Introduction to Bioinformatics [SeMotiva' “Biology easily has 500 years of exciting problems to work on.” Donald Knuth (Stanford Professor & famous computer scientist) By developing techniques for analyzing sequence data and related structures, we can attempt to understand molecular basis of life.Collaborative domains of Bioinformatics A living cell is a system where cellular components such as genome, the gene transcript, and the proteins interact with each other, and these interactions determine the fact of the cell. e.g whether a stem cell is going to become a liver cell or a cancer cell, The three collaborative domains of bioinformaties .. Genomics 2. Transcriptomies 3. PoteomicsGenomics Genomics play a signifi ant role in modern biological research in which the nucleotide sequences of all the chromosomes of an organism are mapped, locatioh of different genes and their sequence are determined This involves extensive analysis of nucleic acids through molecular biology techniques before the data are ready for processing by bioinformatics approaches, It is a science that attempts to describe a living organisms in terms of the sequence of its genome.Genomics Genomics uses the technique of molecular biology and bioinformatics to identify cellular components such as proteins, rRNA, TRAN, and analyse the sequences attributed to the structural genes regulatory sequences, and non-coding sequence. The first automatic DNA sequencer was developed in 1986 by Leroy Hood Haemophilus influenzae was the first bacterium to be sequenced in 1995.Transcriptomics Transcriptomies is the study of transcriptome, which includes the vjhole set of mRNA molecules in one or a population of biological cells. This study helps us to depict the expression level of genes, ofien using techaniques such as DNA microays, capable of sampling ten thousands of different mRNAS SUS Time This kind of new technique has helped biologist to routinely monitor the gene expression between the control cells and treatment cells.Proteomics proteins and their interactions. Proteomics involves the sequencing of amino acid in a protein determi and relating it to the function of the protein. Bioinformatics has enormous analytical and predictive potential. Metabolic proteins such as haemoglobin and insulin have been subjected to intensive proteomic investigation. Scientists feel that the bioinformatics of proteins is crucial, to understands the cellular components and the interactions completely.Genomics and Proteomics Genomics is the study of an organism's genome and the use of genes. It deals with the systematic use of genome information, associated with other data, to provide answers in biology, medicine, and industry. Proteomics is the large-scale study of proteins, particularly their structures and functions Proteomics is much more complicated than genomics. Most importantly, while the genome is a rather constant entity, the proteome differs from cell to cell and is constantly changing through its biochemical interactions with the genome and the environment. One organism will have radically different protein expression in different parts of its body, in different stages of its life cycle and in different environmental conditions.Development of Genomics/Proteomics Data (©) 30000 (a) 89000, 25000 2 4 $0000 2 20000 g & 9000 2 40000 £, 3 0000 z 5 § 20000) = Z 5000 ° ° j9e9 1992 1995 1998 20012004, i aa 28, bene Year 2002 2004Modern map-makers have mapped the entire human genome We know the entire 3.2 billion bps of the human genome !!! «+. but what does it mean ???Metabolic activity in genetic pathwaysHow can we measure metabolic processes and gene activity?Until recently we lacked tools to measure gene activity 1989 saw the introduction of the microarray technique by Stephen Fl But only in 1992 this technique became generally available — but stilGenomics: structure and coding D Deoxyribonucleic acid (DNA) is a nucleic acid that contains thf genetic instructions specifying the biological development of all cellular forms of life. DNA is a long polymer of nucleotides and encodes the sequence of the amino acid residues in proteins using the genetic code, a triplet code of nucleotides.50 micronsDNA under electron microscope 3D model of a section of the DNA moleculeAdenine Thymine 1 Guanine James Watson and Francis Crick GytosineSL heostctane 5-8 omnes tote wonorhosmnae (CORRECT PAIN bhe lines = hpbrogen bonsGenetic code The genetic code is a set of rules that maps DNA sequences to proteins in the living cell, and is employed in the process of protein synthesis Almost, all living things use the same genetic code, called the standard genetie code, although a few organisms use minor variations of the