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Instructor • • • • Prof. Chandrama P. Upadhyaya 220, Life Sciences Building 100-3470-8050, 02-450-3739 [email protected] Teaching Assistant • • • • Mr. Eom Hee-Seok 209 Life Sciences Building 02-450-3739, 02-3436-5439 [email protected] Molecular Biology Fourth Edition Robert F. Weaver Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Evaluation • Three examinations counting 35% each. • - Mid term Exam (date to be announce) • - Final Exam (date to be announce) • Attendance 20% • Home work 10% A: RNA & Transcription: DETAILS 2 Chapter 1: Basic mechanism of Transcription Chapter 2 : Post Transcriptional event: Messenger RNA processing I_Splicing Chapter 3: Messenger RNA processing II _ Capping and Polyadenylation Chapter 4: Other RNA Processing Events B: Protein Synthesis or Translation: Details 3 Chapter 5: Mechanism of Translation I_ Initiation Chapter 6: Mechanism of Translation II_ Elongation and Termination Chapter 7: Ribosomal and Transfer RNA C: DNA and Replication mechanism 1 Chapter 8: DNA Replication I: Basic Mechanism and Enzymology Chapter 9: DNA Replication II: Detailed Mechanism Chapter 10: Homologous Recombination DNA Chapter 11: Genomics. Proteomics and Bioinformatics RNA Protein Chapter 1 INTRODUCTION TO GENOMICS, BIOINFORMATICS & PROTEOMICS • We are in the midst of a "Golden Era" of biology. • The revolution is mostly about treating biology as an information science, not only specific biochemical technologies. GENOMICS Study of sequences, gene organization & mutations at the DNA level This also deals with the study of information flow within a cell Central Dogma DNA Genotype RNA function & structure Protein sequence RNA Protein structure Protein Protein Function Phenotype THE HUMAN GENOME PROJECT 3 billion bases 30,000 genes http://www.genome.gov/ • Would it be important to know your personal DNA sequence? • Would you want to know if you were susceptible to a disease? Why or why not? IMPACT OF GENOMICS ON MEDICINE • • • How to characterize new diseases? What new treatments can be discovered? How do we treat individual patients? Tailoring treatments? IMPLICATIONS FOR BIOMEDICINE • Physicians will use genetic information to diagnose and treat disease. • Virtually all medical conditions have a genetic component • Faster drug development research: (pharmacogenomics) • Individualized drugs • All Biologists/Doctors will use gene sequence information in their daily work normal BIOMARKERS AND GENE EXPRESSION malignant WHAT IS BIOINFORMATICS? What is bioinformatics? • Interface of biology and computers • Conceptualizing biology in terms of molecules and then applying “informatics” techniques from math, computer science, and statistics to understand and organize the information associated with these molecules on a large scale HOW DO WE USE BIOINFORMATICS? • Store/retrieve biological information (databases) • Retrieve/compare gene sequences • Predict function of unknown genes/proteins • Search for previously known functions of a gene • Compare data with other researchers • Compile/distribute data for other researchers There are three major public DNA databases EMBL GenBank Housed Housed at EBI at NCBI European National Bioinformatics Center for Institute Biotechnology Information Go to NCBI website http://www.ncbi.nlm.nih.gov/ DDBJ Housed in Japan SIMILARITY SEARCH: BLAST A tool for searching gene or protein sequence databases for related genes of interest Alignments between the query sequence and any given database sequence, allowing for mismatches and gaps, indicate their degree of similarity The structure, function, and evolution of a gene may be determined by such comparisons http://www.ncbi.nlm.nih.gov/BLAST/ PubMed is… • National Library of Medicine's search service • 12 million citations in MEDLINE • links to participating online journals • PubMed tutorial (via “Education” on side bar) Entrez integrates… • the scientific literature; • DNA and protein sequence databases; • 3D protein structure data; • population study data sets; • assemblies of complete genomes Entrez is a search and retrieval system that integrates NCBI databases OMIM is… •Online Mendelian Inheritance in Man •catalog of human genes and genetic disorders •edited by Dr. Victor McKusick, others at JHU Books is… • searchable resource of on-line books TaxBrowser is… • browser for the major divisions of living organisms (archaea, bacteria, eukaryota, viruses) • taxonomy information such as genetic codes • molecular data on extinct organisms Structure site includes… • Molecular Modelling Database (MMDB) • biopolymer structures obtained from the Protein Data Bank (PDB) • Cn3D (a 3D-structure viewer) • vector alignment search tool (VAST) DATA MINING Handling enormous amounts of data Sort through what is important and what is not Manipulate and analyze data to find patterns and variations that correlate with biological function NEED FOR IMPROVED BIOINFORMATICS Genomics: Proteomics: Human Genome Project Gene array technology Comparative genomics Functional genomics Global view of protein function/interactions Protein motifs Structural databases Human Genome Project HUMAN GENOME PROJECT STATUS Working draft of human genome reported by 2 groups allowed estimates that genome contains fewer genes than anticipated – 25,000 to 40,000 About half the genome has derived from the action of transposons Transposons themselves have contributed dozens of genes to the genome Bacteria also have donated dozens of genes Finished draft is much more accurate than working draft, but there are still gaps Information also about gene birth and death during human evolution Applications of Genomics: Functional Genomics • Functional genomics refers to those areas that deal with the function or expression of genomes. • All transcripts an organism makes at any given time is an organism’s transcriptome. • Use of genomic information to block expression systematically is called genomic functional profiling. • Study of structures and functions of the protein products of genomes is proteomics Transcriptomics • This area is the study of all transcripts an organism makes at any given time. • Create DNA microarrays and microchips that hold 1000s of cDNAs or oligos. • Hybridize labeled RNAs from cells to these arrays or chips • Intensity of hybridization at each spot reveals the extent of expression of the corresponding gene • Microarray permits canvassing expression patterns of many genes at once. • Clustering of expression of genes in time and space suggest products of these genes collaborate in some process PROTEOMICS • Uses information determined by biochemical/crystal structure methods • Visualization of protein structure • Make protein-protein comparisons • Used to determine: conformation/folding antibody binding sites protein-protein interactions computer aided drug design PROTEIN SEPARATIONS AND ANALYSIS Current research in proteomics requires first that proteins be resolved, sometimes on a massive scale. Best tool for separation of many proteins at once is 2-D gel electrophoresis After separation, proteins must be identified Best method of identification involves digestion of proteins one by one with proteases Then identify the peptides by mass spectrometry In the future, microchips with antibodies attached may allow analysis of proteins in complex mixtures without separation MALDI-TOF MASS SPECTROMETRY Detecting Protein-Protein Interactions 24-38 Protein Interactions • Most proteins work with other proteins to perform their functions. • Several techniques are available to probe these interactions. • Yeast two-hybrid analysis has been used for some time, now other methods are available • Protein microarrays • Immunoaffinity chromatography with mass spectrometry • Other combinations DNA genomic DNA databases RNA cDNA ESTs UniGene protein protein sequence databases phenotype educators students bioinformatics researchers institutions