Introduction to Bioinformatics 236523 Lecturer: Dr. Yael Mandel-Gutfreund Teaching Assistance: Shula Shazman Sivan Bercovici Course web site : http://webcourse.cs.technion.ac.il/236523

What is Bioinformatics?

Course Objectives To introduce the bioinfomatics discipline To make the students familiar with the major biological questions which can be addressed by bioinformatics tools To introduce the major tools used for sequence and structure analysis and explain in general how they work (limitation etc..)

Course Structure and Requirements Class Structure 2 hours Lecture 1 hour tutorial 2. Home work Homework assignments will be given every second week The homework will be done in pairs. 5/5 homework assignments will be submitted 2. A final project will be conducted and submitted in pairs

Grading 20 % Homework assignments 80 % final project

Literature list Gibas, C., Jambeck, P. Developing Bioinformatics Computer Skills. O'Reilly, 2001. Lesk, A. M. Introduction to Bioinformatics. Oxford University Press, 2002. Mount, D.W. Bioinformatics: Sequence and Genome Analysis. 2nd ed.,Cold Spring Harbor Laboratory Press, 2004. Advanced Reading Jones N.C & Pevzner P.A. An introduction to Bioinformatics algorithms MIT Press, 2004

What is Bioinformatics?

What is Bioinformatics? “The field of science in which biology, computer science, and information technology merge to form a single discipline” Ultimate goal: to enable the discovery of new biological insights as well as to create a global perspective from which unifying principles in biology can be discerned.

Central Paradigm in Molecular Biology Gene (DNA) mRNA Protein 21ST centaury Genome Transcriptome Proteome

from purely lab-based science to an information science Bioinformatics Bio = Informatics

From DNA to Genome First protein sequence Watson and Crick DNA model 1955 1960 First protein structure 1965 1970 1975 1980 1985

First bacterial genome 1990 First bacterial genome Hemophilus Influenzae 1995 Yeast genome First human genome draft 2000

Complete Genomes 2009 2008 2007 Total 1117 706 456 Eukaryotes 119 78 43 Bacteria 929 578 383 Archaea 69 50 29 2009 2008 2007

The “post-genomics” era 1117 genomes What’s Next ? The “post-genomics” era Annotation Comparative genomics Structural genomics Functional genomics Goal: to understand the living cell

Annotation CCTGACAAATTCGACGTGCGGCATTGCATGCAGACGTGCATG CGTGCAAATAATCAATGTGGACTTTTCTGCGATTATGGAAGAA CTTTGTTACGCGTTTTTGTCATGGCTTTGGTCCCGCTTTGTTC AGAATGCTTTTAATAAGCGGGGTTACCGGTTTGGTTAGCGAGA AGAGCCAGTAAAAGACGCAGTGACGGAGATGTCTGATG CAA TAT GGA CAA TTG GTT TCT TCT CTG AAT ...... .............. TGAAAAACGTA

Annotation Identify the genes within a given sequence of DNA Identify the sites Which regulate the gene Annotation Predict the function

How do we identify a gene in a genome? A gene is characterized by several features (promoter, ORF…) some are easier and some harder to detect…

promoter TF binding site Transcription Start Site Ribosome binding Site ORF=Open Reading Frame CDS=Coding Sequence Transcription Start Site CCTGACAAATTCGACGTGCGGCATTGCATGCAGACGTGCATG CGTGCAAATAATCAATGTGGACTTTTCTGCGATTATGGAAGAA CTTTGTTACGCGTTTTTGTCATGGCTTTGGTCCCGCTTTGTTC AGAATGCTTTTAATAAGCGGGGTTACCGGTTTGGTTAGCGAGA AGAGCCAGTAAAAGACGCAGTGACGGAGATGTCTGATG CAA TAT GGA CAA TTG GTT TCT TCT CTG AAT ................................. .............. TGAAAAACGTA

Using Bioinformatics approaches for Gene hunting Relative easy in simple organisms (e.g. bacteria) VERY HARD for higher organism (e.g. humans)

Comparative genomics

Perhaps not surprising!!! How humans are chimps? Comparison between the full drafts of the human and chimp genomes revealed that they differ only by 1.23%

So where are we different ?? Human ATAGCGGGGGGATGCGGGCCCTATACCC Chimp ATAGGGG - - GGATGCGGGCCCTATACCC Mouse ATAGCG - - - GGATGCGGCGC -TATACCA

And where are we similar ??? VERY SIMAILAR Conserved between many organisms VERY DIFFERENT

Functional genomics

TO BE IN NOT ENOUGH In any time point a gene can be functional or not

From the gene expression pattern we can lean: What does the gene do ? When is it needed? What other genes or proteins interact with it? ….. What's wrong??

