Welcome to CS262: Computational GenomicsGoals of this courseTopics in CS262Course responsibilitiesReading materialBirth of Molecular BiologySlide 7DNAChromosomesThe Genetic DogmaDNA to RNA to Protein to CellGene TranscriptionSlide 13Slide 14Slide 15Slide 16RNA ProcessingGene StructureHow many?ProteinsSlide 21DipeptideProtein structureTranslationThe Genetic CodeTranslation (tRNA)Slide 27Slide 28Slide 29Errors?Reading FramesSynonymous MutationMissense MutationNonsense MutationFrameshiftNoncoding RNAGenetics in the 20th Century21st CenturyComputational BiologySlide 40Some Topics in CS262 1. SequencingSlide 42Complete genomes todaySlide 44Slide 453. Molecular EvolutionEvolution at the DNA level4. Sequence Comparison Sequence conservation implies functionSequence Comparison—Alignment5. RNA Structure6. Protein networksComputer Scientists vs BiologistsComputer scientists vs BiologistsSlide 54Slide 55Slide 56Slide 57Computer Science is to Biology what Mathematics is to PhysicsWelcome to CS262: Computational GenomicsInstructor:Serafim BatzoglouTA:Eugene FratkinTuesday&Thursday 2:45-4:00Skilling AuditoriumGoals of this course•Introduction to Computational Biology & GenomicsBasic concepts and scientific questionsWhy does it matter?Basic biology for computer scientistsIn-depth coverage of algorithmic techniquesCurrent active areas of research• Useful algorithmsDynamic programmingString algorithmsHMMs and other graphical models for sequence analysisTopics in CS262Part 1: Basic AlgorithmsSequence Alignment & Dynamic ProgrammingHidden Markov models, Context Free Grammars, Conditional Random FieldsPart 2: Topics in computational genomics and areas of active researchDNA sequencingComparative genomicsGenes: finding genes, gene regulationProteins, families, and evolutionNetworks of protein interactionsCourse responsibilities•Homeworks4 challenging problem sets, 4-5 problems/pset•Due at beginning of class•Up to 3 late days (24-hr periods) for the quarterCollaboration allowed – please give credit•Teams of 2 or 3 students•Individual writeups•If individual (no team) then drop score of worst problem per problem set•(Optional) ScribingDue one week after the lecture, except special permissionScribing grade replaces 2 lowest problems from all problem sets•First-come first-serve, email staff list to sign upReading material•Books“Biological sequence analysis” by Durbin, Eddy, Krogh, Mitchison•Chapters 1-4, 6, 7-8, 9-10“Algorithms on strings, trees, and sequences” by Gusfield•Chapters 5-7, 11-12, 13, 14, 17•Papers•Lecture notesBirth of Molecular BiologyTCACTGGCGAGTCAGCDNAPhosphate GroupSugarNitrogenousBaseA, C, G, TPhysicistOrnithologistTCACTGGCGAGTCAGCGAGUCAGCDNA RNAA - TG - CT UDNA•DNA is written 5’ to 3’ by convention•AGACC = GGTCT3’5’5’3’ChromosomesH1DNAH2A, H2B, H3, H4~146bptelomerecentromerenucleosomechromatinIn humans:2x22 autosomesX, Y sex chromosomesThe Genetic Dogma3’5’5’3’TAGGATCGACTATATGGGATTACAAAGCATTTAGGGA...TCACCCTCTCTAGACTAGCATCTATATAAAACAGAAATCCTAGCTGATATACCCTAATGTTTCGTAAATCCCT...AGTGGGAGAGATCTGATCGTAGATATATTTTGTCTTAUGGGAUUACAAAGCAUUUAGGGA...UCACCCUCUCUAGACUAGCAUCUAUAUAA(transcription)(translation)Single-stranded RNAproteinDouble-stranded DNADNA to RNA to Protein to CellDNA, ~3x109 long in humansContains ~ 22,000 genesGAGUCAGCmessenger-RNAtranscription translation foldingGene Transcription3’5’5’3’G A T T A C A . . .C T A A T G T . . .Gene Transcription3’5’5’3’The promoter lies upstream of a geneTranscription factors recognize transcription factor binding sites and bind to them, forming a complexRNA polymerase binds the complexG A T T A C A . . .C T A A T G T . . .Gene Transcription3’5’5’3’The two strands are separatedG A T T A C A . . .C T A A T G T . . .Gene Transcription3’5’5’3’An RNA copy of the 5’→3’ sequence is created from the 3’→5’ templateG A T T A C A . . .C T A A T G T . . .G A U U A C AGene Transcription3’5’5’3’G A U U A C A . . . G A T T A C A . . .C T A A T G T . . .pre-mRNA 5’ 3’RNA Processing5’ cappoly(A) tailintronexonmRNA5’ UTR 3’ UTRpre-mRNAGene Structure5’ 3’promoter5’ UTRexons 3’ UTRintronscodingnon-codingHow many?•Genes:~22,000 in the human genome•Exons per gene:~ 8 on average (max: 148)•Nucleotides per exon:170 on average (max: 12k)•Nucleotides per intron:5,500 on average (max: 500k)•Nucleotides per gene:45k on average (max: 2,2M)•Composed of a chain of amino acids. R | H2N--C--COOH | HProteins20 possible groupsAlanineArginineAsparagineAspartateCysteineGlutamateGlutamineGlycineHistidineIsoleucineLeucineLysineMethioninePhenylalanineProlineSerineThreonineTryptophanTyrosineValineR R | | H2N--C--COOH H2N--C--COOH | | H H ProteinsAlanineArginineAsparagineAspartateCysteineGlutamateGlutamineGlycineHistidineIsoleucineLeucineLysineMethioninePhenylalanineProlineSerineThreonineTryptophanTyrosineValineDipeptide R O R | II | H2N--C--C--NH--C--COOH | | H H This is a peptide bondAlanineArginineAsparagineAspartateCysteineGlutamateGlutamineGlycineHistidineIsoleucineLeucineLysineMethioninePhenylalanineProlineSerineThreonineTryptophanTyrosineValineProtein structure•Linear sequence of amino acids folds to form a complex 3-D structure•The structure of a protein is intimately connected to its functionTranslationThe ribosome synthesizes a protein by reading the mRNA in triplets (codons). Each codon is translated to an amino acid. mRNAP site A siteThe Genetic CodeU C A GU UUU Phenylalanine (Phe) UCU Serine (Ser) UAU Tyrosine (Tyr) UGU Cysteine (Cys) U UUC Phe UCC Ser UAC Tyr UGC Cys C UUA Leucine (Leu) UCA Ser UAA STOP UGA STOP A UUG Leu UCG Ser UAG STOP UGG Tryptophan (Trp) GC CUU Leucine (Leu) CCU Proline (Pro) CAU Histidine (His) CGU Arginine (Arg) U CUC Leu CCC Pro CAC His CGC Arg C CUA Leu CCA Pro CAA Glutamine (Gln) CGA Arg A CUG Leu CCG Pro CAG Gln CGG Arg GA AUU Isoleucine (Ile) ACU Threonine (Thr) AAU Asparagine (Asn) AGU Serine (Ser) U AUC Ile ACC Thr AAC Asn AGC Ser C AUA Ile ACA Thr AAA Lysine (Lys) AGA Arginine (Arg) A AUG Methionine (Met) or START ACG Thr AAG Lys AGG Arg GG GUU Valine (Val) GCU Alanine (Ala) GAU Aspartic acid (Asp) GGU Glycine (Gly) U GUC Val GCC Ala GAC Asp GGC Gly C GUA Val GCA Ala GAA Glutamic
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