分子醫(yī)學(xué)組學(xué)與系統(tǒng)生物學(xué)

1、Molecular Medicine IVOmics and Systems Biology組學(xué)與系統(tǒng)生物學(xué)概論KE, Yuehai 柯越海, School of Basic Medical Sciences (BMS-ZJU)浙江大學(xué)醫(yī)學(xué)院al Profile 個(gè)人信息欄目 基本信息 教學(xué)工作(14年春秋學(xué)期)醫(yī)學(xué) ()組學(xué)與系統(tǒng)生物學(xué) 3月18日教408 周二下午 13：15-15：40 、3月19日 紫金港東1A-403 周三教408 周二下午 13：15-15：40 、4月9日 紫金港東1A-403 周三下午 9： 學(xué)術(shù)交流（講座報(bào)告）下午 9：50-12：15細(xì)胞信號(hào)傳導(dǎo) 4月8日5

2、0-12：15 科研資助 招生信息 課題組成員 科研伙伴(PMCB等) 學(xué)校服務(wù)與學(xué)術(shù) NewsCsmg ReadingCsmg English課件注意事項(xiàng)：本網(wǎng)頁(yè)所有課件(PDF)本校本專業(yè)學(xué)員教學(xué)復(fù)習(xí)參考，它用、提供任何第；除特殊注明之外所有課件文字、數(shù)據(jù)、圖表等均來(lái)自公開(kāi)物，請(qǐng)尊重原作者；部分課件有刪除或技術(shù)處理，教學(xué)內(nèi)容以課堂授課為準(zhǔn)。Overview Introduction into omics and systems biology Hierarchy : Systems biology in life sciences Definition and scope Essentia

3、ls and aims History and trends Omics-based systems Genomics (DNA-based) Transcriptome (RNA-based) Proteomics (Protein-based) Metabonomics (Chemical-based) Cytomics (Cell-based) Systems Genetics (Integrated)Lifes hierarchy of continuous evolutionfromto human動(dòng)物界脊索動(dòng)物門動(dòng)物無(wú)脊椎動(dòng)物亞門哺乳綱靈長(zhǎng)目人科人屬現(xiàn)代智人種Lifes hiera

4、rchy of organization:from global to microscopic scaleBiospherelevel systemlevel systemEcosystemCommuPopulationlevel systemlevel systemAll level SystemsSystem biology: Studying biology at level systemsOrganismOrganlevel systemlevel systemlevel systemTissueCellOrganellelevel systemlevel systemlevel sy

5、stemMoleculeHow are biological systems studied ?1.In essential, systems that are composed of molecular components.2.Although systems are composed of matters, the essence of system lies indynamics.3.Structure of the system and componentsplays indispensable role forming symbiotic state of the systemas

6、 a whole.4.Understanding of structure of the systemas regulatory networksCell signal-based system (signal network)Biological systems: from global to microscopic scaleEcosystem is a commuof living organisms (plants, animals and microbes) in conjunctionwith the nonliving components of their environmen

7、t (things like air, water and mineral soil), interacting as a systemBiological systems: from global to microscopic scaleSystems biology: the study of life organizationTrends in Life sciencesCurrent systems biology (系統(tǒng)生物學(xué))Definition of systems biology is biology that understanding of life at system-l

8、evels is emerging integrative approaches applied to biomedical and biological scientific research. is a omics-based inter-disciplinary field of study that focuses on complex interactions within biological systems, using a more holistic (整體的)perspective instead of the more traditional reductive (簡(jiǎn)化的)

9、 approach Integrative systems biology and predictive systems biologyEssentials of systems biology High throughput engineer and techniques (biotechnology) Integrated,systematic theory of complex interactions (systems genetics) Powerful data management and functional analysis (biostatistics) Biostatis

10、tics is the application of statistics to a wide range of topics in biology. It encompasses the design of biological experiments, especially in medicine and agriculture; the collection, summarization, and analysis of data from those experiments; and the interpretation of, and inference from, the resu

11、lts. Bioinformatics is an information science that analyzes life processes using computational tools for solving biological problems and give direction/overview in biologyAims of systems biology Understanding biological knowledge from the omics through integration (Integrative systems biology) Predi

12、cting future of biosystem using systems biology)omics knowledge (PredictiveHistory of systems biology (1)1. Systems biology finds its roots in 1900-1970:a.the quantitative ming of enzyme kinetics, a discipline that flourishedbetween 1900 and 1970;b.c.d.the mathematical ming of population growth;the

13、simulations developed to study neural physiologyOne of the theorists who can be seen as one of the precursors of systems biology is Ludwig von Bertalanffy with his general systems theory.History of systems biology (2)2.The formal study of systems biology as a distinct discipline in 1966a.Is launched

