生物信息学基础讲座

1、第第2讲讲 生物信息学中的生物学生物信息学中的生物学生物学基础知识生物学基础知识l生物学基本概念生物学基本概念biological conceptsl生物大分子 macromoleculesl生物过程 biological processesl生物学实验技术生物学实验技术biological techniquesl测序技术 sequencing：大分子序列lNMR/X-ray技术：大分子结构lMicroarray技术：基因表达l酵母双杂交Y2H：蛋白-蛋白相互作用l生物学数据生物学数据 biological datal序列数据：DNA/RNA/蛋白质序列l结构数据：蛋白质/复合物二维/三维结构

2、l表达数据：microarray/Chip-chip数据l生物学数据库生物学数据库 biological databasesl文献数据库：Pubmedl核酸数据库：Genbank/EMBL/DDBJl基因组数据库：UCSC Genome Browserl蛋白数据库：Genprot/Swissprot/l结构数据库：PDBl表达数据库：GEO/SMDl基因通路数据库：KEGGl其他专业数据库：Flybase/MGI/WormbaseBiological NomenclaturelNeed to know the meaning of:lSpecies, organism, cell, nucle

3、us, chromosome, DNAlGenome, gene, base, residue, protein, amino acidlTranscription, translation, messenger RNAlCodons, genetic code, evolution, mutation, crossoverlPolymer, genotype, phenotype, conformationlInheritance, homology, phylogenetic treesSubstructure and EffectSpeciesOrganismCellNucleusChr

4、omosomeDNA strandGeneBaseProteinAmino AcidFoldsintoAffects theFunction ofAffects theBehaviour ofPrescribesCellslBasic unit of lifelDifferent types of cell:lSkin, brain, red/white bloodlDifferent biological functionlCells produced by cellslCell division (mitosis)l2 daughter cellslEukaryotic cellslHav

5、e a nucleusNucleus and ChromosomeslEach cell has nucleuslRod-shaped particles insidelAre chromosomeslWhich we think of in pairslDifferent number for specieslHuman(46),tobacco(48)lGoldfish(94),chimp(48)lUsually paired uplX & Y ChromosomeslHumans: Male(xy), Female(xx)lBirds: Male(xx), Female(xy)DNA St

6、randslChromosomes are same in every cell of organismlSupercoiled DNA (Deoxyribonucleic acid)lTake a human, take one celllDetermine the structure of all chromosonal DNAlYouve just read the human genome (for 1 person)lHuman genome projectl13 years, 3.2 billion chemicals (bases) in human genomelOther g

7、enomes being/been decoded:lPufferfish, fruit fly, mouse, chicken, yeast, bacteriaDNA StructurelDouble Helix (Crick & Watson)l2 coiled matching strandslBackbone of sugar phosphate pairslNitrogenous Base Pairs lRoughly 20 atoms in a baselAdenine Thymine A,TlCytosine Guanine C,GlWeak bonds (can be brok

8、en)lForm long chains called polymerslRead the sequence on 1 strandlGATTCATCATGGATCATACTAACDifferences in DNA2%tinyRoughly 4%Share MateriallDNA differentiates:lSpecies/race/genderlIndividualslWe share DNA withlPrimates,mammalslFish, plants, bacterialGenotypelDNA of an individual lGenetic constitution

9、lPhenotypelCharacteristics of the resulting organismlNature and nurtureGeneslChunks of DNA sequencelBetween 600 and 1200 bases longl32,000 human genes, 100,000 genes in tulipslLarge percentage of human genome lIs “junk”: does not code for proteinsl“Simpler” organisms such as bacterialAre much more e

10、volved (have hardly any junk)lViruses have overlapping genes (zipped/compressed)lOften the active part of a gene is split into exonslSeperated by intronsThe Synthesis of ProteinslInstructions for generating Amino Acid sequenceslDNA double helix is unzippedlOne strand is transcribed to messenger RNA

11、lRNA acts as a templatelRibosome translate the RNA into the sequence of amino acidslAmino acid sequences fold into a 3d moleculelGene expressionlEvery cell has every gene in it (has all chromosomes)lWhich ones produce proteins (are expressed) & when?TranscriptionlTake one strand of DNAlWrite out the

