Genetics One Gene, One Phenotype

Transcription

1 Review Session Genomics Tuesday 4pm Chapter 19* Site TBA Genetics One Gene, One Phenotype Genotype Sickle Cell Anemia Amino Acid Auxotrophy Antibiotic Resistance Phenotype One Gene, One Phenotype This is a reductionist approach that cannot be used to address most of the major questions in biology! One gene provides little insight about the whole organism. Metabolic capabilities. Development. 1

2 What major questions in biology? How did speech and memory evolve? What are the genetic bases of the major vertebrate innovations? What genetic changes occurred during primate evolution? A history of the term Genomics 1920: Hans Winkler coins term Genome to describe the collection of genes contained within a haploid chromosome set. GENe + chromosome A history of the term Genomics Now: A genome is all the DNA in a set of chromosomes Only 2-3 % of the Human Genome is represented by genes! A history of the term Genomics 1986: Mouse geneticist Thomas Roderick introduces the word genomics to describe the mapping, sequencing, and characterization of genomes. A history of the term Genomics Now: The definition has broadened and has spawned an entirely new lexicon of omics. Omes: Genome Proteome Transcriptome Metabolome Glycome Variome Interactome Intronome A New Lexicon: Prefixes: Comparative Functional Structural Toxico- Pharmaco- 2

3 A History of the Field...of course the most important thing that happened then is that Jack Dunitz told me about all the developments with DNA in Cambridge because he was following it all. He told me that Francis Crick and Jim Watson had solved the structure of DNA, so we decided to go across to Cambridge to see it. This was in April of Jack and I and Leslie [Orgel] and another crystallographer went to Cambridge by car. It was a small car. It was very cold I remember, and the car wasn't heated. No one had heaters in cars then. We must have arrived in Cambridge in the late morning, at about 11am or thereabouts. We went into the Austin wing of the Cavendish Laboratory. I went in with Jack and Leslie, into this room that was lined with brick, and there on the side I can remember very clearly was this small model with plates for the bases - the original model with everything screwed together. And I could see the double helix! Francis was sitting there. This was the first time I met him and of course he couldn't stop talking. He just went on and on and on, and it was very inspiring, you see. Of course at this stage neither of the two famous Nature papers had yet appeared. The first paper was expected in a few weeks. They talked mainly about what eventually was in the second paper. Jim was at his desk in that room which I came to occupy later when I came to the Cavendish, and he was interspersing comments with Francis. So that's when I saw the DNA model for the first time, in the Cavendish, and that's when I saw that this was it. And in a flash you just knew that this was very fundamental. The curtain had been lifted and everything was now clear [as to] what to do. And I got tremendously excited by this. The Goal of Genomics Detailed understanding of all biological functions encoded in the genome and their evolution. Great Scott! That means we must define all the genes and their functions! Genomics Structural Genomics: Organization and sequence of genetic information Functional Genomics: Functions of sequences Comparative Genomics: Comparisons among organisms of gene function and organization Structural Genomics Genetic Maps (linkage maps): Approximate locations of genes Measured in map units (based on recombination) Physical Maps: Measured in base pairs (based on direct analysis of DNA) Low Resolution Genetic Maps 1 cm = 850,000 bp in humans (On Average) Physical distance = Map distance 3

4 A Lame Analogy A Genetic Map is like a road map based on time traveled (recombination frequencies). A A. Simpson Residence 3 Blocks 1 Block B B. Springfield Elementary 3 Blocks A Physical Map is like a road map based on distance (base pairs). D. Church C. Moe s Tavern D C 2 Blocks E 5 Blocks F E. Kwik E Mart F. Van Houten Residence 1 Minute The Physical Map of Springfield A A. Simpson Residence B B. Springfield Elementary 5 Minutes A B C D E F 1 Minute D. Church C. Moe s Tavern D C Minutes E 6 Minutes F E. Kwik E Mart F. Van Houten Residence A B C D E F The Genetic Map of Springfield A B C D E F A B C D E F

5 GENETIC MAPS and PHYSICAL MAPS should give the same gene order, but the distances can be vastly different. Why Genetic Maps? Useful for Assembling Genome Sequence Cheaper and Easier than Physical Maps Quantitative Trait Locus (QTL) mapping Chapter 22 Figure 19.2 Physical Maps Low to High Resolution Restriction Mapping Relative positions of restriction sites We ve already talked about DNA sequencing. DNA Sequencing Direct determination of DNA sequence Most DNA sequencing today is automated. Genome Sequence: The Ultimate Physical Map Haemophilus influenzae Figure

6 Map Based Sequencing Requires initial creation of detailed genetic and physical maps Sequencing is done one large fragment (chromosome) at a time Shotgun Sequencing Figure Breaking free from Hypothesis Driven Research The Human Genome Project Past, Present, and Future Unique Effort Great Potential 6

7 The Collision of Politics and Science Another challenge proved to be that managers of "big science" endeavors also have their own bosses, replete with the power to make or break a project. The HGP provided us with unavoidable training in the art of keeping a long-term scientific project--and its budget--on course in an ever-changing sea of political masters with many different agendas. Though there were moments of puzzlement, even hilarity, when politics and science collided (such as a conversation with a lawmaker who thought the genome was only found in the gonads), for the most part we found elected leaders of our countries interested and inspired by this project. The Advent of BIG BIOLOGY Source: Collins et al Science BIG Government Projects Project Space Station Freedom Earth Observing System Projected cost ($ billion) Target Completion Date Estimated Life Span (years) A Historical Perspective on the HGP Super Conducting Supercollider Human Genome Project Perpetual Hubble Space Telescope to 20* Source: Collins et al Science 7

8 Ethical Considerations Budget setasides in the HGP: DOE 3% NIH 5% Ehtical, Legal, and Social Issues (ELSI) programs What ethical, legal, and social issues could possibly be associated with the Human Genome Project? Ethical Considerations Budget setasides in the HGP: DOE 3% NIH 5% Ehtical, Legal, and Social Issues (ELSI) programs 8

9 Area Goal Achieved Date Genetic Map 2-5cM resolution ( Markers) 1 cm resolution (3000 Markers) September 1994 Physical Map 30,000 STS 52,000 STS October 1998 DNA Sequence 95% of gene containing regions to 99.99% accuracy >98% of gene containing regions to 99.99% accuracy April 2003 Capacity and Cost (Finished Sequence) 500 Mb / < $0.25 per finished base > 1400 Mb / < $0.09 per finished base November 2002 Human Sequence Variation 100,000 mapped human SNPs 3.7 Million Mapped human SNPs February 2003 Gene Identification Full length cdnas 15,000 full length cdnas March 2003 Model Organisms Complete Sequences of E. coli, S. cerevisiae, C. elegans, D. melanogaster Goal organisms plus drafts of C. briggsae, D. pseudoobscura, mouse, rat, etc.. April 2003 Functional Analysis Develop Genomic Scale Technologies High Throughput Oligonucleotide Synthesis 1994 DNA Microarrays 1996 Normalized and subtracted cdna libraries 1996 Eukaryotic whole genome knockouts (yeast) 1999 Two Hybrid Mapping 2002 Source: Collins et al Science 9

10 Why? Next time we ll discuss some implications of the HGP and look at some other genome projects. 10