构、功能及其变异、传递和表达规律的学科。早期对遗传的认识关于遗传物质基础，科学家早就有所臆测:1864年英国哲学家斯宾塞曾提出“生理单位”;1868年达尔文将其称为“微芽”;1884年瑞士植物学家冯内格列称之为“异胞质”;1889年荷兰学者雨果德弗里斯称为“泛生子”;1883年德国魏斯曼称之为“种质”,并指明生殖细胞中的染色体便是种质，认为种质是遗传的，体质不遗传，种质影响体质，而体质不影响种质。遗传学的发展阶段遗传学的诞生遗传学的发展：三个时期：1.细胞遗传学2.生化与微生物遗传学3.分子遗传学遗传学发展简史遗传学发展简史-19世纪世纪Gregor Mendel 1.孟德尔自觉地运用假说-推理方法2.孟德尔十分注意实验材料的选择豌豆具有明显的，稳定的形状自花授粉，易得纯种易于栽培、分离和杂交一直被植物杂交学者作为理想材料3.充分运用科学的研究方法-统计学精选和纯化实验材料尽可能使实验材料达到一定数量，确保统计结果可靠性强调物种和它的环境是相对稳定的采用由简至繁的研究方法孟德尔通过豌豆杂交实验，发现了遗传学上的重要法则提出了遗传因子的概念和假说支持了遗传的颗粒学说孟德尔实现了遗传学研究方法上的一次大突破遗传学发展简史-19世纪弗雷德里希米歇尔（1844年1895年），瑞士生物学家，出生于巴塞尔。他在1869年，首先从白血球的细胞核中，分离 出 一 种 他 称 为“核 素”（nuclein，现称核酸）的化学物质。Friedrich Miescher遗传学发展简史-19世纪德国科学家Richard Altmann（1852-1900）获得无蛋白的核酸制备，于1889年提出核酸的名词（Altmann，1889）。Kossel用Altmann的制备进一步分析，1891年宣布发现核酸含磷酸、腺嘌呤、鸟嘌呤（guanine，G）（Kossel，1891）。1893年他和学生发现核酸含胞嘧啶（cytosine，C）、胸腺嘧啶（thymine，T）。1901年他的学生Ascoli发现尿嘧啶（uracil）。遗传学发展简史-1900s1902,an English physician who pioneered the field of inborn errors of metabolism.He also discovered alkaptonuria(黑酸尿综合征),understanding its inheritance.常于出生后数天内发病，临床上以尿色变黑、巩膜和耳郭软骨有黑色素沉着、多关节炎及耻骨联合处剧痛为特征，是一种先天性代谢缺乏尿黑酸氧化酶引起的代谢遗传病Archibald Garrod遗传学发展简史-1900sEstablished the chromosome theory（1902-1904）Walter Sutton(left)and Theodor Boveri(right)遗传学发展简史-1900s1908-G.H.Hardy and Wilhelm Weinberg proposed the Hardy-Weinberg equilibrium model遗传学发展简史-1910s1910-Thomas Morgan determined the nature of sex-linked traits by studying Drosophila melanogaster.1933-Thomas Morgan received the Nobel prize for linkage mapping.His work elucidated the role played by the chromosome in heredity.(1)证明了基因是染色体的一部分；(2)证明了孟德尔定律，发现了伴性遗传；(3)测定了果蝇中基因的相对位置和距离，绘制了果蝇染色体图谱；(4)发现了缺失、重复、倒位和易位等染色体畸变现象。遗传学发展简史-1910s1911-Alfred Sturtevant,one of Morgans students,invented the procedure of linkage mapping which is based on the frequency of recombination.遗传学发展简史-1920s1923-Frederick Griffith studied bacterial transformation and observed that DNA carries genes responsible for pathogenicity.遗传学发展简史-1940s1944-Oswald Avery,Colin MacLeod and Maclyn McCarty refined the experiment done by Griffith in 1923.Their experiment on bacterial transformation involving the use of ribonuclease,protease,as well as deoxyribonuclease provided more evidence that DNA carries genetic information responsible for pathogenicity.遗传学发展简史-1940s1941-George Beadle and Edward Tatum,using Neurospora,demonstrated that genes code for enzymes.遗传学发展简史-1950s1950-Erwin Chargaff determined the pairing method of nitrogenous bases.Chargaff and his team studied the DNA from multiple organisms and found three things(also known as Chargaffs rules).遗传学发展简史-1950s1952 The HersheyChase experiment provided key evidence that DNA,as distinct from protein,is the genetic material of a bacteriophage and thus the likely genetic material generally遗传学发展简史-1950s1953-James Watson and Francis Crick with the contributions of Rosalind Franklin and Maurice Wilkins proposed a double helix model for the structure of DNA.遗传学发展简史遗传学发展简史-1950sRosalind Elsie Franklin遗传学发展简史-1950s1955-Alexander R.Todd determined the chemical makeup of nitrogenous bases.Todd also successfully synthesized Adenosine Triphosphate(ATP)and Favin Adenine Dinucleotide(FAD).He was awarded the Nobel prize in Chemistry in 1957 for his contributions in the scientific knowledge of nucleotides and nucleotide co-enzymes.徐道觉发现在人类染色体制片过程中采用低渗溶液预处理能得到分散得非常好的中期染色体（1952年）。成功地诱导染色体特定位点的断裂，是最早报告的染色体“脆性位点”（1961-1963年）。创建显示组成型异染色质的方法即染色体C显带技术（1971年）。提出诱变剂敏感性与环境致癌作用相关的假说并用实验证明（1983年1989年）。创建测量抗氧化剂效率的方法（1992年）。遗传学发展简史-1950s1955-Joe Hin Tjio（蒋有兴）determined the number of chromosomes in humans to be of 46遗传学发展简史-1950s1957-Arthur Kornberg with Severo Ochoa synthesized DNA in a test tube 遗传学发展简史-1950s1957/1958-Robert W.Holley,Marshall Nirenberg,Har Gobind Khorana proposed the nucleotide sequence of the tRNA molecule遗传学发展简史-1950s1958-The MeselsonStahl experiment showed that DNA replication is semiconservative.