Genomics
Vincent Nardone
March 24, 2014
Overview
 What is Genomics?
 How does it apply to chronic diseases?
 Background
 The human genome project
 Genetics 2000-2014
 Ethical Concerns
 Recent Genomics articles
What is genomics?
 Something to do with:
 Genes?
 The human genome
project?
 Health/Diseases?
 DNA?
 Science?
Quiz 1
 When was the term genomics first coined?
 A. In 1953 after Watson and Crick published a paper on the
structure of DNA
 B. In 1975 after DNA sequencing began with DNA polymerase
 C. In 1986 over a beer following a genetics conference
 D. In 2003 after the human genome project was complete
Quiz 1
 When was the term genomics first coined?
 A. In 1953 after Watson and Crick published a paper on the
structure of DNA
 B. In 1975 after DNA sequencing began with DNA polymerase
 C. In 1986 over a beer following a genetics conference
(geneticist Dr. Tom Roderick)
 D. In 2003 after the human genome project was complete
What is Genomics?
 Merriam-Webster
 Genomics (n)- a branch of biotechnology concerned with
applying the techniques of genetics and molecular biology to
the genetic mapping and DNA sequencing of sets of genes or
the complete genomes of selected organisms using high-speed
methods, with organizing the results in databases, and with
applications of the data (as in medicine or biology)
What is Genomics?
 Wikipedia
 Genomics is a discipline in genetics that applies recombinant
DNA, DNA sequencing methods, and bioinformatics to
sequence, assemble, and analyze the function and structure
of genomes (the complete set of DNA within a single cell of an
organism)
What is Genomics?
 World Health Organization
 Genomics is defined as the study of genes and their functions,
and related techniques.
 The main difference between genomics and genetics is that
genetics scrutinizes the functioning and composition of the
single gene where as genomics addresses all genes and their
inter relationships in order to identify their combined influence
on the growth and development of the organism.
Why Should I Care?
 Genes have a large effect in susceptibility to chronic diseases
 Sickle Cell disease
 GAG replaced by GTG; valine replaces glutamine
 Cystic Fibrosis
 66% of cases from CFTR-phenylalanine 508 deletion
 Familial Dysbetalipoproteinemia
 Chromosome 19 ApoE2 mutation
Quiz 2
 What is the current life expectancy for people with sickle
cell disease?
 A. 25
 B. 35
 C. 45
 D. 55
 E. 65
Quiz 2
 What is the current life expectancy for people with sickle
cell disease?
 A. 25
 B. 35
 C. 45
 D. 55
 E. 65
https://www.nhlbi.nih.gov/news/spotlight/success/reducing-the-burden-of-sickle-cell-disease.html
Sickle Cell disease
 Autosomal Recessive (2 HbS required)
 1 in 5000 Americans affected; 1 in 500 African Americans
 $500 million per year cost to US in 2004 (CDC)
 Causes RBCs to stick together and occlude arteries
 Leads to pain, strokes, heart attacks
 RBCs live shorter than normal
 Heterozygotes thought to be resistant to malaria
Sickle Cell and Malaria
Sickle Cell Trait Distribution
Historical Malaria
Distribution
http://www.understandingrace.org/humvar/sickle_01.html
Quiz 3
 How many different genetic mutations have been shown to
cause cystic fibrosis?
 A. 1
 B. 10
 C. 100
 D. 1000
 E. >1000
Quiz 3
 How many different genetic mutations have been shown to
cause cystic fibrosis?
 A. 1
 B. 10
 C. 100
 D. 1000
 E. >1000
Cystic Fibrosis
 Due to homozygous defect in cystic fibrosis transmembrane
conductance regulator (7)
 Diagnosed by sweat test
 Life expectancy: 1959: 6 months; 2007: 37 yrs
 1 in 3500 children born with CF
 1 in 30 Caucasians carrier mutation
 1 in 65 Africans
 Costs US $450 million per year
Familial Dysbetalipoproteinemia
 Autosomal Recessive
 Only 10% of apoE2 homozygotes develop dz.
 Is essential but not sufficient
 Characterized by:
 Increased LDL
 Increased Triglycerides
 Decreased HDL
 Leads to heart attacks and strokes in 30s and 40s
http://ghr.nlm.nih.gov/gene/APOE
Quiz 4
 If a child is born to a mom with homozygous apoE2 and a dad with
heterozygous apoE2/apoE (wt), what is the chance that this child
develops familial dysbetalipoproteinemia?