standard code. Ribonucleic acid U c 6 6. rn s c uv A s.Proteomics: structure and function Protein Structure: primary structure Residue i—1 Residue i Residue i+1 a } Sidechains variable N= Ca G = N Ca C+N-Ca-¢-* ; I} Il } Mainchain constant 6 0: °wee. “if EA AM dy oh are e 3Structure secondary upel Protein Structure:Protein Structure = protein function:Evolution and the origin of species a Tree of Life oon ste een ‘reer aes sine EEE tetera rtaongn angi nN famine (Martotacters tum Trermocozaus == = ie ree wee SN | mee oe Dolorenate eta nas cans sq) Spun parsons) ‘ratosensica estas Naas fousnor) Prapaca orcs Ontmproa evel noms) Taga nerd) Artcpo sacs cats) arptna coro es) Cecio sears p98) Fung yes, natoons) Pers cooDefinition of Bioinformatics General Definition: A computational approach solves the biological prdplem. Bioinformatics is emerging and advance branch of biological scienge, contain Biology mathematics and Computer Science. Bioinformatics developed a new thought, to maintain the concepts and"store huge amount o| Biological data. Bioinformatics, A logical and technical means by which not only solve the Biological problems but also can predicts the new aspects.Introduction to Bioinformatics The first look at a genome (sequence siatistics) A mathematical model should be as simple as possible, but not too simple! (A. Einstein) “All models are wrong, but some are usefil. (G. Box)Definition Bioinformatics is the science concemed with the development and application of computer hardware and software to the acquisition, storge.analysis, and visuslization of biological information Ithas the following three component. The development of new algorithms and statistics for assessing the relationship among large sets of biological data. e.g DNA Sequence data. Application of these tools for the analysis and interpretation of various biological data. e.g nucleotide sequences, amino acid. sequences. The development of database for an efficient storage, access and management of various biological information. The ‘bioinformatics’ is a combination of ‘biology’ and informatics. @Introduction Bioinformatics derives knowledge from computer analysis of biological data. These databases consist of information stored in genetic code, experimental results from various sources, patient statistics, and scientific literature. Research in bioinformatics includes method development for storage, retrieval, and analysis of the data Bioinformatics is a rapidly developing branch of biology and is highly interdisciplinary, using techniques and concepts from informatics, statistics, mathematics, chemistry, biochemistry, and physics. Ithas many practical applications in different areas of biology and medicine. €Bioinformatics * Bioinformatics is the application of Information technology to store, organize and analyze the vast amount of biological data. « The stored data is available in the form of sequences and structures of proteins and nucleic acids. = The biological information of nucleic acids is available as sequences while the data of proteins is available as sequences and structures = Sequences are represented in single dimension where as the structure contains the three dimensional data of sequences.BIOINFORMATICSInsilico Aveas of BioinformaticsHistory The collection of amino acids sequences was complied in the “Aths of protein sequence and structure’ by the National Biomedical Foundation. This collection was edited by Margaret 0. Dayhoff from 1965 to 1978 Dayhoff and coworkers contribute to the comparison of amino acid sequences by developing computer software for detecting distantly related sequences. The EMBL established their data library in 1980 to collect, organize and distribute nucleotide sequence data and related information. * NCBI was established in U.S.A, NCBI serves as primary information databank and provider of information. - The National Biomedical Rescarch Foundation establishedt PIR in 1984. @History and scope of bioinformatics 1859 — The “On the Origin of Species”, published by Charles theory of genetic evolution — allows adaptation over time to produce to the environment. 1951 — Linus Pauling and Corey propose the structure for the alpha- 1953 - Watson and Crick propose the double helix model for DNA based on x-ray data obtained by Franklin and Wilkins. 1955 - The sequence of the first protein to be analyzed, bovine insulin, is announced by F. Sanger. 1958 - The Advanced Research Projects Agency (ARPA) is formed in the US.History and scope of bioinformatics 1973 - The Brookhaven Protein Data Bank (PDB) is announced 1987 - Perl (Practical Extraction Report Language) is released by Larry Wall. 1988 - National Centre for Biotechnology Information (NCBI) founded at NIH/NLM. 1990 - Human Genome Project launched, BLAST program introduced by S. Karlin and SF. Altshul. Tim Bemers-Lee, a British scientist invented the World Wide Web in 1990. 