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Principles of Genetic Medicine: Part I Caitrin W Principles of Genetic Medicine: Part I Caitrin W. McDonough, Ph.D. Research Assistant Professor Department of Pharmacotherapy and Translational Research Precision Medicine Conference [email protected] Disclosure • I declare no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria. The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Learning Objectives • Review DNA • Explain The Human Genome Project • Discuss the Central Dogma of Molecular Biology Additional Resources • Websites: – http://www.dnaftb.org/ – http://genomics.energy.gov/ – http://ghr.nlm.nih.gov/ – https://www.genome.gov/10000464 • Genomics Glossary App: – http://www.genome.gov/glossary/index.cfm • Literature: – Feero, Guttmacher, and Collins. Genomic Medicine –An Updated Primer. 2010. N Engl J Med. 362;21: 2001‐2011. – Guttmacher and Collins. Genomic Medicine –A Primer. N Engl J Med. 2002. 347;19:1512‐1520. Clinical Relevance • Most drugs are dosed on a “one size fits most” basis • Drug response rate – 30‐60% response rate of drug therapies for Alzheimer’s, depression, – hypertension, osteoporosis (Physician's Desk Reference, 2007) • Adverse drug reactions (ADRs) – Many ADRs are reported from medical errors, which could potentially be minimized when pharmacogenomic information is integrated into practice • Up to 100,000 people/year die of medical errors in the U.S. (1999 IOM Report, To Err is Human) – ↑ Morbidity and Mortality – ↑ Cost • Pharmacogenomics aims to improve drug response rate and minimize ADRs Genetics and Genetic Medicine • Genetics – The study of biologic variation – Some variations are advantageous – Some variations are disadvantageous – Some variations are neutral • Genetic Medicine – The study of the variation associated with illness, death, and drug response Potential Benefits of Genomic Medicine • Molecular Medicine • Disease • Drugs/Pharmacogenomics • Microbial Genomics • Detection/Treatment of Pathogens • Biofuels • Agriculture, Livestock • Protection from biological warfare Breeding, and Bioprocessing • Crops – • DNA Identification (Forensics) Disease/Insect/Drought • Identification resistant • Match organ donors • Edible vaccines • Establish family relationships Pharmacogenetics or Pharmacogenomics? • Pharmacogenetics study of how genetic differences at a single variation or in a single gene (locus) influence the variability in patients’ response to drugs – e.g. CYP2C9 SNPs and response to warfarin • Pharmacogenomics study of how genetic (genome) differences in multiple genes (genome‐wide) influence the variability in patients’ response to drugs – e.g. Genome‐wide Association study on response to clopidogrel 8 Science 1999;286:487‐91. Lancet 2000;355:1615‐6. Lancet 1998;353:717‐9. What is a Genome • Genome: The entire genetic make‐up of an organism Not to scale Organism: E. coli Homo sapiens Genome size (base pairs): 4.6 million 3.2 billion Make up of the Human Genome Human Karyotype Humans are a diploid organism http://www.genome.gov/glossary/index.cfm?id=48 http://www.genome.gov/Glossary/index.cfm?id=114 DNA Basics “ We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest.” “Two helical chains each coiled around the same axis” = DOUBLE HELIX DNA • Sugar‐Phosphate Backbone • Only 4 nucleotides in DNA – A: Adenine – T: Thymine – C: Cytosine – G: Guanine U.S. Department of Energy Genome Programs: http://genomics.energy.gov Human Genome Project • Completed in 2003 – 13 year project (1990‐2003) • Project Goals: – Identify all the genes in human DNA – Determine the sequences of the 3 billion chemical base pairs that make up human DNA – Store this information in databases – Improve tools for data analysis – Transfer related technologies to the private sector – Address the ethical, legal, and social issues (ELSI) that may arise from the project http://www.ornl.gov/sci/techresources/Human_Genome/home.shtml What we learned from the Human Genome Project • The human genome contains ~3 billion nucleotide bases (A, T, C, and G) • The average gene consists of 3,000 bases, but sizes vary greatly • At completion, the total number of genes was estimated at 30,000 –much lower than previous estimates of 80,000 to 140,000 • Less than 2% of the genome codes for protein • The functions are unknown for over 50% of discovered genes • Almost all (99.9%) of nucleotide bases are exactly the same in all people http://www.ornl.gov/sci/techresources/Human_Genome/project/info.shtml Comparison of the Human Genome and other Genomes Feero, Guttmacher, and Collins. N Engl J Med. 2010. 362;21: 2001-2011 The Central Dogma of Molecular Biology Replication DNA Reverse Transcription Transcription RNA Translation Protein 16 http://ghr.nlm.nih.gov/handbook/howgeneswork/makingprotein The Increasing Complexity of the Central Dogma Feero, Guttmacher, and Collins. N Engl J Med. 2010. 362;21: 2001-2011 Gene Structure – Introns/Exons Transcription Splicing http://www.genome.gov/Images/EdKit/bio2i_large.gif From Genes to Proteins http://www.genome.gov/glossary/index.cfm?p=viewimage&id=200 RNA to Amino Acids http://www.nature.com/scitable/topicpage/the-information-in-dna-determines-cellular-function-6523228 RNA to Amino Acids http://www.nature.com/scitable/topicpage/the-information-in-dna-determines-cellular-function-6523228 The Human Genome by the Numbers • Human Genome 3,000,000,000bp • Chromosome (avg.) 150,000,000 bp • Gene (avg.) 3,000 bp –But some are MUCH bigger • Unit of genetic code (codon) 3 bp • Smallest variation 1 bp Genome vs. Exome • Genome: – The entire genetic make‐up of an organism • ALL OF IT!!! • Genes, Exons and Introns • DNA between your genes GENOME • Exome: Only the exons of our genes • Only the protein coding segments • VERY small percentage of our genome (<2%) EXOME Summary • Genome: The entire genetic make‐up of an organism • Human Genome: – 3.2 billion base pairs – Diploid Organisms with 2 copies of each chromosome • Genes (DNA) RNA Protein.
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