 A. 0%
 B. 5%
 C. 25%
 D. 50%
 E. 100%
Quiz 4
 If a child is born to a mom with homozygous apoE2 and a dad with
heterozygous apoE2/apoE (wt), what is the chance that this child
develops familial dysbetalipoproteinemia?
 A. 0%
 B. 5%
 C. 25%
 D. 50%
 E. 100%
Background
 1953- James D. Watson and Francis Crick Publish an article
on the structure and composition of deoxyribose nucleic acid
(DNA)
Background
 1955- Fred Sanger publishes the amino acid sequence of
insulin
 1964- Robert Holley publishes the ribonucleotide sequence
of alanine tRNA
 1976-Walter Fiers and team publish the complete nucleotide
sequence of bacteriophage MS2-RNA (3569 base pairs)
Background-DNA sequencing
 1980- Frederick Sanger and Walter Gilbert share the Nobel
Prize for developing independent methods to sequence DNA
www.nobelprize.org
Background DNA sequencing
 1981- The human mitochondrion was completely sequenced




(16,568 bp)
1983- First Genetic Disease Mapped (Huntington’s Disease)
1989- Cystic Fibrosis gene mutation recognized
1992- Chromosome III of brewers yeast was completely
sequenced (315,000 bp)
1995- Haemophilus influenza completely sequenced
(1,800,000 bp)
Disease gene sequencing
http://www.genome.gov/Pages/Education/AllAbouttheHumanGenomeProject/CumulativePaceofGeneDiscovery1981-2005.pdf
Cost changes over time
http://upload.wikimedia.org/wikipedia/commons/7/73/Number_of_prokaryotic_genomes_and_sequencing_costs.svg
Cost changes over time
http://upload.wikimedia.org/wikipedia/commons/7/73/Number_of_prokaryotic_genomes_and_sequencing_costs.svg
Quiz 5
 How many base pairs are in the human genetic code?
 A. 33,000,000
 B. 330,000,000
 C. 3,300,000,000
 D. 33,000,000,000
Quiz 5
 How many base pairs are in the human genetic code?
 A. 33,000,000
 B. 330,000,000
 C. 3,300,000,000
 D. 33,000,000,000
Human Genome Project
 Goal: To map all of the genes of the human genome
 Timeline:
 1987- funding is submitted in budget to Congress
 1990- Project begins
 1999- Chromosome 22 first chromosome fully decoded
 2001- First draft released
 2003-Human genome project completed
Facts: The Human Genome Project
 Was completed under budget and 2 years ahead of schedule
 Fueled the discovery of more than 1800 disease genes and
2000 genetic tests
 350 biotech products resulting from the Human Genome
Project are currently in clinical trials
http://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=45&key=H#H
Future: The Human Genome project
 The Cancer Genome Atlas aims to identify genetic
abnormalities in 50 major cancer types
 Aims to target interventions and drugs that will be more
effective and less side effects
 Aim to cut the cost of sequencing an individual genome to
less than $1,000
http://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=45&key=H#H
Quiz 6
 Which costs more, a full body CT scan or an individual
genomic sequencing?
Quiz 6
 Which costs more, a full body CT scan or an individual
genomic sequencing?
 Individual genomic sequencing- $5,000
 Full body CT- $3,000
Genomics- 2000-2014
 EGAPP
 OPHG
 Epigenetics
 Genomics Testing
 Translational Applications
EGAPP
 Evaluation of Genomic Applications in Practice and
Prevention
 The EGAPP Working Group was established in 2005 to support
the development of a systematic process for assessing the
available evidence regarding the validity and utility of rapidly
emerging genetic tests for clinical practice. This independent,
multidisciplinary panel prioritizes and selects tests, reviews
CDC-commissioned evidence reports and other contextual
factors, highlights critical knowledge gaps, and provides
guidance on appropriate use of genetic tests in specific clinical
scenarios.
http://www.egappreviews.org/
EGAPP
 Founded from the CDC Public Health
 CDC is interested because 2000 tests exists and many recent
one have population-based applications
 For diseases, this genetic screening needs to be evaluated if cost
effective for entire populations
 If genomics affects clinical practice, must be evidence based
OPHG
 Office of Public Health Genomics
 Classifies which genetic tests if implemented properly
 Developed, maintains and updates the Genomic Applications
in Practice and Prevention Knowledge Base
http://www.cdc.gov/genomics/about/AAG/index.htm
OPGH Three-tiered Framework
 Tier 1- recommended for clinical used based
on systematic assessment and validity
 Current 47 tier on genomic applications
OPGH Three-tiered Framework
 Tier 2- May be useful for informed decision
making in clinical practice, based on
synthesized evidence of validity and
promising utility
OPGH Three-tiered Framework
 Tier 3- Not ready for clinical use due to
validity or utility not established, or
systematic assesment finding harms
outweigh benefits
 Might be candidates for population or clinical
research
What is Epigenetics?
