1. December 14, 2001Slide 1 Some Biology That Computer Scientists Need for Bioinformatics Lenwood S. Heath Virginia Tech Blacksburg, VA 24061 heath@cs.vt.edu University of Maryland December 14, 2001

2. Slide 2 I. Some Molecular Biology and Genomics II. Language of the New Biology III. Existing bioinformatics tools IV. Bioinformatics challenges V. Bioinformatics at Virginia Tech Overview

3. December 14, 2001Slide 3 I. Some Molecular Biology The instruction set for a cell is contained in its chromosomes. Each chromosome is a long molecule called DNA. Each DNA molecule contains 100s or 1000s of genes. Each gene encodes a protein. A gene is transcribed to mRNA in the nucleus. An mRNA is translated to a protein on ribosomes.

4. December 14, 2001Slide 4 Transcription and Translation DNAmRNAProtein TranscriptionTranslation

5. December 14, 2001Slide 5 Elaborating Cellular Function DNAmRNAProtein TranscriptionTranslation Reverse Transcription Degradation Regulation Functions: Structure Catalyze chemical reactions Respond to environment (Genetic Code) Thousands of Genes!

6. December 14, 2001Slide 6 Chromosomes Long molecules of DNA: 10^4 to 10^8 base pairs 26 matched pairs in humans A gene is a subsequence of a chromosome that encodes a protein. Proteins associated with cell function, structure, and regulation. Only a fraction of the genes are in use at any time. Every gene is present in every cell.

7. December 14, 2001Slide 7 DNA Strand C (cytosine) complements G (guanine) CTCAATTGAGCG Bases A (adenine) complements T (thymine) 2’-deoxyribose (sugar) 5’ End3’ End

8. December 14, 2001Slide 8 Complementary DNA Strands Double-Stranded DNA C G TGA CTCAATTGAGCG C G C G A T A T A T A TA T A T C G C G C G GC C TTAA C G

9. December 14, 2001Slide 9 RNA Strand CUCAAUUGAGCG Bases U (uracil) replaces T (thymine) Ribose (sugar) 5’ End3’ End

10. December 14, 2001Slide 10 Transcription of DNA to mRNA C G C G C G A T A T A T A TA T A T C G C G C G TGAGC C TTAA C G CUCAAUUGAGCG mRNA Strand Template DNA Strand Coding DNA Strand Template DNA Strand

11. December 14, 2001Slide 11 Proteins and Amino Acids Protein is a large molecule that is a chain of amino acids (100 to 5000). There are 20 common amino acids (Alanine, Cysteine, …, Tyrosine) Three bases --- a codon --- suffice to encode an amino acid. There are also START and STOP codons.

12. December 14, 2001Slide 12 Genetic Code

13. December 14, 2001Slide 13 Translation to a Protein CUCAAUUGAGCG Phenylalanine ArginineHistidineAlanine Unlike DNA, proteins have three-dimensional structure essential to protein function. Protein folds to a three-dimensional shape that cannot yet be predicted from the primary sequence. mRNA Strand Nascent Polypeptide: Amino Acids Bound Together by Peptide Bonds

14. December 14, 2001Slide 14 Transcription and Translation DNAmRNAProtein TranscriptionTranslation

15. December 14, 2001Slide 15 Transcription of DNA to mRNA C G C G C G A T A T A T A TA T A T C G C G C G TGAGC C TTAA C G CUCAAUUGAGCG mRNA Strand Template DNA Strand Coding DNA Strand Template DNA Strand

16. December 14, 2001Slide 16 Translation to a Protein CUCAAUUGAGCG Phenylalanine ArginineHistidineAlanine mRNA Strand Nascent Polypeptide: Amino Acids Bound Together by Peptide Bonds

17. December 14, 2001Slide 17 Cell’s Fetch-Execute Cycle Stored Program: DNA, chromosomes, genes Fetch/Decode: RNA, ribosomes Execute Functions: Proteins --- oxygen transport, cell structures, enzymes Inputs: Nutrients, environmental signals, external proteins Outputs: Waste, response proteins, enzymes

18. December 14, 2001Slide 18 A new language has been created. Words in the language that are useful for today’s talks. Genomics Functional Genomics Proteomics cDNA Microarrays Global Gene Expression Patterns II. The Language of the New Biology

19. December 14, 2001Slide 19 Discovery of genetic sequences and the ordering of those sequences into individual genes; gene families; chromosomes. Identification of sequences that code for gene products/proteins; sequences that act as regulatory elements. Genomics