遗传学发展简史-1960s1960 Jacob and collaborators discovered the operon,a group of genes whose expression is coordinated by an operator遗传学发展简史-1960s1961-Francis Crick and Sydney Brenner discovered frame shift mutations.遗传学发展简史-1960s1961-Sydney Brenner,Francois Jacob and Matthew Meselson identified the function of messenger RNA.遗传学发展简史-1960s1966-Marshall W.Nirenberg,Philip Leder,Har Gobind Khorana cracked the genetic code by using RNA homopolymer and heteropolymer experiment遗传学发展简史-1970s1970-Hamilton O.Smith and Daniel Nathans purified the first restriction enzyme(EcoRI).遗传学发展简史-1970s1972-Stanley Norman Cohen and Herbert Boyer at UCSF and Stanford University constructed Recombinant DNA遗传学发展简史-1970s1972-Stanley Norman Cohen and Herbert Boyer at UCSF and Stanford University constructed Recombinant DNA遗传学发展简史-1970s1976-DNA sequencing methodology is devised.Frederick Sanger and Charles Coulson described a method for determining the sequence of DNA using a four lane polyacrylamide gel electrophoresis(PAGE).遗传学发展简史-1970sRay WuWu did important work in DNA sequencing and genetic engineering,and is regarded as one of founding fathers of plant genetic engineering他的引物延伸法进行DNA测序早在1971年前就取得成功。是后来F.Sanger末端终止法快速测序的基础。引物延伸法也是PCR和DNA定点突变技术的基础，这些都是得到诺贝尔奖的成果。遗传学发展简史-1980s1980-Paul Berg,Walter Gilbert and Frederick Sanger developed methods of mapping the structure of DNA.In 1972,recombinant DNA molecules were produced in Paul Bergs Stanford University laboratory.Berg was awarded the 1980 Nobel Prize in Chemistry for constructing recombinant DNA molecules that contained phage lambda genes inserted into the small circular DNA mol遗传学发展简史-1980s1982-The U.S.Food and Drug Administration(FDA)approved the release of the first genetically engineered human insulin1983-Barbara McClintock was awarded the Nobel Prize in Physiology or Medicine for her discovery of mobile genetic elements.1983-Kary Mullis of the Cetus Corporation drafted a technique for amplifying DNA through a cloning procedure that became known as polymerase chain reaction.1985-Alec Jeffreys announced DNA fingerprinting method1986-Jeremy Nathans found genes for color vision and color blindness,working with David Hogness,Douglas Vollrath and Ron Davis as they were studying the complexity of the retina.1992-American and British scientists unveiled a technique for testing embryos in-vitro(Amniocentesis)for genetic abnormalities such as Cystic fibrosis and Hemophilia.1993-Phillip Allen Sharp and Richard Roberts awarded the Nobel Prize for the discovery that genes in DNA are made up of introns and exons.1993年诺贝尔生理学或医学奖授予了Phillip Sharp和Richard Roberts，以表彰他们发现了断裂基因（splite gene)。然而，该发现在 1977年细胞杂志第11卷第4期发表时，论文领衔署名的作者是出生在中国湖南（后来从台湾旅居美国）的女科学家周芷，而获奖的Roberts根本就未署名。第二篇论文发表于同年同一杂志第12卷第1期，第一作者仍是周芷，而作为实验室同事的罗伯茨则署名在最后（很像大多数文章中通讯作者的地位）。1994-The first breast cancer gene is discovered.BRCA I,was discovered by researchers at the King laboratory at UC Berkeley in 1990 but was first cloned in 1994.BRCA II,the second key gene in the manifestation of breast cancer was discovered later in 1994 by Professor Michael Stratton and Dr.Richard Wooster.1997-Dolly the sheep was cloned by Ian Wilmut and colleagues from the Roslin Institute in Scotland2000-The full genome sequence of Drosophila melanogaster is completed.2003-The Human Genome Project is officially completed after being funded by Congress in 1988.我国基因诊断主要开拓者之一，率先将基因工程与临床医学相结合，发展了一整套基因诊断技术，系统地攻克了一些主要遗传病的基因诊断和产前诊断1998年11月在世界上最先克隆了神经性高频听力下降的耳聋疾病基因，实现了在我国本土上克隆遗传病疾病基因零的突破。在国际上首次发现了八核苷高识别特性限制酶Sfi I，并与他人合作鉴定出第二种核苷酸酶NotI的识别特异性，为当今真核基因组尤其人类基因组作图和全序列测定提供了DNA大片段剪切工具1.国际“人类基因计划”协作组中国协调人1999-20032.国际“人类单体型图（HapMap）计划”协作组中国协调人2002-2005揭开了倍受世人关注的遗传界百年之迷第一例孟德尔常染色体遗传病，率先完成了A-1型短指(趾)症致病基因精确定位、克隆与突变检测，发现了IHH基因的3个点突变是致病的直接原因。与天津医科大学口腔医学院合作，在国际上首次发现牙齿涎磷蛋白基因突变导致遗传性乳光牙本质。与北大医院儿科合作，在国际上首次发现T型钙离子通道H基因变异与儿童失神癫痫发病有关。与北大医院皮肤科合作，在国际上首次发现钠离子通道a亚单位SCN9A基因突变导致红斑肢痛症。