Transcript Goals of pharmacogenomics

Pharmacogenomics Ch 9 pg 232
 Pharmacology + Genomics
 How genome affects body response to disease, drugs
 People inherit/exhibit differences in drug
:
 Absorption
 Metabolism and degradation of the drug
 Transport of drug to the target molecule
 Excretion of the degradation products
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Goals of pharmacogenomics
Use drugs better and use better drugs
Patient Outcomes by Year
1 AERS =
Adverse Events
Reporting
System. This
system managed
by the U.S. Food
and Drug
Administration
(FDA) contains
over four million
reports of
adverse events
and reflects data
from 1969 to the
present.
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Year
2004
2005
2006
2007
2008
2009
2010
Total 2006-2010
% Chg
Death
34,928
40,238
37,465
36,834
49,958
63,846
82,724
Serious
199,510
257,604
265,130
273,276
319,741
373,535
471,291
270,827
+66.7%
1,702,973
+77.5%
GOALS
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Dosage and drug specific to individual
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Get it right first time
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Create individual metabolic profile
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Screen
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presymptomatic
carriers
preimplantation, prenatal, newborn
disease susceptibility
 Barriers
 Complexity – there are millions of SNPs
 Which genes affect drug response?
 Disincentive for companies $$ for small population
 Educating physicians in genetics
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Will be commonplace in the doctors office
 Genetic ID cards?
 Certain diseases have gene expression “signatures”
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SNPs Chapter 8 pg 192
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DNA polymorphisms
 People differ in nucleotide sequence
 Coding sequences
 Non-coding sequences (most)
 Used as DNA markers
 Evolution
 To identify individuals
 To diagnose disease
 To diagnose genetic predisposition
 Potential of individual to develop disease based on
hereditary factors
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 Can assist in
The study of how non-genetic factors interplay with genetic
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SNPs = Single nucleotide polymorphisms
(handout and CH 8 pg 270)
 DNA sequence variations due to a single nucleotide in the
genome
 Occur ~1/300 bases in human genome
 ~ 90% of all human genetic variation
 Effort underway to map all human SNPs (~3 million)
What is the size of the human genome in base pairs?
SNPs
Albuterol and
SNPs
Utah
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 Many SNPs have no effect on
cell function
 Others could:
 cause disease
 predispose
 influence disease progression
 influence response to a drug
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SNP
Read the gel results
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Tumor gene
Find the SNP
HapMap project
 Haplotype
 SNPs that tend to be inherited together.
 Association studies
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DNA Microarrays pg. 239
Microarrays =small, glass slide spotted with short ssDNA
sequences from ~20,000 different genes at fixed
locations
oligonucleotides
~20 bases
single stranded
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Skin cancer microarray animation
1. Obtain samples
 blood, tissue, tumor etc.
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What is the difference in gene expression in normal versus
cancerous tissue?
2,3. Isolate mRNA
 Expressed genes only
 Quantitative
4. Reverse transcribe mRNA to cDNA
 cDNA more stable than mRNA
 Fluorescently labeled nucleotides used
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5. Coat microarray chip with tagged cDNAs
Hybridization - Immobilized target oligos found by
probe DNA (the cDNAs) and nucleotides
hybridize
Transcriptic microarray (vs. genomic)
You tube phg foundation plants
 6. Scan for fluorescence
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GREEN =Control DNA, cDNA derived from
normal tissue hybridized to oligo DNA.
RED = Sample DNA, cDNA iderived from
diseased tissue hybridized
YELLOW = combination of Control and
Sample DNA, both hybridized equally to
target DNA.
BLACK =neither Control nor Sample DNA
hybridized .
.
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Yeast flash animation
Case study microarray
 76 patients with acute myeloid leukemia
 DNA microarrays of 23,040 genes used to study gene expression .
 Identified 63 overexpressed genes and 373 suppressed genes
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Among the over- and underexpressed genes, 28 were found to
have different expression levels between patients who responded
to chemotherapy and those who did not respond. (!)
 40 of 44 patients with a certain expression pattern underwent
remission.
 Compared 3of 20 patients in the other group.
 Similar investigations are being undertaken in many other diseases,
with the common goal of being able to predict therapeutic
response prospectively through genomic methods, thereby
allowing physicians to create far more specific and personalized
treatment plans.
http://radiology.rsna.org/content/231/3/613.full
2011 Microarrays and molecular markers for tumor
classification Brian Z Ring and Douglas T Ross
Human cancers have been classified according to tissue of origin, histological
characteristics and, to some extent, molecular markers. Clinical studies have
associated different tumor classes with differences in prognosis and in
response to therapy.
Measurement of the expression of thousands of genes in hundreds of cancer
specimens has begun to reveal novel molecularly defined subclasses of
tumor; some of these classes appear to predict clinical behavior, while others
may define tumor types that are ripe for directed development of
therapeutics.
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The future (and present)
 Transcriptome
 Collection of all RNA transcripts (m, t, rRNA)
 Tissue specific gene expression
 Which genes are on/off
 Varies with cell type, environment, disease, etc..
 Use microarrays
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 The transcriptome includes transcribed:
coding sequences
 non-coding sequences
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<5% of human genome is transcribed
Metabolome
 All the small molecules involved in metabolic pathways
 3000 common metabolites in body tissues and biofluids
 Dynamic!
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 Proteome
 All proteins in the cell
 Larger than the genome
 Alternative splicing
 Post translational modification
 Different proteins are found in different cells
 Why proteins
 Catalyze chemical reactions
 Mount an immunological response to infection
 chemical messengers to regulate growth, development, reproductive function,
and metabolism.
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Microbiome
 Human gut and how it
changes with disease
 10X more bacteria
in/on human body than
human cells
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 600 species in oral cavity (most uncultivated, unnamed!)
 Over 1000 species in human gut
 Influence development, breakdown and absorption of
nutrients , immunity, physiology
 Study microbes as community
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Recent articles
 Gut bacteria in Japanese people borrowed sushi-digesting genes from ocean
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bacteria
The bacterial zoo in your bowel
Gut bacteria – fat or thin, family or friends, shared or unique
Human gut bacteria linked to obesity
Divided by language, united by gut bacteria – people have three common gut
types
Gut bacteria recap the evolution of apes
Gut bacteria change the sexual preferences of fruit flies
You are what you eat – how your diet defines you in trillions of ways
Baby’s first bacteria depend on route of delivery
The Effects of Circumcision on the Penis Microbiome
Characterization of the Oral Fungal Microbiome (Mycobiome) in Healthy
Individuals
Gnotobiotic mouse models
 born, removed from the mother by C-section in sterile
environment
 Can be “humanized”
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 Our colons harbor trillions of microbes including a
prominent archaea, Methanobrevibacter smithii. To examine the
contributions of Archaea to digestive health, we colonized
germ-free mice with Bacteroides thetaiotaomicron, an adaptive
bacterial forager of the carbohydrates that we consume, with
or without M. smithii
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