14、 by systems theorist Mihajlo Mesarovic in 1966 with an international symposium at the Case Institute of Technology in Cleveland, Ohio entitled Systems Theory and Biology”.Mathematical theory of coordinationMulti-level HierarchicalSystems Developergeneral systems theory1928-Mihajlo Mesarovic1901-1972

15、Ludwig von BertalanffyState University of New York at Buffalo馮Case Institute of TechnologyHistory of systems biology (3)However the birth of genomics in the 1990s meant that large quantities of high quality data became available, while the computing power exploded, making more realisticms possible.A

16、round the year 2000, after Institutes of Systems Biology were established in Seattle and Tokyo, systems biology emerged as a movement in its own right, spurred on by the completion of various genome projects, the large increase in data from the omics (e.g. genomics and proteomics) and the accompanyi

17、ng advances in high-throughput experiments and bioinformatics.Since then, various research institutes dedicated to systems biology have been developed. NIH established a project grant that is currently supporting over ten systems biology centers in the United States.2006年 中國(guó)上海生命科學(xué)組建中國(guó)系統(tǒng)生物學(xué)重點(diǎn)實(shí)驗(yàn)室建立“組學(xué)

18、”研究平臺(tái)，依托計(jì)算科學(xué)、論科學(xué)方面的理論和工具，研究復(fù)雜的生命活動(dòng)如細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)和發(fā)育，以及危害人類健康的復(fù)雜性疾病，如腫瘤、和神經(jīng)退行性疾病Systems Biology and Translational ResearchThe NIH, Elias Zerhouni Science, 2003Translational and clinical sciences- Time for a new vision EliasZerhouni NEJM; 2003Elias Zerhouni Former Director of NIHBenchBedsideCommuSeeking a ne

19、w solutions to accelerate the Bench to Bedside (B-2-B) and Bench to Commutranslations (B-2-C).Molecular Approaches for Translational MedicinesOmics and System levelsWhat is Omics?A broad discipline of science and engineering for analyzing the interactions of biological information objects in various

20、 omics.Mapping information objects such as DNA, RNA and Proteins;Finding interaction relationships among the objects;Engineering the networks and objects to understand and manipulate the regulatory mechanisms;Omics-based systemsEvolving System Biology Introduction into omics and systems biology Hier

21、archy : Systems biology in life sciences Definition and scope Essentials and aims History and trends Omics-based systems Genomics (DNA-based) Transcriptome (RNA-based) Proteomics (Protein-based) Metabonomics (Chemical-based) Cytomics (Cell-based) Systems Genetics (Integrated)Genomics (DNA-based Omic

22、s) Genomics & Variomics Functional genomics Comparative genomics Kinomics/ptpomics PharmacogenomicsGenomics and Variomics Gene, Genome, Genomices Human Genomics Projects, HGP HapMap SNP,Haplotype, Haplotype in population and Origin of Modern Human HardyWeinberg Equilibrium andLinkage Disequilibrium

23、HapMap for Mapping Genes in population (M Human Veriome Projects, HVPof MALD)Gene, Genome and GenomicsGene is a sequence of DNA that has a known function, such as encoding protein or controlling gene expression, which determine inherited traits.Genome: the entire genetic complement, all of the hered

24、itary material possessed by an organism including chromosomal and mitochondrial genome.Genomics: the study of functions andinteractions of all tetic information intome, including their interactionswith environmental factorstone of Genomics and HGP 1985 DNA sequence Proposed(May) Robert Sinsheimer ho

25、sts a meeting at the University of California (UC), Santa Cruz, to discuss the feasibility of sequencing the human genome.(December) Kary Mullis and colleagues at Cetus Corp. develop PCR, a technique to replicate vast amounts of DNA 1988 DNA Sequencer released on the marketApplied Biosystems Inc. pu

26、ts the first automated sequencing machine on the market. 1988. Initiated and funded by NIH and US Dept. of Energy (February) In a pivotal report, the NRC endorses the Human Genome Project (HGP), calling for a phased approach and a rapid scale-up to $200 million a year of new money. (October) NIH and

27、 DOE sign a memorandum of understanding and agree to collaborate on the HGP. 1990. Work begins. (April) NIH and DOE publish a 5-year plan. Goals include a complete genetic map, a physical map with markers every 100 kb, and sequencing of an aggregate of20 Mb of DNA in morganisms by 2005. (October) NI

28、H and DOE restart the clock, declaring 1 October the official beginning of the HGP.tone of Genomics and HGP1992 (October) U.S. and French teams complete the first physical maps of chromosomes: David Page of the Whitehead Institute and colleagues map the Y chromosome (Science); Daniel Cohen of the Ce

