How can computers help cure cancer? (computational biology and bioinforamtics)Molecular biology 101 or “why bother?”Cells are fundamental working units of all organismsEvolution is key!Yeast are unicellular organismsBiological macromoleculesLipidsDNAProteinsHow does a cell function? The “Central Dogma” of biologyHow does a cell function?So what con computer science do to help study biology?How is the genome sequenced?We have a sequence – now what?P53 how would you find this?Where is this gene in the genome?Need large databases for all the information!So what con computer science do to help study biology?Remember – evolution can help!Human hereditary colon cancer gene was found by looking for a gene similar to MSH2 gene in yeast (these genes are 65% similar)So what’s next? Genomics is a collaborative discipline Now we are trying to understand how small differences in DNA lead to large differences in phenotypesThe answer is probably in regulation “Gene Regulatory Circuits”Regulatory NetworksAny questions?What is genomics all about?The “omes”Beyond the “omes” – systems biologySystems-level challengesFunction Biological networksGene expression microarrays – one type of high-throughput functional dataWhy microarray analysis: the questionsWhy study gene expressionComputational biology/bioinformaticsComputational Molecular BiologyWhat are functions of genes?What are the functions of genes?Biology and Medicine are fundamentally information sciences. http://www.ncbi.nlm.nih.gov/Genbank/genbankstats.htmlComplete Genomes Known (900 currently available publically)Computer Science & GenomicsComputational Molecular Biology (bioinformatics)Sequence analysisStructure analysisFunction analysisMicroarray analysisBiological networksCOS116Instructor: Olga TroyanskayaHow can computers help cure cancer?(computational biology and bioinforamtics)Molecular biology 101 or “why bother?”Cells are fundamental working units of all organismsCommon descent of organisms implies that they will share many “basic technologies.”Development of new adaptations in response to environmental pressure can lead to “specialized technologies.”More recent divergence implies more shared technologies between species.All of biology is about two things: understanding shared or unshared features.Evolution is key!Yeast are unicellular organismsHumans are multi-cellular organismsUnderstanding how a cell works is critical to understanding how the organism functionsBecause of evolutionary similarities – we can use yeast and other small organisms to study human biology and disease!Biological macromoleculesWhat are the main players in molecular biology?What is DNA, RNA, protein, lipid?Lipids• Each lipid consists of a hydrophilic (water loving) and hydrophobic fragment• Spontaneously form lipid bilayers => membranesDNA• Uses alphabet of 4 letters {ATCG}, called bases• Encodes genetic information in triplet code• Structure: a double helixProteins• A sequence of amino acids (alphabet of 20)• Each amino acid encoded by 3 DNA bases• Perform most of the actual work in the cell• Fold into complex 3D structureCourtesy of the Zhou Laboratory, The State University of New York at BuffaloHow does a cell function?The “Central Dogma” of biologyHow are proteins made?What are translation & transcription?How does a cell function?Courtesy U.S. Department of Energy Genomes to Life program DNA is a sequence of bases {A, T, C, G}TAT-CGT-AGTProteins consist of amino acids, whose sequence is encoded in DNATyr-Arg-SerEach 3 bases of DNA encode 1 amino acidSo what con computer science do to help study biology?Case study 1: sequencing the human genomeHow is the genome sequenced?We have a sequence – now what?Where are the genes?*start with “atg”*go in triplets*end with “act”So how do we find them?P53how would you find this?Where is this gene in the genome?• Human genome is 3 billion bases long• TP53 is on:– Chromosone 17– Small arm– Position 17.3– Around base 9.5 mil in chromosome 17 (Human chromosomes range in length from 51 million to 245 million base pairs )• Could you find this by hand?Need large databases for all the information!So what con computer science do to help study biology?Case study 2: so what do these genes do?Common descent of organisms implies that they will share many “basic technologies.”Thus, can use yeast to understand what proteins do in humans!Remember – evolution can help!Human hereditary colon cancer similar to MSH2 gene in yeasgene was found by looking for a gene t (these genes are 65% similar)!So what’s next? Genomics is a collaborative discipline • To study WHAT proteins DO, HOW they INTERACT, and HOW they are REGULATED, need data beyond genomic sequence• Genomics/Bioinformatics is fundamentally a COLLABORATIVE and MULTIDISCIPLINARY effortCar partsAutomobilesBlueprints of automobile partsDNAPeopleGene ExpressionNow we are trying to understand how small differences in DNA lead to large differences in phenotypesProteinsProteinsThe answer is probably in regulation“Gene Regulatory Circuits”• Genes =? wires• Motifs =? gatesA B Make DCIf C then DIf B then NOT DIf A and B then DDMake BDIf D then BCgene Bgene DRegulatory NetworksAny questions?What is genomics all about?The “omes” in biology.Why bioinformatics?What is “systems biology”?The “omes”• Genome – organism’s complete set of DNA– Relatively stable through an organism’s lifetime– Size: from 600,000 to several billion bases– Gene is a basic unit of heredity (only 2% of the human genome)• Proteome – organism’s complete set of proteins– Dynamic – changes minute to minute– Proteins actually perform most cellular functions, they are encoded by genes (not a 1-to-1 relationship)– Protein function and structure form molecular basis for diseaseBeyond the “omes” – systems biology• Understanding the function and regulation of cellular machinery, as well as cell-to-cell communication on the molecular level• Why? Because most important biological problems are fundamentally systems-level problems– Systems-level understanding of disease (e.g. cancer)– Molecular medicine– Gene therapySystems-level challenges• Gene function annotation – what does a gene do– ~30,000 genes in the human genome => systems-level approaches necessary– A modern human microarray experiment produces ~500,000 data points => computational analysis &
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