Genomics, Proteomics, and Bioinformatics

1. Genomics, Proteomics, and Bioinformatics Biology 224 Instructor: Tom Peavy January 29, 2008

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

3. What is Genomics? What is Proteomics? What is the Transcriptome?

4. What do you want out of this course?

5. Top ten challenges for bioinformatics [1] Precise models of where and when transcription will occur in a genome (initiation and termination) [2] Precise, predictive models of alternative RNA splicing [3] Precise models of biological pathways; ability to predict cellular responses to external stimuli [4] Determining protein:DNA, protein:RNA, protein:protein recognition codes [5] Accurate ab initio protein structure prediction

6. Top ten challenges for bioinformatics [6] Rational design of small molecule inhibitors of proteins [7] Mechanistic understanding of protein evolution [8] Mechanistic understanding of speciation [9] Development of effective gene ontologies: systematic ways to describe gene and protein function [10] Education: development of bioinformatics curricula Source: Ewan Birney, Chris Burge, Jim Fickett

7. 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

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

10. DNA RNA protein phenotype protein sequence databases cDNA ESTs UniGene genomic DNA databases

11. There are three major public DNA databases EMBL GenBank DDBJ Housed at EBI European Bioinformatics Institute Housed at NCBI National Center for Biotechnology Information Housed in Japan

12. Growth of GenBank Base pairs of DNA (billions) Sequences (millions) 1982 1986 1990 1994 1998 2002 Updated 8-12-04: >40b base pairs Year

13. Press Release (August 22, 2005) • 100 gigabases of sequence data (NCBI, EMBL, & DDBJ) • over 165,000 organisms

14. The growth of GenBank. The blue area shows the total number of bases including those from whole genome shotgun sequencing projects (WGS). The checkered area shows only the non-WGS portion. With release 149, the number of WGS bases exceeded the number of bases in the traditional GenBank divisions.

15. Go to NCBI website http://www.ncbi.nlm.nih.gov/

16. 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)

17. Entrez integrates… • the scientific literature; • DNA and protein sequence databases; • 3D protein structure data; • population study data sets; • assemblies of complete genomes

18. Entrez is a search and retrieval system that integrates NCBI databases

19. 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

20. OMIM is… • Online Mendelian Inheritance in Man • catalog of human genes and genetic disorders • edited by Dr. Victor McKusick, others at JHU

21. Books is… • searchable resource of on-line books

22. 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

23. 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)

24. Review ofGenetics, Biochemistry& Evolution

25. Human Genome Project

26. What is a typical Genomic structure for a Eukaryotic gene?

30. Synonymous vs. nonsynonymous changes

31. Synonymous Substitution Non-synonymous Substitution

32. Central Dogma • DNA  RNA  protein • sequence  structure  function  evolution

33. What kind of modifications Are made to Eukaryotic mRNAs?

34. RNA Modifications

37. What are cDNAs?

38. 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

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

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

43. How do we determine functions of genes?

44. 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

45. 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

46. 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

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

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

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