29、ntre dEtude du Polymorphisme Humain (CEPH) and Gnthon and colleagues map chromosome 21 (Nature).1995 (September) The Japanese government funds several sequencing groups for a total of $15.9 million over 5 years: Tokai University, University of Tokyo, and Keio University.1996 (April) NIH funds six gr

30、oups to attempt large-scale sequencing of the human genome.1998 (January) NIH announces a new project to find SNPs.(May) Craig Venter announces a new company named Celera and declares that it will sequence the human genome within 3 years for $300 million.Francis CollinsCraig Venter(1950-)(1946-)tone

31、 of Genomics and HGP2000 (June) At a White House ceremony, HGP and Celera jointly announce working drafts of the human genome sequence, declare their feud at an end, and promise simultaneous publication.2001 (February) The HGP consortium publishes its working draft in Nature(15 February), and Celera

32、 publishes its draft in Science (16 February).2002 (Oct) . The International HapMap Project officially started2003 (April) HGP sequencing is completed and Project is declared finished two years ahead of scheduleHow they did it DNA from 5 humansThree-stage approach to sequencing an entire genome 2 ma

33、les, 3 females 2 Caucasians, one each of Asian, Af Hispanic Cut up DNA with restriction enzym Sequenced the fragments Let a supercomputer put the piecesWhat does the draft human genome sequence tell us? The human genome contains 3 billion chemical nucleotide bases (A, C, T, and G). The average gene

34、consists of 3000 bases, but sizes vary greatly, with the largest known human gene being dystrophin at 2.4 million bases. The total number of genes is estimated at around 30,000-much lower than previous estimates of 80,000 to 140,000. Almost all (99.9%) nucleotide bases are exactly the same in all pe

35、ople.試題分析有研究顯示人類數(shù)量可能比蟲還少，在20世紀(jì)60年代時(shí)，科學(xué)家就人類組至少含有200萬(wàn)個(gè)編碼蛋白質(zhì)的DNA序列。不過(guò)隨著科學(xué)的發(fā)展，這個(gè)預(yù)測(cè)的數(shù)字越來(lái)越小，最新的一份表明人類組里只有不到1.9萬(wàn)編碼蛋白的，這一數(shù)字甚至比線蟲還要小。此前的一系列的研究已經(jīng)證明并不是越復(fù)雜的生物體擁有越多的。據(jù)，某類水蚤有3.1萬(wàn)，是動(dòng)物界之最。但它還不是最多的，一種開(kāi)花植物草（Paris japonica）是最多的保持者，大致1490億個(gè)堿基對(duì)。請(qǐng)根據(jù)本學(xué)期學(xué)習(xí)的組遺傳與變異相關(guān)知識(shí)，如何理解這個(gè)生物學(xué)現(xiàn)象？Post-genomics: Variation and RegulationGenet

36、ic variationGenetics: is the biology of heredity and variation in living organismsGenetic variation: any variation in t within and among populationses and genome, occurs both A genetic resource for biological diversity A power of evolution A compromised pattern by genetic-environmental interaction A

37、 genetic basis for regulation (How does interaction work?) A powerful tool to understand human diseases(genetic markers)Genetic variationn Chromosomal variationStructural variation Numberic variationnnn Genomic polymorphism and Genetic markersStructural polymorphismnDNA segmentsnRFLP (Restriction fr

38、agment length polymorphism)STR (short tandem repeat) Microsatellite polymorphismnnDNA MutationnnSNP (Single nucleotide polymorphism)Haplotype (A set of genetic polymorphic markers on the one chromosome)nNumberic polymorphismnCNPs (Copy number polymorphisms)nMicrosatellite system (STR) Short segments

39、 of DNA that have a repeated sequence with repeatingunit in 2-6 bp, normally 4 bps. for example, (CA)n, (CAG)n, (GATA)n Non-coding DNA segments with Evenly distributed in the whole human genome. Increased rate of mutation compared to other neutral regions of DNA, as high as 0.10.2% per generation Fo

40、llow Mendelian inheritance. Co-dominant inheritanceHow to detect Microsatellite?Multiple PCRsMicrosatellite for forensic identificationGenescan: High-throughput microsatellite detectionFacts to be determined for a set of multiple PCR Panel: Size of PCR products Fluorescent-labeled primers Alignment

41、of multiple sequences Hyper-variable Microsatellite in sampled populationGenome-wide scan for sets of MicrosatelliteDevelopment of multiplex marker panelsDistribution of microsatellite markers across the rat genomeSNPs (single nucleotide polymorphisms)A SNP is defined as a single base change in a DN