1992 - The Institute for Genome Research (LIGR), associated with plans to exploit sequencing commercially through gene identification and drug discovery, was formed. 2001 - The human genome (3,200 Mbp) is published.Genomic era, year zero 1958: Fred Sanger (Cambridge, UK): Nobel prize for developing) protein sequencing techniques 1978: Fred Sanger: 1980: Fred Sanger: First mitochrondrial genome irst complete viral genome 1980: Fred Sanger: Nobel prize for developing DNA sequencing techniques 1995: Craig Venter (TIGR): complete genome of Haemophilus influenza 2001; entire genome of Homo sapiensGenomic era, year zero Organism Phage phiX 74 Human mtDNA HIV H. influenza IL. sapiens Date 1978 1980 1985 1995 2001 Size 5,368 bp 16,571 bp 9,193 bp 1,830 Kb 3,200 Mb Description Ist viral genome Ist organelle genome AIDS retrovirus Ist bacterial genome complete human genomeFuture Goals Of Molecular Biology and Bioinformatics Research 2050: To complete the first computational model of a complete cell, or maybe even already of a complete organismHuman Genome Project U.S. govt. project coordinated by the Department of Energy and the National Institutes of Health, launched in 1986 by Charles DeLisi Definition: GENOME ~ the whole hereditary information of an organism that is encoded in the DNA. Aims of the project: To identify the approximate 100,000 genes in the human DNA Determine the sequences of the 3 billion bases that make up human DNA. Store this information in databases. Develop tools for data analysis. Address the ethical, legal, and social issues that arise from genome research.Benefits of Human Genome Project research Improvements in medicine and [Drugs used in genetic or metabolic disorder. Microbial genome research for Bio-fuel and environmental cleanup. DNA finger printing & forensics. Improved agriculture by improving the wild gene of high yielding variety of grain and livestock, Better understanding of species evolution and Human genome. More accurate risk assessment by gene mapping.Internet and Bioinformatics Intemet plays an important role to retrieve the biological information. ‘The Computational part of bioinformatics use to optimize the biological problems like (metabolic disorder, genetic disorders). Computational part contains: Database Development. eInternet and Bioinformatics ‘The Mathematical portion helps to understand the algorithms used in B}oinformatics software and tools. The mathematical portion which, used in Bioinformatics are:Internet and Bioinformatics The Internet is a global data communications system. It is a infrastructure that provides connectivity between computers. The Web is one of the services communicated via the Internet. It }s a collection of interconnected documents and other resources, linked by hyperlink ang URLs. fn ipeeee Web Service [ear Web Browser vomtl intrtace [sev] [i] sone ed Senco [ian] Inventory | Web Service Ex rcen screen Product Data Windows Client/Server eInternet Resources for Bioinformatics Online Data KEGG) ModBase\P DB \Zine Database\Mol| oft Relational Database ‘Management SystemBiological Databases ‘Type of databases Bibliographic databases Taxonomic databases ‘Nucleic acid databases Genomic databases Protein databases Protein families, domains and functional sites Enzymes/metabolic pathways Information Contain Literature Classification DNA information Gene level information Protein information Classification of proteins and identifying domains Metabolic pathwaysFinding data: GenBank, EMBL, and DDB. Online databases FASTA: a standard data formatDatabases Generalized (DNA, proteins and carbohydrates, 3D-structures) Specialized (FST, STS, SNP, RNA, genomes, protein families, pathways, microarray data...)1. Database indexing and specification of search terms (retrieval, follow-up, analysis) 2. Archives (databases on: nucleic acid sequences, genome, protein Sequences, structures, proteomics, expression, pathways) 3. Gateways to Archives (NCBI, Entrez, PubMed, ExPasy, Swiss-Prot, SRS, PIR,Generalized DNA, protein and carbohydratedatabases Primary sequence databases EMBL (European Molecular Biology Laboratory nucleotide sequence database at EBI, Hinxton, UK) GenBank (at National Center for Biotechnology information, NCBI, Bethesda, MD, USA) DDBJ (DNA Data Bank Japan at CIB , Mishima, Japan)Types Of Biological Databases Accessible There are many different types of database but for routine sequence arplysis, following are initially the most important. Primary databases Secondary databases Composite