Introduction and Update on the Fundamentals of Genomics: part 1

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Introduction and Update on the Fundamentals of
Genomicspart 1

• Washington State Board of Health
• Genetics Task Force Meeting
• January 3, 2002
• David L. Eaton, Ph.D.Director,
• Center for Ecogenetics Environmental Health
  Associate Dean for Research
• School of Public Health Community Medicine
• University of Washington

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Overview of todays talk

• Fundamentals of molecular biology
• Structure of genes and chromosomes
• The Human Genome Project
• How genetic alterations cause, or contribute to,
  disease
• How genomics will influence the practice of
  medicine in the future
• Ethical, Legal and Social Implications
• Dr. Burke will expand on this

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From the DOE Human Genome Program
http//www.ornl.gov/hgmis
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From the DOE Human Genome Program
http//www.ornl.gov/hgmis
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Gene Expression
DNA ? RNA ? Protein
RNA Transcription
Protein Translation
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Gene Structure and Expression
Exons
Promoter
I
III
DNA
II
Introns
Transcription
I
III
II
PrimaryRNA
(Temporary)
Splicing
II
III
I
mRNA
(Mature)
Protein
Translation
Exons
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Two discoveries that changed the world of biology
and medicine

• Soil microorganisms that express restriction
  enzymes
• Selectively cut DNA at specific nucleotide
  sites
• Recognition sites of 3-8 base pairs
• RFLP - primary basis for forensic DNA fingerprint
• Thermophilic bacteria
• Express heat stable DNA polymerases
• Allows fragments of DNA to be copied, melted
  and re-copied
• Polymerase Chain Reaction (PCR)

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The Human Genome ProjectObjectives

• 1. Sequence the entire human genome
• 2. Develop technology for sequencing
• 3. Identify variation in sequence
• 4. Interpret function (functional genomics)
• 5. Sequence model organisms (yeast, round worm,
  fruit fly, mouse)
• 6. Examine Ethical, Legal and Social Issues
  (ELSI)
• 7. Develop bioinformatics and computation
• 8. Train scientists

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Human Genome 3,000,000,000 base pairs
An analogy - the genome encyclopedia
average 5 letters per word gt 600,000,000
words average 12 words per line gt
50,000,000 lines average 70 lines per page
gt 700,000 pages
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Genetic Determinants of Disease

• Chromosomal abnormalities
• Loss or gain of chromosomes
• Loss or gain of chromosomal regions
• Chromosomal translocation
• Single gene mutations
• Coding regions loss, gain, or alteration of
  protein function
• Regulatory regions increased, decreased or
  inappropriate expression
• Polygenic or multifactorial problems
• Multiple gene mutations
• Gene/Gene, Gene-Environment interactions

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Genetic Mutations are Alterations in DNA Sequence

• Natural (spontaneous) mutations are changes
  induced by cellular processes such as mis-copying
  DNA, or oxidative damage to DNA
• Induced mutations are caused by environment,
  i.e., diet, chemicals, radiation, viruses,
  lifestyle
• Most Mutations are repaired efficiently, but
  errors occur
• Mutations can be harmful or helpful
• Most mutations have no known function

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Human Variability in DNA(polymorphism)

• SNPs (single nucleotide polymorphisms)
• indels (insertions and deletions)
• Chromosomal rearrangements
• Repetitive sequence (alu, di- and tri-nucleotide
  repeats - microsatellites)
• Gene duplication
• Pseudogenes (non-transcribed exonic sequence with
  high homology to an expressed gene)

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How common are SNPs?

• On average, 1 nucleotide difference per 1,000
  nucleotides when comparing the same gene in two
  different individuals
• Across the human population, average SNP
  differences 1 difference/200-400 NT
• Non-uniform - 10x higher variability in intronic
  vs. exonic sequence
• In total, several million NT differences between
  any two individuals

Majority of human genome variance is
represented within rather than between populations
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Significance of Polymorphic Variants

• Many examples of highly penetrant allelic
  variants that directly cause disease
• Huntingtons, cystic fibrosis, Muscular
  Dystrophy, etc.
• However, most other diseases are clearly
  multigenic - a given gene will have limited
  penetrance for the disease trait
• The environment also plays a big role

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Common Cystic Fibrosis Mutation
Deletion of 3 nucleotides
...Ile Ile Phe Gly...
Normal
...AUC AUC UUU GGU...
...AUC AU- --U GGU...
CF
...Ile Il e Gly...
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Examples of Gene-Environment Interactions

• PKU and consumption of phenylalanine
• Malaria and Sickle Cell gene
• HIV infection and CCR5 receptor variant
• Adverse drug response and CYP2D6 poor metabolism
• Alcohol intolerance and aldehyde dehydrogenase
• Smoking, Bladder cancer risk glutathione
  S-transferase M1 null genotypes and NAT2 slow
  genotypes

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Genetic Modulation of Exposure Risk
No Exposure
Exposure
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Implications of Genomicsto the Practice of
Medicine

• Discern the molecular basis of diseases
• Key component to prevention
• Better and earlier diagnosis
• Molecular biomarkers of early stages
• More effective and selective treatment
• Will require difficult cost-benefit decisions
• Policy makers
• Pharmaceutical companies
• Insurance companies / HMOs, etc.
• Physicians, providers

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Implications of Genomicsto the Practice of
Medicine

• Pharmacogenomics
• Taylor the drug to the patient
• gene chips will identify
• variant kinetics (absorption, distribution,
  metabolism, excretion)
• variant receptors - selective efficacy
• Predict / avoid adverse drug responses
• Examples
• Thipurine methyl transferase deficiency
• N-acetyl transferase slow metabolizers

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Implications of Genomicsto the Practice of
Medicine

• Ecogenetics (gene-environment interactions)
• Susceptible sub-populations
• GSTM1 polymorphism and lung cancer risk
• Genetic response to dietary factors
• Occupational risks
• HLA variants and susceptibility to Berrylium
  disease
• CYP2E NQO1 variants and benzene toxicity
• Identify / prevent adverse drug - environment
  interactions

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Benefits of HGP Research Medical Benefits

• improved diagnosis of disease
• earlier detection of predispositions to disease
• rational drug design
• gene therapy and control systems for drugs
• pharmacogenomics personal drugs
• organ replacement

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Ethical, Legal, and Social Implications of HGP
Research

• fairness in the use of genetic information
• privacy and confidentiality
• psychological impact and stigmatization
• genetic testing
• education, standards, and quality control

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