Personalized Genomics
Overview
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Genetic testing status and prospects
Types of human variation
Detection of human genomic variation
GWAS
Nextgen sequencing
Challenges
Ethical questions
Types of Genetic Testing
• Scientific Research
– Between species: phylogenetics
– Within human species
• Medical
– Diagnostic, predictive, carrier, prenatal, newborn
• Identification: DNA Fingerprinting
– Military/large scale disasters
• Identification of remains
– Paternity
– Forensic
• Criminal investigations
• DNA Databases: UK; USA
• Exoneration of wrongfully convicted
Genetic Testing: Concerns
• Uncertainties surrounding test interpretation
-The tests give only a probability for developing
the disorder
• Lack of available medical options for some of
these diseases
• The tests' potential for provoking anxiety;
family issues
• Risks for discrimination and social stigmatization
-Legislative progress: GINA
GINA
• Genetic Information Non-discrimination
Act: Passed into law May 2008
• Prohibits group health plans and health
insurers from denying coverage to a
healthy individual or charging that person
higher premiums based solely on a genetic
predisposition to developing a disease in
the future
• Bars employers from using individuals’
genetic information when making hiring,
firing, job placement, or promotion
decisions
Nature Genetics
Genetic research on specific
human populations
• deCODE model
• Uses DNA from over
100,000 Icelandic
people
• Medical/genealogical
records date back
to 1,000 years ago
• Extensive informed
consent/privacy
measures
implemented
Process of IVF
1.
Hyper ovulation
2.
Egg Retrieval
3.
Artificial Insemination
4.
Embryo Transfer
Pre-implantation Genetic Diagnosis (PGD):
Genetic testing performed prior to embryo transfer
“The debate [around PGD]
has been building since the
late 1980s, when doctors at
London's Hammersmith
Hospital learned how to tease
a cell from a 3-day-old
embryo and study its
chromosomes for gender.”
(Zitner 2002)
•Adds $2000 to IVF
•Reduces rate of miscarriages from 23% to 10%
•Does not increase chance of pregnancy
Preimplantation Genetic Diagnosis (PGD)
• Gender selection
• Prenatal genetic diagnosis
-Spinal muscular atrophy (deletions in SMA gene)
-Huntington’s Disease
-CF: mutations that represent 75% of known CF
mutations
-Chromosomal translocations (single cell FISH)
• Future: fetal genome sequencing???
• IVF & PGD
- selection of bone marrow matched offspring
(Nash family)
- other medical/non-medical uses
(taken from Genetics and IVF Institute Website)
PGD for Family Balancing*
Preimplantation Genetic Diagnosis (PGD) may be used to
obtain cells for genetic analysis from embryos created
by in vitro fertilization (IVF). GIVF offers PGD for
gender selection for the purpose of family balancing for
couples that meet qualifying criteria. Initial
qualifications are:
•Couple is married
•Have at least one child
•Desire a child of the less represented sex of
children in the family
*italics added
DNA Testing for Forensics Applications
• CODIS (Combined DNA Index System)
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Evidence for guilt
• new: involvement of relatives
Evidence for innocence
•Innocence Project (>200 exonerations)
Genomic variation & their effects
• Single gene defects (rare)
- e.g., CF, Huntington’s
• Multigenic diseases (more common)
- e.g., diabetes, heart disease,
schizophrenia
• Non-disease conditions (all)
- enhancements: immune system, cognition,
physical ability, appearance
Direct-to-Consumer Marketing
• Companies:
– Use of genetic profiling to “guide”
diet/lifestyle
– Lack of regulation
• Research:
– Direct web-based solicitation of volunteers
with specific diseases/traits
– Avoidance of red-tape; greater scope
GAO 'Sting' 'Doesn't Bode Well' for
DTC Industry
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July 23, 2010
The United States Government Accountability Office dealt a blow
to several direct-to-consumer genetic testing firms
Issued a 33-page report outlining the group's investigation of the
"deceptive" marketing claims made by four DTC firms.
GAO team sent 10 saliva samples to each of the four companies —
not named in the report — from volunteer donors, and submitted
along with them both accurate and fictitious health information.
The GAO team received "test results that are misleading and of
little or no practical use," and found "10 egregious examples of
deceptive marketing
– including claims made by four companies that “a consumer’s
DNA could be used to create personalized supplement to cure
diseases," according to the report
– A customer service representative at one of the companies told
a GAO volunteer that "an above average risk prediction for
breast cancer meant she was 'in the high risk of pretty much
getting' the disease."
