An Introduction to Bioinformatics Algorithms: Understanding the Building Blocks of Life, Study notes of Computer Science

Download An Introduction to Bioinformatics Algorithms: Understanding the Building Blocks of Life and more Study notes Computer Science in PDF only on Docsity! www.bioalgorithms.infoAn Introduction to Bioinformatics Algorithms Current Topics in Computer Science: Computational Genomics CSCI 7000-005 Debra Goldberg debra.goldberg@cs.colorado.edu www.bioalgorithms.infoAn Introduction to Bioinformatics Algorithms Molecular Biology Primer Angela Brooks, Raymond Brown, Calvin Chen, Mike Daly, Hoa Dinh, Erinn Hama, Robert Hinman, Julio Ng, Michael Sneddon, Hoa Troung, Jerry Wang, Che Fung Yung An Introduction to Bioinformatics Algorithms www.bioalgorithms.info All 3 are specified linearly • DNA and RNA are constructed from nucleic acids (nucleotides) • Can be considered to be a string written in a four- letter alphabet (A C G T/U) • Proteins are constructed from amino acids • Strings in a twenty-letter alphabet of amino acids An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Central Dogma of Biology: DNA, RNA, and the Flow of Information TranslationTranscription Replication An Introduction to Bioinformatics Algorithms www. bioalgorithms.info DNA An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Nucleic Acid Components • Nitrogenous Base: N is important for hydrogen bonding between bases A – adenine with T – thymine (double H-bond) C – cytosine with G – guanine (triple H-bond) • Sugar: Ribose (5 carbon) Base covalently bonds with 1’ carbon Phosphate covalently bonds with 5’ carbon Normal ribose (OH on 2’ carbon) – RNA deoxyribose (H on 2’ carbon) – DNA dideoxyribose (H on 2’ & 3’ carbon) – used in DNA sequencing • Phosphate: negatively charged An Introduction to Bioinformatics Algorithms www.bioalgorithms.info The Purines The Pyrimidines An Introduction to Bioinformatics Algorithms www.bioalgorithms.info DNA • Stores all information of life • 4 “letters” base pairs. AGTC (adenine, guanine, thymine, cytosine ) which pair A-T and C-G on complimentary strands. http://www.lbl.gov/Education/HGP-images/dna-medium.gif An Introduction to Bioinformatics Algorithms www.bioalgorithms.info DNA, continued • DNA has a double helix structure. However, it is not symmetric. It has a “forward” and “backward” direction. The ends are labeled 5’ and 3’ after the Carbon atoms in the sugar component. 5’ AATCGCAAT 3’ 3’ TTAGCGTTA 5’ DNA always reads 5’ to 3’ for transcription replication An Introduction to Bioinformatics Algorithms www.bioalgorithms.info DNA: the building blocks of genetic material • DNA provides a code, consisting of 4 letters, for all cellular function. An Introduction to Bioinformatics Algorithms www.bioalgorithms.info MUtAsHONS • The DNA can be thought of as a sequence of the nucleotides: C,A,G, or T. • What happens to genes when the DNA sequence is mutated? An Introduction to Bioinformatics Algorithms www.bioalgorithms.info DNA - replication • DNA can replicate by splitting, and rebuilding each strand. • Note that the rebuilding of each strand uses slightly different mechanisms due to the 5’ 3’ asymmetry, but each daughter strand is an exact replica of the original strand. http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/D/DNAReplication.html An Introduction to Bioinformatics Algorithms www.bioalgorithms.info DNA: The Code of Life • The structure and the four genomic letters code for all living organisms • Adenine, Guanine, Thymine, and Cytosine which pair A-T and C-G on complimentary strands. Human chromosomes Tea Te | ee Fs rm || 16 17 «18 Tee x ru An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Central Dogma Revisited • Note: Some mRNA stays as RNA (ie tRNA,rRNA). DNA hnRNA mRNA protein Splicing Spliceosome Translation Transcription Nucleus Ribosome in Cytoplasm An Introduction to Bioinformatics Algorithms www.bioalgorithms.info DNA: The Basis of Life • Humans have about 3 billion base pairs. • How do you package it into a cell? • How does the cell know where in the highly packed DNA where to start transcription? • Special regulatory sequences • DNA size does not mean more complex • Complexity of DNA • Eukaryotic genomes consist of variable amounts of DNA • Single Copy or Unique DNA • Highly Repetitive DNA An Introduction to Bioinformatics Algorithms www.bioalgorithms.info NHGRI Packing it in An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Superstructure Lodish et al. Molecular Biology of the Cell (5th ed.). W.H. Freeman & Co., 2003. An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Superstructure Implications • DNA in a living cell is in a highly compacted and structured state • Transcription factors and RNA polymerase need ACCESS to do their work • Transcription is dependent on the structural state – SEQUENCE alone does not tell the whole story Transcriptional Regulation Transeription 2 Promoter Coding region region of gene of gene An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Types of RNA • mRNA – carries a gene’s message out of the nucleus. • The type “RNA” most often refers to. • tRNA – transfers genetic information from mRNA to an amino acid sequence • rRNA – ribosomal RNA. Part of the ribosome. • involved in translation. • siRNA – small interfering RNA. Interferes with transcription or translation. Recent discovery. An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Terminology • Promoter: A special sequence of nucleotides indicating the starting point for RNA synthesis. • Terminator: Signal in DNA that halts transcription. • RNA Polymerase II: Multisubunit enzyme that catalyzes the synthesis of an RNA molecule on a DNA template from nucleoside triphosphate precursors. An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Transcription • The process of making RNA from DNA • Catalyzed by “transcriptase” enzyme • Needs a promoter region to begin transcription. • ~50 base pairs/second in bacteria, but multiple transcriptions can occur simultaneously http://ghs.gresham.k12.or.us/science/ps/sci/ibbio/chem/nucleic/chpt15/transcription.gif