42、A sequence that occurs in a significant proportion (more than 1 percent) of a large population.SNPs may / may not alter protein structureSNPs and HaplotypesSNPs: A Single Nucleotide Polymorphism is a small genetic variation very similar to point mutationsHaplotype：The scientists mapping the SNPs in

43、the human genome noticedthat groups of SNPs tended to be inherited together, in blocks known as haplotypes, ranging in length from 5,000 to 200,000 base pairs. There are as few as four or ve commonly occurring combinations of SNPs per haplotype.SNPs-Haplotype: A set of single nucleotide polymorphism

44、s (SNPs) on a single chromatid that are statistically associated. It is thought that these associations, and the identification of a few alleles of a haplotype block, can unambiguously identify all other polymorphic sites in its region.STR-HaplotypeD6S1719 D6S264 D6S261 D6S446D6S101 103Allele No. Si

45、ze of Products110121033105.462SNP-Haplotypers901104 rs1385600 rs2510038 rs7101429rs7115850Haplotypes: A set of SNPs and STRsC A CC T TA CA TBeyond the HGP: HapMaPProject was launched in Oct 2002.In the first phase genotyped 1.1 million SNPs in 269 individuals from four ethnic origins.Second phase wi

46、ll genotype another4.6 million SNPs.Goal was to find most SNPs that occur with frequencies of at least 5% in the human population.HapMapChart genetic variation within the human genomeY-chromosome haplotypes in human population1.is much smaller than its homolog, the X chromosome2.holds only a dozen o

47、r so genes genes)(X holds 2,000 to 3,0003.holds a gene - SRY (sex determining region) encodes a protein that triggers formation of testes by activating genes on several of the autosomes.4.5.holds lots of junk DNAincluding STR and SNPsBulks of non recombinant regions (NRY)Y chromosome as a genetic to

48、ol for modern human originPhylogenetic analysis Rooted or Unrooted Genetic Distance: neighbor joining treeSTR-based mappingDistance matrix考題分析據(jù)， “”在沉寂千年后驟然現(xiàn)世，真?zhèn)我皇恰Ｈ涨?，?guó)內(nèi)某知名大學(xué)從事人類遺傳學(xué)研究的學(xué)者，開(kāi)始征集男性志愿者，擬用DNA技術(shù)來(lái)解答真?zhèn)沃畣?wèn)，消息一出，眾說(shuō)紛紜。請(qǐng)你根據(jù)遺傳變異及組多態(tài)性方面的知識(shí)談?wù)勀愕目捶?，你認(rèn)為哪些不確定因素？學(xué)及技術(shù)是否可行？還Genomics and Variomics Gene, Geno

49、me, Genomices Human Genomics Projects, HGP HapMap SNP, Haplotype, Linkage Disequilibrium HapMap for Mapping Genes in population (M Human Veriome Projects, HVPof MALD)Linkage disequilibrium (LD)1.An non-random association of alleles at two or more loci.2.A situation in which some combinations of alle

50、les or genetic markers occur more or less frequently in a population than would be expected from a random formation of haplotypes from alleles based on their frequencies.3.Non-random associations between polymorphisms at different loci are measured by the degree of linkage disequilibrium (LD).DMMDXM

51、DMapping by AdmixtureLinkage Disequilibrium (MALD)The first ARG gene identified in 1996Dr Stephen J OBrienChief of the Laboratory of Genomic Diversity and head of the Section of Genetics, NIHEyam, a town of Plague“Black Death”Haplotype in populationHaplotypes, the groups of closely linked alleles th

52、at tend to be inherited together, can be used to map human disease genes very accurately.Basic Concept for MALD Mapping by admixture linkage disequilibrium (MALD) is a genetic strategy for discovering genes that underlie complex diseases. The method is based on differences in disease-gene frequency

53、between the parental racial groups of admixed populations. A MALD-based full-genome scan can be carried out using a few thousand markers that are able to differentiate, to a high degree, between chromosomal ancestries in relation to the parental populations. This enables the discovery of regions tha

54、t harbour genes associated with complex diseases. The marker set will improve as frequency data accumulate from the HapMap project and HVP. Proof of the efficacy of MALD awaits its successful application among African- Americans for potentially amenable diseases, such as prostate cancer, multiple sc

55、lerosis and end-stage renal disease. MALD could then be applied to other groups over the next few years following theHapMap project ended, which produced many sets of Haplotypes in HVP.MALD Mfor African-AmericansAncestor in AfricaAfrican populationEuropean populationAfrican- AmericansThe MALD strategy involved 5 stepsFirst, a cohort for a particular disease is developed from an admixed ethnic group, ideally with large disease-incide