Personal Genomics: Current Status &
Prospects
• Sequencing cost and speed:
– Nextgen sequencing: advantages & limitations
– Strong motivation ($$) to get even better
• Personal Genome Project (PGP): George Church
– “Public availability” experiment
– See book: “Here is a human being” Misha Angrist
– Privacy issues:Can DNA really be “deidentified”?
• 1000 Genomes Project
– Genome sequences from different human populations:
HapMap Phase II
Personal account of personal genomics
Studies on human height
• Heritability of height is 0.8
– (80% of variation in height is due
to genetic factors)
• 3 GWAS studies genotyped 63,000
individuals at 500,000 loci (biggest
cohort analyzed to date)
• 54 loci explain ~4% of the variance.
– What explains the remaining
96%?
Lessons from GWAS for understanding
common traits or diseases
• Chip-based, not sequencing-based
• GWAS only analyzes common known variants (that
you put on the chip)
• Lander: Some regions of the genome are not
“HapMap-able”
– i.e. cannot be typed by SNP technology
• Consequence: potentially important genomic
regions are unexamined
– Also a problem for current sequencing
technology
What have GWAS studies found?
• Mostly low associations of common SNPs with
diseases/traits
– Height = 80-90% genetic  GWAS explains <5%
– Autism = 90% genetic  GWAS explains <5%
• GWAS studies have found significant
associations, with over 400 genes IDed from
different studies
– But cumulative effects of all these explain very
little phenotype variation
• Two options: GWAS missed them or they are
not there
GWAS Limitations
Missing Heritability & Strategies for
Finding the Underlying Causes of Complex
Disease
Nat Rev Gen 2010 – Eichler, et al
The Case of the Missing Heritability
Nature 2008 – Brendan Maher
Genetic Mapping in Human Disease
Science 2009 – Altschuler, Daly, Lander
G
One Possible Explanation: Non-SNP
Variants Important
• GWAS ignored all but SNPs – no structural or
copy-number variants (CNVs):
– Detection of CNVs using SNP arrays is very limited
• These have been shown important in
schizophrenia, autism, microcephaly, heart
disease…many more.
• Also, we know major genome differences
between humans (even monozygotic twins)
• Good evidence that these regions are very
dynamic, i.e. non-Mendelian
The 1,000 Genomes Project
• Currently being sequenced using 35-mer illumina
reads
• If you get a rare variant, may not be able to map
the read to the genome
- “Reference genome” vs “de novo” assembly
• Structural/CNVs –very unlikely to catch much of
these. Difficult to ID these with 35-mers…
• Strategy being explored: Read-depth
proportional to copy number (e.g. MrFast;
SUNs)
• Helped by long-read sequencing: e.g PacBio
• May only be good at catching rare SNPs or
structural variants that are small (maybe 10 or
less bp)
Structural variations among human genomes
DUF1220/NBPF Sequences & Recurrent Disease-associated 1q21.1 CNVs
A Walk Through Our Genome
--All regions of the genome are not created equal
“Good genes & bad genes”: the value of a
gene/allele is context-dependent
• Effect on the individual
-extensive/some/no knowledge
• Genetic background of the individual
-between 2 individuals, 1 change every 1,000 bp
-99.9% identical = 3 million DNA differences
• Environment
-geographic (e.g. malarial region or not)
-social issues (culture, customs, laws)
-medical (status of non-genetic interventions
e.g., PKU vs. HD)
• Effect on the species
-homogeneity vs. diversity
Good genes and bad genes (cont.)
• Example of a good gene:
- the globin gene variant that, when
heterozygous, protects against malaria
• Example of a bad gene:
-the globin gene variant that, when
homozygous, produces sickle-cell
anemia
-they are the same gene!
Coming DNA Attractions
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The $1,000 genome
“Personalized Medicine”
Reading your own genome
Tracing the evolution of the human genome
“Evolutionary Genomics”
What genes made us human?
– “Evolutionary Neurogenomics”
What are the genomic changes that underlie
the evolutionarily unique capacities of the
human brain?
-New way to study human brain function
Many, many, many more A’s, C’s, G’s and T’s
Graduate Studies in
Evolutionary Genomics?
• “It's money and adventure and fame.
It's the thrill of a lifetime”
– Carl Denham from “King Kong” (1933)
King Kong (1933)