An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Transcription: DNA hnRNA Transcription occurs in the nucleus. RNA polymerase reads promoter sequence and opens a small portion of the double helix exposing DNA bases. RNA polymerase II unwinds helix just ahead of active site • During transcription, DNA helix reforms as RNA forms. • When the terminator sequence is met, polymerase halts and releases both the DNA template and the RNA. An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Definition of a Gene • Regulatory regions: up to 50 kb upstream of +1 site • Exons: protein coding and untranslated regions (UTR) 1 to 178 exons per gene (mean 8.8) 8 bp to 17 kb per exon (mean 145 bp) • Introns: splice acceptor and donor sites, junk DNA average 1 kb – 50 kb per intron • Gene size: Largest – 2.4 Mb (Dystrophin). Mean – 27 kb. An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Terminology • Exon: A portion of the gene that appears in both the primary and the mature mRNA transcripts. • Intron: A portion of the gene that is transcribed but excised prior to translation. An Introduction to Bioinformatics Algorithms www.bioalgorithms.info RNA secondary structures • Some forms of RNA can form secondary structures by “pairing up” with itself. This can change its properties dramatically. http://www.cgl.ucsf.edu/home/glasfeld/tutorial/trna/trna.giftRNA linear and 3D view: • DNA and RNA can bind with each other. An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Genomic Information • Cells store all information to replicate itself • Human genome is around 3 billions base pair long • Almost every cell in human body contains same set of genes • But not all genes are used or expressed by those cells www.bioalgorithms.infoAn Introduction to Bioinformatics Algorithms Proteins An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Uncovering the code • Scientists conjectured that proteins came from DNA; but how did DNA code for proteins? • If one nucleotide codes for one amino acid, then there’d be 41 amino acids • However, there are 20 amino acids, so at least 3 bases codes for one amino acid, since 42 = 16 and 43 = 64 • This triplet of bases is called a “codon” • 64 different codons and only 20 amino acids means that the coding is degenerate: more than one codon sequence code for the same amino acid An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Translation • The process of going from RNA to polypeptide. • Three base pairs of RNA (called a codon) correspond to one amino acid based on a fixed table. • Always starts with Methionine and ends with a stop codon An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Terminology • Codon: The sequence of 3 nucleotides in DNA/RNA that encodes for a specific amino acid. • mRNA (messenger RNA): A ribonucleic acid whose sequence is complementary to that of a protein-coding gene in DNA. • Ribosome: The organelle that synthesizes polypeptides under the direction of mRNA • rRNA (ribosomal RNA):The RNA molecules that constitute the bulk of the ribosome and provides structural scaffolding for the ribosome and catalyzes peptide bond formation. • tRNA (transfer RNA): The small L-shaped RNAs that deliver specific amino acids to ribosomes according to the sequence of a bound mRNA. An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Purpose of tRNA • The ribosome continually binds tRNA, joins the amino acids together and moves to the next location along the mRNA • The proper tRNA is chosen by having the corresponding anticodon for the mRNA’s codon. • The tRNA then transfers its aminoacyl group to the growing peptide chain. • For example, the tRNA with the anticodon UAC corresponds with the codon AUG and attaches methionine amino acid onto the peptide chain. An Introduction to Bioinformatics Algorithms www. bioalgorithms.info Purpose of tRNA 3 Aminoacid if] attachment site Amino acid a ip} anticod (3) SBE ‘A 6 (5) ‘ lion Anticodon Anticodon (a) (b) (c) ©1999 Addison Wesley Longman, ine An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Terminology • Molecular chaperone: Protein that binds to unfolded or misfolded proteins to refold the proteins in the quaternary structure. An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Protein Synthesis: Summary • There are twenty amino acids, each coded by three- base-sequences in DNA, called “codons” • This code is degenerate • The central dogma describes how proteins derive from DNA • DNA mRNA (splicing?) protein • The protein adopts a 3D structure specific to it’s amino acid arrangement and function An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Polypeptide v. Protein • A protein is a polypeptide, however to understand the function of a protein given only the polypeptide sequence is a very difficult problem. • Protein folding an open problem. The 3D structure depends on many variables. • Current approaches often work by looking at the structure of homologous (similar) proteins. • Improper folding of a protein is believed to be the cause of mad cow disease. http://www.sanger.ac.uk/Users/sgj/thesis/node2.html for more information on folding An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Protein Folding • Proteins are not linear structures, though they are built that way • The amino acids have very different chemical properties; they interact with each other after the protein is built • This causes the protein to start fold and adopting it’s functional structure • Proteins may fold in reaction to some ions, and several separate chains of peptides may join together through their hydrophobic and hydrophilic amino acids to form a polymer An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Protein folding – secondary structure • Most proteins take the form of secondary structures: α helices and β sheets. An Introduction to Bioinformatics Algorithms www.bioalgorithms.info Protein Folding (cont’d) • The structure that a protein adopts is vital to it’s chemistry • Its structure determines which of its amino acids are exposed carry out the protein’s function • Its structure also determines what substrates it can react with