databases a ee a Primary Database Gerba > (Nucleic Acid Protein)Secondary DatabasesComposite Databases Combine different sources of primary databases iThe International Sequence Database Collaboration DDBJ EMBLGenBank GenBank® is the NIH genetic sequence database, an annotated collection of all publicly available DNA sequences DDBJ DDBJ (DNA Data Bank of Japan) began DNA data bank activities in earnest in 1986 at the National Institute of Genetics (NIG) with the endorsement of the Ministry of Education, Science, Sport and Culture. The Center for Information Biology at NIG was reorganized as the Center for Information Biology and DNA Data Bank of Japan (CIB-DDBJ) in 2001. The new center is to play a major role in carrying out research in information biology and to run DDBJ operation in the world.leotide Sequence Database The EMBL Nucleotide Sequence Database (also known as EMBL-Bank) constitutes Europe's primary nucleotide sequence resource. Main sources for DNA and RNA sequences are direct submissions from individual researchers, genome sequencing projects and patent applications. The database is produced in an international collaboration with GenBank (USA) and the DNA Database of Japan (DDBJ).NCBI: National'Center for < a>) WI e B | Biotechnology information Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops sofwware~ tools for analyzing genome data, and disseminates biomedical information - all for the better understanding of molecular processes affecting human health and disease. The EMBL Nucleotide Sequence Database (also known as EMBL-Bank) constitutes Europe's primary nucleotide sequence resource. Main sources for DNA and RNA sequences are direct submissions from individual researchers, genome sequencing projects and patent applications. 4EBI: European Bioinformatics Institute ‘The European Bioinformatics Institute (EBD) is a non-profit academic organisation that forms part of the European Molecular Biology Laboratory (EMBL). The EBI is a centre for research and services in bioinformatics. The Institute manages databases of biological data including nucleic acid, protein sequences and macromolecular structures.DDBJ DDBJ (DNA Data Bank of Japan) began DNA data bank activities the National Institute of Genetics (NIG). DDBJ has been functioning as the international nucleotide sequence database in collaboration with EBI/EMBL and NCBI/GenBank.\ DNA sequence records the organismic evolution more directly than other biological materials and thus, is invaluable not only for research in life sciences, but also human welfare in general. The databases are, so to speak, a common treasure of human beings. eExPASy Proteomics Server (SWISS-PROT) The ExPASy (Expert Protein Analysis System) proteomics server of He SWE Bioinformatics (SIB) is dedicated to the analysis of protein sequences and structures as well as 2-D PAGEGeneralized DNA, protein and carbohydra' Protein sequence databases SWISS-PROT (Swiss Institute of Bioinformatics, SIB, Geneva, G TrEMBL (Translated EMBL: computer annotated protein seqet EBI, UK) PIR-PSD (PIR-International Protein Sequence Database, annotated protein database by PIR, MIPS and JIPID at NBRF, Georgetown University, USA) UniProt (Joined data from Swiss-Prot, TTEMBL and PIR) UniRef (UniProt NREF (Non-redundant REFerence) database at EBL, UK) IPI (International Protein Index; human, rat and mouse proteome database at EBI, UK)Generalized DNA, protein and carbohydra' Carbohydrate databases CarbBank (Former complex carbohydrate structure database, CCSD) 3D structure databases PDB (Protein Data Bank cured by RCSB, USA) EBI-MSD (Macromolecular Structure Database at EBI, UK) NDB (Nucleic Acid structure Datatabase at Rutgers State University of New Jersey , USA)Database search Text-based (SRS, Entrez ...) Sequence-based (sequence similarity search) (BLAST, FASTA...) Motif-based (ScanProsite, eMOTIF) Structure-based (structure similarity search) (VAST, DALL..) Mass-based protein search (ProteinProspector, Peptident, Prowl ...)Goals Bioinformatics is fourfold and includes data acquisition, tool and database development, data analysis, and data integration. Data Acquisition is primarily concerned with accessing and storing data generated directly from the biological experiments. -The data generated by various sequencing projects have to be retrieved in the appropriate format, and capable of being linked to all the information related to the DNA samples, * The data are organized in different databases so that the researchers can access existing information.Goals * To uncover the wealth of Biological information hidden in the njass of sequence, structure, literature and biological data. = Itis being used now and in the foreseeable