Principles of Genetic Medicine: Part IPrecision Medicine Conference Caitrin W. McDonough, Ph.D....

Precision Medicine Conference

Caitrin W. McDonough, Ph.D.Research Assistant Professor

Department of Pharmacotherapy and Translational Research

cmcdonough@cop.ufl.edu

Principles of Genetic Medicine: Part I

• 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.

Disclosure

The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

• Review DNA

• Explain The Human Genome Project

• Discuss the Central Dogma of Molecular Biology

Learning Objectives

• 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.

Additional Resources

• 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

Clinical Relevance

• 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

Genetics and Genetic Medicine

Potential Benefits of Genomic Medicine• Molecular Medicine

• Disease• Drugs/Pharmacogenomics

• Microbial Genomics• Detection/Treatment of Pathogens• Biofuels• Protection from biological warfare

• DNA Identification (Forensics)• Identification• Match organ donors• Establish family relationships

• Agriculture, Livestock Breeding, and Bioprocessing

• Crops –Disease/Insect/Drought resistant

• Edible vaccines

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

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• 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

Science 1999;286:487‐91.  Lancet 2000;355:1615‐6.  Lancet 1998;353:717‐9.

• Genome: The entire genetic make‐up of an organism

What is a Genome

Homo sapiens3.2 billion

E. coli4.6 million

Organism:Genome size (base pairs):

Not to scale

Make up of the Human Genome

http://www.genome.gov/glossary/index.cfm?id=48 http://www.genome.gov/Glossary/index.cfm?id=114

Human Karyotype

Humans are a diploid organism

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

• Sugar‐Phosphate Backbone

• Only 4 nucleotides in DNA– A: Adenine– T: Thymine– C: Cytosine– G: Guanine

DNA

U.S. Department of Energy Genome Programs: http://genomics.energy.gov

• 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

Human Genome Project

http://www.ornl.gov/sci/techresources/Human_Genome/home.shtml

• 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

What we learned from the Human Genome Project

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

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The Central Dogma of Molecular Biology

DNA

RNA

Protein

Replication

Transcription

Translation

Reverse Transcription

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

http://www.genome.gov/Images/EdKit/bio2i_large.gif

Transcription

Splicing

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

• Human Genome• Chromosome (avg.)• Gene (avg.)

–But some are MUCH bigger• Unit of genetic code (codon)• Smallest variation

The Human Genome by the Numbers

3,000,000,000bp150,000,000 bp

3,000 bp

3 bp1 bp

• Genome: – The entire genetic make‐up of an organism

• ALL OF IT!!!• Genes, Exons and Introns• DNA between your genes

• Exome: Only the exons of our genes• Only the protein coding segments• VERY small percentage of our genome (<2%)

Genome vs. Exome

GENOME

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