Genomics, Proteomics, and Bioinformatics Biology 224 Instructor: Tom Peavy August 31, 2009

Interface of biology and computers Analysis of genomes, genes, mRNA and proteins using computer algorithms and computer databases What is bioinformatics?

What is Genomics? What is Proteomics? What is the Transcriptome?

On bioinformatics “Science is about building causal relations between natural phenomena (for instance, between a mutation in a gene and a disease). The development of instruments to increase our capacity to observe natural phenomena has, therefore, played a crucial role in the development of science - the microscope being the paradigmatic example in biology. With the human genome, the natural world takes an unprecedented turn: it is better described as a sequence of symbols. Besides high-throughput machines such as sequencers and DNA chip readers, the computer and the associated software becomes the instrument to observe it, and the discipline of bioinformatics flourishes.” Martin Reese and Roderic Guigó, Genome Biology (Suppl I):S1, introducing EGASP, the Encyclopedia of DNA Elements (ENCODE) Genome Annotation Assessment Project

What do you want out of this course?

Themes throughout the course: gene/protein families Retinol-binding protein 4 (RBP4)  member of the lipocalin family  small, abundant carrier protein We will study it in a variety of contexts including --homologs in various species --sequence alignment --gene expression --protein structure --phylogeny

Tool-users Tool-makers bioinformatics public health informatics medical informatics infrastructure databases algorithms

DNARNA cDNA ESTs UniGene Microarrays phenotype genomic DNA databases protein sequence databases protein

GenBankEMBLDDBJ Housed at EBI European Bioinformatics Institute There are three major public DNA databases Housed at NCBI National Center for Biotechnology Information Housed in Japan

Growth of GenBank Year Base pairs of DNA (billions) Sequences (millions) Updated : >40b base pairs

Growth of GenBank + Whole Genome Shotgun (1982-November 2008) Number of sequences in GenBank (millions) Base pairs of DNA in GenBank (billions) Base pairs in GenBank + WGS (billions)

Taxonomy at NCBI: ~200,000 species are represented in GenBank

The most sequenced organisms in GenBank Homo sapiens 13.1 billion bases Mus musculus 8.4b Rattus norvegicus 6.1b Bos taurus5.2b Zea mays 4.6b Sus scrofa3.6b Danio rerio 3.0b Oryza sativa (japonica) 1.5b Strongylocentrotus purpurata1.4b Nicotiana tabacum 1.1b Updated GenBank release Excluding WGS, organelles, metagenomics

Go to NCBI website

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

BLAST is… Basic Local Alignment Search Tool NCBI's sequence similarity search tool supports analysis of DNA and protein databases 80,000 searches per day

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)

Review of Genetics, Biochemistry & Evolution

Human Genome Project

What is a typical Genomic structure for a Eukaryotic gene?

Synonymous vs. nonsynonymous changes

Synonymous Substitution Non-synonymous Substitution

Central Dogma DNA  RNA  protein sequence  structure  function  evolution

What kind of modifications Are made to Eukaryotic mRNAs?

RNA Modifications

What are cDNAs?

Protein structures X-ray crystallography and Nuclear magnetic resonance (NMR) Primary structure – linear AA Secondary structure- –alpha helix and beta sheet Tertiary structures- –3-d that exposes binding domains etc

Linkage maps YAC Yeast artificial chromosome & BAC Bacterial artificial chromosome -used to clone large pieces of DNA -overlapping clones Are genes linked?

Organization of genomes Groups of genes within a species -Comparative Genomics plastid genomes and mt genomes

How do we determine functions of genes?

Expression patterns –Northerns –RT-PCR –SAGE –Microarrays Transgenics –insert genes what results? Mutants –classical genetics –molecular genetics And Functional Protein Assays

Charles Darwin Descent with modification –species change through time and are related to a common ancestor Natural Selection is the process by which this change occurs

Understanding Natural selection acts on individuals though consequences occur in populations –Individual’s phenotype reason survived and reproduced –after a time this will change the distribution in the population, –what ultimately changes? Gene pool

New alleles Point change is all that is needed –not always a "big deal" neutral change –can be in Sickle cell anemia

Gene duplication creates an additional copy of a gene –unequal cross-over –X-rays Are these duplicates maintained in populations? –Psuedogenes

Polyploidy additional set of chromosomes –Found in plants –Amphibians, invertebrates Through a type of parthenogenesis –Triploid Poor fertility Hybridization or meiosis malfunction

Homology study of likeness (literal) Similarity between species (or genes) that results from inheritance of traits from a common ancestor –Unless know of a common ancestor have to be careful when using this word.

Orthologous vs Paralogous Genes        Gene Duplication Speciation Species 1 Species 2

Species All organisms alive today can trace their ancestry back to the origin of life some 3.8 billion years ago –Since then millions if not billions of branching events have occurred Mechanisms have to be in place for change to occur –genetic drift and natural selection