1Computational Genomics and Molecular BiologyDannie DurandFall 2006Lecture 1Course overviewCourse web page:http://www.cs.cmu.edu/~durand/03-711Reading:http://www.cs.cmu.edu/~durand/03-711/reading.htmlElectronic reserves:http://www.library.cmu.edu/Recommended text books(No required textbook)Course overview cont’dSyllabus:http://www.cs.cmu.edu/~durand/03-711/2006/Coursework and policies:http://www.cs.cmu.edu/~durand/03-711/policies.htmlResourceshttp://www.cs.cmu.edu/~durand/03-711/resources.html2How to do well in this course• Come to class• Take notes• Come to office hours• Preparing for exams– Homework is more focused on working problems– Exams are more focused on concepts– Study from your notes as well as your homeworkOutlineA whirlwind review of molecular biologyAn overview of computational molecular biologyNew problems in genomics (next week)Genes Encode ProteinsGTGCACCTGACTCCTGAG...V H L T P E...A gene is a DNA sequenceA protein is an amino acid sequenceA protein folds into a 3D structureDNA forms a double stranded helixATGC3DNA replication…aggaggcctcgcctctcccagcatgggctggggctcctgtcccccactgtgtgtgcctggggcctggccaggactcccagtga…chromosomeDNAcellProtein SynthesisDNAProtein Synthesis: TranscriptionRNADNA4RNA transcriptiondouble-stranded DNA sequence...GTGTCGCTGACTCCTTGGCTACCCGAG......CACAGCGACTGAGGAACCGATGGGCTC...GTGCACRNA transcriptionopen DNA helixGTGCAC aCTGACTCCTTGGCTACCCGAG...GaTGTCGGTGCACCTGACTCCTGAGGTGCACCTGACTCCTGAGCACGTGGACTGAGGACTC...CACaAGCa..CACGTG aGACTGAGGAACCGATGGGCTC...GTGCAC aCTGACTCCTTGGCTACCCGAG...GaTGTCGGTGCACCTGACTCCTGAGGTGCACCTGACTCCTGAGCACGTGGACTGAGGACTC...CACaAGCaCACGTG aGACTGAGGAACCGATGGGCTC...RNA transcriptionRNA transcriptCUGACUCCUUGGCUACCCGAG...RNA• Adenine, Guanine, Cytosine, Uracil (AGCU)• Single stranded• Secondary structure...CUGACUCCUUGGCUACCCGAG......GACTGAGGAACCGATGGGCTC...5RNA Secondary StructureCCGUGAACGUGUACCGGAUUUUUAUUCCC...Protein Synthesis: TranslationtranslationRNAProtein Translation...GUGCACCUGACUCCUGAG...UGAGGATVLHP....messenger RNAamino acid sequencetransfer RNAribosometransfer RNAsecondary structure tertiary structureECUC6Protein Translation...GUGCACCUGACUCCUGAG...UGATVLHGGAP....messenger RNAamino acid sequencetransfer RNAribosomeCUCEProtein Translation...GUGCACCUGGUGCACCUGACUCCUGAGGUGCACCUGACUCCUGAGCUCCUGAG...messenger RNAamino acid sequencetransfer RNAribosome....tertiary protein structrureGene RegulationIf I have the same set of genes in every cell, how come my liver cells look so different from my skin cells?Only a small number of genes are being translated into protein at any one time…aggaggcctcgcctctcccagcatgggctggggctcctgtcccccactgtgtgtgcctggggcctggccaggactcccagtga…protein coding sequenceA gene is a location on a chromosome that encodes a protein7Translating Genes into ProteinsBacteriamessenger RNA:amino acid sequence:transcriptiontranslationRNA polymeraseDNA:promoter geneGene Regulation Controls When a Gene Is TranscribedRNA polymeraseDNA:promoter genetryptophanRNA polymeraseDNA:promoter generepressortryptophanGene Regulation Controls When a Gene Is TranscribedDNA:promoter generepressortryptophanGene Regulation Controls When a Gene Is Transcribed8Gene Regulation