 Something to do with:
 Genes?
 Genetics?
 Epidemiology?
 Science?
Epigenetics
 All cells in your body have the same DNA
 Why do these cells appear phenotypically different?
 “Heritable changes in gene activity that are NOT caused by
DNA sequence changes”
 DNA methylation and histone modifications
 Cellular differentiation
 Methylation of mRNA
http://www.commed.vcu.edu/Chronic_Disease/genetics/whatisepigenetics.pdf
Quiz 7
 What is the chance that a woman with a BRCA1 mutation
will develop breast cancer by age 70?
 A. 0%
 B. 20%
 C. 40%
 D. 60%
 E. 80%
Quiz 7
 What is the chance that a woman with a BRCA1 mutation
will develop breast cancer by age 70?
 A. 0%
 B. 20%
 C. 40%
 D. 60%
 E. 80%
Quiz 8
 What is the relative risk that a woman with a BRCA1
mutation will develop breast cancer before age 40?
 A. 0
 B. 1
 C. 5
 D. 10
 E. 20
Quiz 8
 What is the relative risk that a woman with a BRCA1
mutation will develop breast cancer before age 40?
 A. 0
 B. 1
 C. 5
 D. 10
 E. 20
cebp.aacrjournals.org/content/10/5/467.full
Genetic Testing
 Most Tests look at single genes and diagnose rare genetic
disorders (all listed Tier 1)
 BRCA1, BRCA2, HER2 in breast cancer
 Fragile X Syndrome
 Duchenne’s Muscular Dystrophy
 Lynch Syndrome
 Philadelphia Chromosome in leukemia
 Familial Hypercholesterolemia
Genetic Testing
 For those that can change management and increase survival,
there is obvious benefit
 What about genetic tests that exists for slowly developing
diseases with no cures?
 Huntington’s disease
 Neurodegenerative and psychiatric disease
 Symptoms begin in 40s, die in 50s
 27% attempt suicide
Quiz 9
 Which of the following are potential applications of
genomics?
 A. Individual genetic testing to identify diseases like Sickle
Cell, CF
 B. Individual genomic sequencing to identify predisposition to
diseases
 C. Individual genomic sequencing to identify predisposition to
drug side effects
 D. Individual genomic sequencing to identify better medication
for individuals
 E. All of the above
Quiz 9
 Which of the following are potential applications of
genomics?
 A. Individual genetic testing to identify diseases like Sickle
Cell, CF
 B. Individual genomic sequencing to identify predisposition to
diseases
 C. Individual genomic sequencing to identify predisposition to
drug side effects
 D. Individual genomic sequencing to identify better medication
for individuals
 E. All of the above
Translational Applications
http://www.commed.vcu.edu/Chronic_Disease/genetics/BMJ_Clinical_Review_2010.pdf
Translational Applications
http://www.commed.vcu.edu/Chronic_Disease/genetics/BMJ_Clinical_Review_2010.pdf
Translational Applications
http://www.commed.vcu.edu/Chronic_Disease/genetics/BMJ_Clinical_Review_2010.pdf
Translational Applications
http://www.ncbi.nlm.nih.gov/pubmed/21406285
Translational Applications-Gene Therapy
 Mutated gene causes expression of some diseases
 Replacing mutated gene with wild type gene would cure
disease
 Could potentially impact 1000s of diseases
 Targeted gene replacement has been difficult with little
progress over the last 20 years
Translation Applications-Gene Therapy
http://photos.the-scientist.com/legacyArticleImages/2012/06/06_12_Delivery-New-Genes.jpg
Gene Therapy-Cautionary Tales
 1999- Gene therapy trial participant with mild liver disease
caused by x-linked mutation died 4 days after gene therapy
injection from massive immune response to adenovirus
carrier
 2002- Gene therapy for SCID patients inserted improperly
close to proto-oncogene for WBCs causing leukemia in 5 of
20 patients
Gene therapy curing AIDS?
http://photos.the-scientist.com/legacyArticleImages/2012/06/06_12_MessingWithHIV.jpg
Quiz 10
 In US law, which of the following is patentable?