20. December 14, 2001Slide 20 Genome Sequencing Projects Drosophila Yeast Mouse Rat Arabidopsis Human Microbes …

21. December 14, 2001Slide 21 Drosophila Genome

22. December 14, 2001Slide 22 The biological role of individual genes. Mechanisms underlying the regulation of their expression. Regulatory interactions among them. Functional Genomics

23. December 14, 2001Slide 23 Glycolysis, Citric Acid Cycle, and Related Metabolic Processes

24. December 14, 2001Slide 24 Only certain genes are “turned on” at any particular time. When a gene is transcribed (copied to mRNA), it is said to be expressed. The mRNA in a cell can be isolated. Its contents give a snapshot of the genes currently being expressed. Correlating gene expressions with conditions gives hints into the dynamic functioning of the cell. Gene Expression

25. December 14, 2001Slide 25 Gene Expression: Control Points

26. December 14, 2001Slide 26 Responses to Environmental Signals

27. December 14, 2001Slide 27 Intracellular Decision Making

28. December 14, 2001Slide 28 Microarray Technology In the past, gene expression and gene interactions were examined known gene by known gene, process by process. With microarray technology: –Simultaneous examination of large groups of genes and associated interactions –Possible discovery of new cellular mechanisms involving gene expression

29. December 14, 2001Slide 29 Flow of a Microarray Experiment Hypotheses Select cDNAs PCR Test of Hypotheses Extract RNA Replication and Randomization Reverse Transcription and Fluorescent Labeling Robotic Printing HybridizationIdentify SpotsIntensitiesStatisticsClusteringData Mining, ILP

30. December 14, 2001Slide 30 Spots: (Sequences affixed to slide) 123 1 1 2 2 1 3 12 2 3 3 3 TreatmentControl Mix 123 Excitation Emission Detection Relative Abundance Detection Hybridization

31. December 14, 2001Slide 31 Gene Expression Varies Cy5 to Cy3 ratios

32. December 14, 2001Slide 32 III. Existing Computational Tools in Bioinformatics Sequence similarity Multiple sequence alignments Database searching Evolutionary (phylogenetic) tree construction Sequence assemblers Gene finders

33. December 14, 2001Slide 33 Existing Biological Databases Molecular Sequences: Genomic DNA, mRNA, ESTs, proteins Protein domains, motifs, or blocks Protein families Genomes Nomenclature and ontologies Biological literature

34. December 14, 2001Slide 34 IV. Challenges for Bioinformatics Analyzing and synthesizing complex experimental data Representing and accessing vast quantities of information Pattern matching Data mining --- whole genome analysis Gene discovery Function discovery Modeling the dynamics of cell function

35. December 14, 2001Slide 35 Computer science interacts with the life sciences. V. Bioinformatics at Virginia Tech Computer Science in Bioinformatics: Joint research with: plant biologists, microbial biologists, biochemists, cell-cycle biologists, animal scientists, crop scientists, statisticians. Projects: Expresso; Nupotato; MURI; Arabidopsis Genome; Barista; Cell-Cycle Modeling Graduate option in bioinformatics Virginia Bioinformatics Institute (VBI)

36. December 14, 2001Slide 36 Integration of design and procedures Integration of image analysis tools and statistical analysis Data mining using inductive logic programming (ILP) Closing the loop Integrating models Expresso: A Problem Solving Environment (PSE) for Microarray Experiment Design and Analysis

37. December 14, 2001Slide 37 Nupotato Potatoes originated in the Andes, where there are many varieties. Many varieties survive at high altitude in cold, dry conditions. Microarray technology can be used to investigate genes that are responsible for stress resistance and that are responsible for the production of nutrients.

38. December 14, 2001Slide 38 MURI Some microorganisms have the ability to survive drying out or intense radiation. Their genomes are just being sequenced. Using microarrays and proteomics, we will try to correlate computationally the genes in the genomes with the special traits of the microorganisms. We are currently using multiple genome analysis.

39. December 14, 2001Slide 39 Arabidopsis Genome Project Arabidopsis is a model higher plant. It is the first higher plant whose genome has been fully sequenced. Gene finder software has been used to identify putative genes. We are computationally mining the regulatory regions of these genes for promoter patterns.

40. December 14, 2001Slide 40 Barista Barista serves Expresso! Software development team across projects to minimize duplication of effort. Work with Linux, Perl, C, Python, cvs, Apache, PHP, …

41. December 14, 2001Slide 41 Virginia Bioinformatics Institute (VBI) Research institute based at Virginia Tech Established July 1, 2000, with $3 million Will occupy 2 building and have 100+ employees in 4 years

42. December 14, 2001Slide 42 Getting Into Bioinformatics Learn some biology --- genetics, cell biology Study computational (molecular) biology Get involved with bioinformatics research in interdisciplinary teams Work with biologists to solve their problems