Controls When a Gene Is TranscribedDNA:promoter generepressortryptophanRNA polymeraseTranslating Genes into Proteins:Multicellular organismsmRNA:RNA splicingDNA:intronsexon1 exon2 exon3 exon4amino acid sequencetranslationtranscriptionRNA transcript:Alternative splicingAlternate splice forms:exon6exon1 exon2 exon3 exon5exon1 exon2 exon3 exon4DNA:mRNA:exon1 exon2 exon3 exon4exon6exon5exon1 exon2 exon3 exon4exon6exon5femalemaleGene RegulationIn single cell organisms, gene regulation orchestrates– Responses to changing environment– Cell cycleIn multicellular organisms, gene regulation orchestrates– Tissue type differentiation– Development from embryo to adulthood9A whirlwind review of molecular biologyAn overview of computational molecular biology– Sequence comparison– Reconstruct evolutionary history – Gene prediction – Predict structure from sequence• RNA •ProteinsNew problems in genomicsOutlineThis courseComputational Structural Biology 15-879The Origins of Computational BiologySanger-Coulson sequencingMaxam-Gilbert sequencingGilbert, Sanger winNobel PrizeCongress establishes GenbankHuman Genome Project beginsGenBank goes online.197019801990ARPANETFirst royal emailUSENET newgroupsTCP/IPInternetWorld Wide Web, GopherNCSA MosaicPizza Hut goes on lineGrowth of sequence data during the ’90’sCollins et al, Science, Oct 1998National Center for Biotechnology InformationOutlineA whirlwind review of molecular biologyAn overview of computational molecular biology– Sequence comparison– Reconstruct evolutionary history – Gene prediction – Predict structure from sequence• RNA •ProteinsNew problems in genomicsThis courseComputational Structural Biology 15-87910Sequence Comparisonvtfisll v..frrda.h ksevahrfkd lgeenfkalv…vtfisll v..frrea.h kseiahrfnd vgeehfiglv…vtfisll v..frrdt.y kseiahrfkd lgeqyfkglv…vtlisfi lqrfardaeh kseiahrynd lkeetfkava……mkwvtfisll flfssaysrg v..frrda.hkseva…mkwvtfisll flfssaysrg v..frrea.hkseia…~~wvtfisll flfssaysrg v..frrdt.y kseia…mkwvtlisfi flfssatsrn lqrfardaehkseialocal multiple alignmentglobal multiple alignment…atgcaaggagtcccagagcctgagctgactacgt……atgcgaggtctcccagtgtctgaactgactaagt……atgcaagtcgtcccagtgccagaactccctacgt……accagtggtctccgagtggctgaactgactaaca…global pairwise alignment local pairwise alignmentApplications• Database searching• RNA structure prediction• Evolutionary tree reconstruction• Gene finding• Sequence assembly….…atgccaggtcccagtga…early mammal…atgcaaggagtccgagc… …atgcgaggtccagtagt……atgggaggtccagtagt……atgcgaggtccaacagt……atgcaaggagtcggagc…mousehuman ratWhy sequence data is so powerful: Sequences are related!…atgcaaggagtcgcagagc……atgcgaggtctcacagtgt……atgggaggtctcccagtgt……atgcaaggagtccgagc……atgcgaggtccagtagt…Sequence similarity => functional similarity…LWDEFNQLGTEMIVTKAGRRMFPTFQVKLFGMDPMADYMLLMDFVPVDDKRYRYAFHS…O…LWDPTFQVEFNQLG……TMFPTFEMIVTKAG……RRMFPTFQVPTFQV……KLFMFPTFGEMDPM……ADYMMCFPTFLLMD……FVPVDDKPTSFQVR…...BLASTOutlineA whirlwind review of molecular biologyAn overview of computational molecular biology– Sequence comparison– Reconstruct evolutionary history – Gene prediction – Predict structure from sequence• RNA •ProteinsNew problems in
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