future in the areas of mol + [thas environmental benefits in identifying waste and clean up bacteria. + In agriculture, it can be used to produce high yield, low maintenance crops.Tools and Database Development Many laboratories generate large volumes of data such as DNA. sequences, gene expression information, 3D molecular structure, and high-throughput screening Effective databases for storing and quickly accessing data must generated and to develop tools and resources that aid in the analysis of data. Data Analysis To use these tool to analyse the data and interpret the results in a biologically meaningful manner. Efficient analysis require an efficiently deigned database. Data Integration Once information has been analyzed, a researcher must often associate or integrate it with e related data from the other databases.Molecular medicine The human genome have profound effects on the fields of biomedipal research and clinical medicine. Every disease has a genetic component. This may be inherited or a result of the body's response to an envirpnmental stress which causes alterations in the genome (eg. cancers, heart disease, dial ‘The completion of the human genome means that we can search for the genes directly associated with different diseases and begin to understand the molecular basis of these diseases more clearly. This new knowledge of the molecular mechanisms of disease will enable better treatments, cures and even preventative test to be developed.Personalized medicine Clinical medicine will become more personalised with development pharmacogenomics. ‘This is the study of how an individual's genetic ineritance affects the body's response to drugs At present, some drugs fail to make it to the market because a small perce: patient population show adverse affects to a drug due to sequence variants in their DNA. As a result, potentially life saving drugs never make it to the marketplace. Today, doctors have to use trial and error to find the best drug to treat a particular patient as those with the same clinical symptoms can show a wide range of responses to the same treatment.Drug development At present all drugs on the market target only about 500 proteins. With an improved understanding of disease mechanisms and using computational tools to identify and validate new drug targets, more specific medicines that act on the cause, not merely the symptoms, of the disease can be developed. These highly specific drugs promise to have fewer side effects than many of today's medicines.Gene therapy Gene therapy is the approach used to treat, cure or even prevent disease by changing the expression of a persons genes. Currently, this field is in its infantile stage with clinical trials for cancer and other diseases ongoingNeed of Bioinformatics * The need for bioinformatics has arisen from the recent explosidn of publicly available genomic information, including Human Genome Project * Gain a better understanding of gene analysis, taxonomy & evolutioh. * To work efficiently on the rational drug designs and reduce the time taken for the development of drug manually.Domains/Fields = Molecular Medicine = Gene Therapy « Drug Development * Microbial genome applications = Crop Improvement + Forensic Analysis of Microbes « Biotechnology * Evolutionary Studies = Bio-Weapon CreationParticipation of Bioinformatics + In Experimental Molecular Biology + In Genetics and Genomics + In generating Biological Data + Analysis of gene and protein expression * Comparison of genomic data + In Simulation & ModelingApplications Protein Structure prediction It is easy to determine the primary structure of proteins in the fe however difficult to determine the secondary, tertiary or quaternary structures of proteins. Tools of bioinformatics can be used to determine the complex protein structures.Applications Genome Annotation In genome annotation, genomes are marked to know the regulatory sequences and protein coding. It is a very important part of the human genome project as it determines the regulatory sequences.Applications ‘Comparative Genomics Comparative genomics determines the genomic structural and functipnal relation between different biological species, For this purpose, intergenomic maps at@-CORS ii enable the scientists to trace the processes of evolution occur in genomes of different species.Applications Health and Drug discovery Bioinformatics approaches are helpful in drug discovery, dizgnosis and disease management.Applications * Waste cleanup * Microbial genome applications « Antibiotic resistance + Alternative energy sources « Crop improvement and development of resistant varieties « Forensic analysis = Bio-weapon creation + Insect resistance # Sequence anal