Structural Genomics

The protein three dimensional structure can tell much more then the sequence alone protein complexes Biologic processes fold Evolutionary relationship Shape and electrostatics Active sites Protein-ligand complexes Functional sites

Resources and Databases The different types of data are collected in database Sequence databases Structural databases Databases of Experimental Results All databases are connected

Sequence databases Gene database Genome database Disease related mutation database ………….

Genome Browsers Easy “walk” through the genome

Genome Browsers UCSC Genome Browser http://genome.ucsc.edu/ Ensembl Genome Browser (http://www.ensembl.org) WormBase: http://www.wormbase.org/ AceDB: http://www.acedb.org/ Comprehensive Microbial Resource: http://www.tigr.org/tigr-scripts/CMR2/CMRHomePage.spl FlyBase: http://flybase.bio.indiana.edu/

Mutation database Single base difference in a single position among two different individuals of the same species Play an important role in differentiation and disease

Sickle Cell Anemia Due to 1 swapping an A for a T, causing inserted amino acid to be valine instead of glutamine in hemoglobin Image source: http://www.cc.nih.gov/ccc/ccnews/nov99/

Healthy Individual >gi|28302128|ref|NM_000518.4| Homo sapiens hemoglobin, beta (HBB), mRNA ACATTTGCTTCTGACACAACTGTGTTCACTAGCAACCTCAAACAGACACCATGGTGCATCTGACTCCTGA GGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGGGC AGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATG CTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGGCCTGGC TCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCACGTGGAT CCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCA CCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCA CTAAGCTCGCTTTCTTGCTGTCCAATTTCTATTAAAGGTTCCTTTGTTCCCTAAGTCCAACTACTAAACT GGGGGATATTATGAAGGGCCTTGAGCATCTGGATTCTGCCTAATAAAAAACATTTATTTTCATTGC >gi|4504349|ref|NP_000509.1| beta globin [Homo sapiens] MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLG AFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVAN ALAHKYH

Diseased Individual >gi|28302128|ref|NM_000518.4| Homo sapiens hemoglobin, beta (HBB), mRNA ACATTTGCTTCTGACACAACTGTGTTCACTAGCAACCTCAAACAGACACCATGGTGCATCTGACTCCTGA GGTGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGGGC AGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATG CTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGGCCTGGC TCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCACGTGGAT CCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCA CCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCA CTAAGCTCGCTTTCTTGCTGTCCAATTTCTATTAAAGGTTCCTTTGTTCCCTAAGTCCAACTACTAAACT GGGGGATATTATGAAGGGCCTTGAGCATCTGGATTCTGCCTAATAAAAAACATTTATTTTCATTGC >gi|4504349|ref|NP_000509.1| beta globin [Homo sapiens] MVHLTPVEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLG AFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVAN ALAHKYH

Structure Databases 3-dimensional structures of proteins, nucleic acids, molecular complexes etc 3-d data is available due to techniques such as NMR and X-Ray crystallography

Databases of Experimental Results Data such as experimental microarray images- gene expression data Proteomic data- protein expression data Metabolic pathways, protein-protein interaction data, regulatory networks ETC………….

PubMed Literature Databases http://www.ncbi.nlm.nih.giv/PubMed Service of the National Library of Medicine

Putting it all Together Each Database contains specific information Like other biological systems also these databases are interrelated

PROTEIN DISEASE ASSEMBLED GENOMES GENOMIC DATA ESTs GENES SNPs PIR SWISS-PROT DISEASE LocusLink OMIM OMIA ASSEMBLED GENOMES GoldenPath WormBase TIGR MOTIFS BLOCKS Pfam Prosite GENOMIC DATA GenBank DDBJ EMBL ESTs dbEST unigene GENES RefSeq AllGenes GDB SNPs dbSNP GENE EXPRESSION Stanford MGDB NetAffx ArrayExpress PATHWAY KEGG COG STRUCTURE PDB MMDB SCOP LITERATURE PubMed