12、 counterparts to each baselG becomes C (and vice versa)lA becomes T (and vice versa)lChange Thymine T to Uracil UlYou have transcribed DNA into messenger RNAlExample:Start: GGATGCCAATGIntermediate: CCTACGGTTACTranscribed: CCUACGGUUACGenetic CodelHow the translation occurslThink of this as a function

13、:lInput: triples of three base letters (Codons)lOutput: amino acidlExample: ACC becomes Threonine (T)lGene sequences end with: lTAA, TAG or TGAGenetic CodeA=Ala=AlanineC=Cys=CysteineD=Asp=Aspartic acidE=Glu=Glutamic acidF=Phe=PhenylalanineG=Gly=Glycine H=His=HistidineI=Ile=IsoleucineK=Lys=LysineL=Le

14、u=LeucineM=Met=MethionineN=Asn=AsparagineP=Pro=ProlineQ=Gln=GlutamineR=Arg=ArginineS=Ser=SerineT=Thr=ThreonineV=Val=ValineW=Trp=TryptophanY=Tyr=TyrosineExample SynthesislTCGGTGAATCTGTTTGAT Transcribed to:lAGCCACUUAGACAAACUATranslated to:lSHLDKLProteinslDNA codes for lstrings of amino acidslAmino aci

15、ds stringslFold up into complex 3d molecule l3d structures:conformationslBetween 200 & 400 “residues”lFolds are proteinslResidue sequenceslAlways fold to same conformationlProteins play a partlIn almost every biological processEvolution of Genes: InheritancelEvolution of specieslCaused by reproducti

16、on and survival of the fittestlBut actually, it is the genotype which evolveslOrganism has to live with it (or die before reproduction)lThree mechanisms: inheritance, mutation and crossoverlInheritance: properties from parentslEmbryo has cells with 23 pairs of chromosomeslEach pair: 1 chromosome fro

17、m father, 1 from motherlMost important factor in offsprings genetic makeupEvolution of Genes: MutationlGenes alter (slightly) during reproductionlCaused by errors, from radiation, from toxicityl3 possibilities: deletion, insertion, alterationlDeletion: ACGTTGACTC ACGTGACTClInsertion: ACGTTGACTC AGCG

18、TTGACTClSubstitution: ACGTTGACTC ACGATGACTTlMutations are almost always deleteriouslA single change has a massive effect on translationlCauses a different protein conformationEvolution of Genes: Crossover (Recombination)lDNA sections are swapped lFrom male and female genetic input to offspring DNAPh

19、ylogenetic trees lUnderstand our evolutionlGenes are homologouslIf they share a common ancestorlBy looking at DNA seqslFor particular geneslSee who evolved from wholExample:lMammoth most related tolAfrican or Indian Elephants?lLUCA:lLast Universal Common AncestorlRoughly 4 billion years agoGenetic D

20、isorderslDisorders have fuelled much genetics researchlRemember that genes have evolved to functionlNot to malfunctionlDifferent types of genetic problemslDowns syndrome: three chromosome 21slCystic fibrosis:lSingle base-pair mutation disables a proteinlRestricts the flow of ions into certain lung c

21、ellslLung is less able to expel fluidsPredicting Protein StructurelProteins fold to set up an active sitelSmall, but highly effective (sub)structurelActive site(s) determine the activity of the proteinlRemember that translation is a functionlAlways same structure given same set of codonslIs there a

22、set of rules governing how proteins fold?lNo one has found one yetl“Holy Grail” of bioinformaticsProtein Structure KnowledgelBoth protein sequence and structurelAre being determined at an exponential ratel1.3+ Million protein sequences knownlFound with projects like Human Genome Projectl20,000+ prot

23、ein structures knownlFound using techniques like X-ray crystallographylTakes between 1 month and 3 yearslTo determine the structure of a proteinlProcess is getting quickerSequence versus Structure009590850100000200000300000400000500000YearNumberProtein sequenceProtein structureDatabase ApproacheslSlow(er) rate of finding protein structurelStill a good idea to pursue the Holy GraillStructure is much more conservative than sequencel1.3m genes, but only 2,000 10,000 different conformationslFirst approach to sequence prediction:lStore sequence,structure pairs in a databaselFind ways to s