 A. Naturally occurring human DNA
 B. Artificially occurring DNA sequences
 C. Both
 D. Neither
Quiz 10
 In US law, which of the following is patentable?
 A. Naturally occurring human DNA
 B. Artificially occurring DNA sequences
 C. Both
 D. Neither
Quiz 11
 How much does a BRCA1 and BRCA2 test approximately
cost?
 A. $100
 B. $300
 C. $1000
 D. $3000
 E. $10000
Quiz 11
 How much does a BRCA1 and BRCA2 test approximately
cost?
 A. $100
 B. $300
 C. $1000
 D. $3000
 E. $10000
Ethics of Genomics
 Huntington’s Disease testing
 BRCA testing and impact on decision to have complete
bilateral mastectomy
 Genetic links to other diseases discovered
 Increased health insurance premiums?
 Patients give up trying to be healthy?
 Obesity as a disease
5 Recent Genomics Articles
 Is Evidence Based Medicine the enemy of Genomic




Medicine? (Feb 13, 2014)
Susceptibility to type 2 diabetes mellitus-from genes to
prevention (Feb 18, 2014)
Innovation, Risk, and Patient Empowerment: The FDAMandated Withdrawal of 23andMe’s Personal Genome
Service (Feb 26, 2014)
NCCN Updates Guidelines for Hereditary Colon Cancer
Testing (Mar 4, 2014)
Clinical Application of Whole-Genome Sequencing: Proceed
with Care (Mar 12, 2014)
Is Evidence Based Medicine the enemy
of Genomic Medicine?
 Fear about many genomics discoveries being statistically
significant but not clinically significant
 Tough to put a clinical significance on genomics research
 Many results of genomics research are personalized and do
not apply to the population as a whole
http://blogs.cdc.gov/genomics/2014/02/13/is-evidence-based/
Susceptibility to type 2 diabetes
mellitus-from genes to prevention
 65 loci credibly associated with T2DM
 Intensive lifestyle modifications can prevent T2DM even with
individuals having the highest genetic susceptibility
 Counseling patients to inform them of their genetics had no
significant impact on lifestyle changes
http://www.nature.com/nrendo/journal/v10/n4/full/nrendo.2014.11.html
Quiz 12
 Discussion- Should individual people be able to receive
copies of their genomic sequence even if this information
may not be presented in the clearest way and cause them to
make questionable decisions about their health?
Innovation, Risk, and Patient
Empowerment: The FDA-Mandated
Withdrawal of 23andMe’s Personal
Genome Service
 23andMe “helps individuals and their doctors identify health
areas that they need to keep an eye on”
 Estimates the risk 250 diseases through SNPs
 FDA asked 23andMe to cease marketing and 23andMe eventually
complied
NCCN Updates Guidelines for
Hereditary Colon Cancer Testing
 Updated guidelines:
 A recommendation that all patients who meet a five percent or
greater risk threshold for Lynch syndrome are appropriate for testing;
 A recommendation against sequential testing for the five Lynch
syndrome genes in lieu of panel testing; and
 An acknowledgement that patients with cancer can proceed directly
to sequencing tests without a complicated tissue screening algorithm.
 Myriad estimates that approximately 30 percent of newly
diagnosed colorectal cancer patients, 100 percent of newly
diagnosed endometrial cancer patients, and three percent of
asymptomatic patients will now qualify for Lynch syndrome
testing under the new medical guidelines.
http://finance.yahoo.com/news/nccn-updates-guidelines-hereditary-colon-120500779.html
Clinical Application of Whole-Genome
Sequencing: Proceed with Care
 Need sufficient power to determine clinical implications for
rarer genetic conditions
 Millions of different variations of individual genes, daunting
task to find out which are clinically significant or not
 Accuracy of making sure all 3.3 billion base pairs are
sequenced correctly
jama.jamanetwork.com/article.aspx?articleID=1840218
Future Directions
 Gene Therapy
 Genomics impact on primary care and disease susceptibility
 Genomics impact on drug prescribing
 Genomics and health data privacy
Thank You
 Questions?!?