1. Introduction to Bioinformatics Part 1 of 2 Jonathan Pevsner, Ph.D. pevsner@jhmi.edu M.E:440.714 September 8, 2003

2. Many of the images in this powerpoint presentation are from Bioinformatics and Functional Genomics by Jonathan Pevsner (ISBN 0-471-21004-8). Copyright © 2003 by John Wiley & Sons, Inc.John Wiley & Sons, Inc These images and materials may not be used without permission from the publisher. We welcome instructors to use these powerpoints for educational purposes, but please acknowledge the source. The book has a homepage at http://www.bioinfbook.orghttp://www.bioinfbook.org Including hyperlinks to the book chapters. Copyright notice

3. Hugh Cahill Mayra Garcia Gek Ming Sia Teaching assistants

4. People with very diverse backgrounds in biology People with diverse backgrounds in computer science and biostatistics Most people have a favorite gene, protein, or disease Who is taking this course?

5. What are the goals of the course? To provide an introduction to bioinformatics with a focus on the National Center for Biotechnology Information (NCBI) and EBI To focus on the analysis of DNA, RNA and proteins To introduce you to the analysis of genomes To combine theory and practice to help you solve research problems

6. Themes throughout the course Textbooks Web sites Literature references Gene/protein families Computer labs

7. Themes throughout the course: textbooks Several textbooks are available on reserve: Baxevanis and Ouellette David Mount Durbin et al. I have written a textbook that will appear Oct. 1, Bioinformatics and Functional Genomics. The chapters contain content, lab exercises, and quizzes that were developed in this course. We will provide chapters as handouts. Once the book becomes available, we will put copies on reserve. The book is recommended (not required).

8. Themes throughout the course: web sites The course website is: http://pevsnerlab.kennedykrieger.org/ bioinfo_course.htm The textbook website is: http://www.bioinfbook.org This has 1000 URLs, organized by chapter The site offers a 15% discount on book purchases (although the book is not required) The principal website we will explore is NCBI: http://www.ncbi.nlm.nih.gov

9. Themes throughout the course: Literature references You are encouraged to read original source articles. Although articles are not required, they will enhance your understanding of the material. You can obtain articles through PubMed and through the WelDoc service at Welch. Some articles will be available on reserve.

10. Themes throughout the course: gene/protein families We will use retinol-binding protein 4 (RBP4) as a model gene/protein throughout the course. RBP4 is a member of the lipocalin family. It is a small, abundant carrier protein. We will study it in a variety of contexts including --sequence alignment --gene expression --protein structure --phylogeny --homologs in various species We will also use the Pol protein of HIV-1 as an example.

12. The HIV-1 pol gene encodes three proteins Aspartyl protease Reverse transcriptase Integrase PRRTIN

13. Themes throughout the course: computer labs There is a computer lab each Friday. This is a chance to gain practical experience using a variety of web resources. You can do the lab on your own if you wish. However, during the lab you can get help on problems, and in some cases the computers will have specialized software.

14. Grading 30% weekly quizzes (open book) 30% final exam November 13 40% discovery of a novel gene (by Oct. 9) and phylogenetic tree (by Nov. 13) extra credit: find a mistake in a database

15. What is bioinformatics? Interface of biology and computers Analysis of proteins, genes and genomes using computer algorithms and computer databases Genomics is the analysis of genomes. The tools of bioinformatics are used to make sense of the billions of base pairs of DNA that are sequenced by genomics projects.

16. 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 signal transduction 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

17. 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

18. Three perspectives on bioinformatics The tree of life The organism The cell

20. Time of development Body region, physiology, pharmacology, pathology

22. DNARNAphenotypeprotein

24. DNARNA cDNA ESTs UniGene phenotype genomic DNA databases protein sequence databases protein

25. GenBankEMBLDDBJ There are three major public DNA databases The underlying raw DNA sequences are identical

26. 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

27. >100,000 species are represented in GenBank all species128,941 viruses6,137 bacteria31,262 archaea2,100 eukaryota87,147

28. The most sequenced organisms in GenBank Homo sapiens (6.9 million entries) Mus musculus (5.0 million) Zea mays (896,000) Rattus norvegicus (819,000) Gallus gallus (567,000) Arabidopsis thaliana (519,000) Danio rerio (492,000) Drosophila melanogaster (350,000) Oryza sativa (221,000)

29. National Center for Biotechnology Information (NCBI) www.ncbi.nlm.nih.gov

32. PubMed is… National Library of Medicine's search service 11 million citations in MEDLINE links to participating online journals PubMed tutorial (via “Education” on side bar)

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

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

35. 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

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

37. Books is… searchable resource of on-line books

38. 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

39. 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)

40. Four questions we can answer at NCBI (and elsewhere): [1] How can I do a literature search using PubMed? [2] How can WelchWeb help? [3] How can I use Entrez to find information about a particular gene or protein? (What is an accession number?) [4] How can I find information about a particular disease?

41. Question #1: How can I use PubMed at NCBI to find literature information?

42. PubMed is the NCBI gateway to MEDLINE. MEDLINE contains bibliographic citations and author abstracts from over 4,000 journals published in the United States and in 70 foreign countries. It has 12 million records dating back to 1966.

43. MeSH is the acronym for "Medical Subject Headings." MeSH is the list of the vocabulary terms used for subject analysis of biomedical literature at NLM. MeSH vocabulary is used for indexing journal articles for MEDLINE. The MeSH controlled vocabulary imposes uniformity and consistency to the indexing of biomedical literature.

46. PubMed search strategies Try the tutorial (“education” on the left sidebar) Use boolean queries lipocalin AND disease Try using “limits” Try “LinkOut” to find external resources Obtain articles on-line via Welch Medical Library (and download pdf files): http://www.welch.jhu.edu/

47. lipocalin AND disease (35 results) lipocalin OR disease (1,300,000 results) lipocalin NOT disease (350 results) 1 AND 2 1 OR 2 1 NOT 2 1 1 1 2 2 2

48. Question #2: How can I use WelchWeb (from the Welch Medical Library) to do literature (and other) searches? WelchWeb is available at http://www.welch.jhu.edu

50. E-mail gateway

51. PubMed gateway

52. Library catalog

53. Remote access to Welch services

54. Request literature

55. Browse journals

56. Browse databases

57. Basic Sciences Subject Guide http://www.welch.jhu.edu/internet/bsci.html RAUL (remote access) http://proxy.hcf.jhu.edu/ Weldoc (Inter Library Loan, and electronic delivery of articles) http://weldoc.welch.jhmi.edu/weldoc/logon.html MyWelch (personal library portal) https://mywelch.welch.jhmi.edu Welch E-Learning page (online tutorials and hand-outs) http://www.welch.jhu.edu/classes/elearning/index.html Johns Hopkins Author Publishing Tool http://openaccess.jhmi.edu/authors_resource.cfm Browse Welch E-Resources by Subject http://www.welch.jhu.edu/eresources/edatabases_subject.cfm Liaison Librarian Program (every dept has a liaison librarian) http://www.welch.jhu.edu/liaison/index.html Thanks to Brian Brown (bbrown20@jhmi.edu), the Welch Medical Library liason to the basic sciences WelchWeb URLs of interest

58. Visit the Basic Sciences Subject guide for a long list of bioinformatics- related sites...

59. This lecture continues in part 2 with a discussion of more NCBI resources http://pevsnerlab.kennedykrieger.org/ppts/lecture_bioinf_ch2.ppt