Download From genes to traits and back again

From genes to traits and
back again
Yaniv Erlich
Courtesy “Inside Out”
@erlichya
How do we know if a trait has a genetic basis?
Options:
1.  Clustering is due to chance
2.  Clustering is due to shared
environment
3.  Clustering is due to a genetic
component
How can we do that?
Heritability: “a measure of the contribution of genes to a trait”
How to measure heritability? Twin studies
-
2*
Identical twins
=
Heritability
Non-identical twin
Genetic variants explain 80% of height variability
Results of complex traits
Disease/Trait
Heritability
Alzheimer
70%
Asthma
30%
Depression
50%
Heart disease
45%
Hypertension
30%
Height
81%
IQ
82%
IQ and heritability
Jensen: If 82% of IQ is
determined by genes,
what is the value of
large investments in the
education system?
Harvard Educational Review, 1969
Genetic determinism = pseudoscience
Heritability: “a measure of the contribution of genes to a trait”
Heritability is measured for a given environment
80
Longevity is 20% heritable.
Yet, environmental changes (antibiotics,
bypass surgeries, sanitation) totally
transformed this trait.
Longevity
75
70
65
60
55
50
45
1840
1890
1940
1990
Year of death
Genes encode options not traits
Environment
Regular diet
PKU
Mental retardation
Phenylketonuria
Phe-restricted diet
PKU
Healthy life
Outline – finding genes
Mendelian
disorders
Complex
traits
Mendelian disorders
Prenatal carrier screens
Carrier couple
No
Carrier
Carriers
Affected
Predating carrier screens
Genetic Disorder
Carrier
rate
Tay-Sachs
1:25
Cystic Fibrosis
1:30
Familial
Dysautonomia
1:30
Usher Syndrome
1:40
Canavan
1:40
Glycogen Storage
1:71
Fanconi Anemia C
1:80
Niemann-Pick
1:80
Mucolipidosis type 4
1:100
Bloom Syndrome
1:102
Nemaline Myopathy
1:108
The main question
Did we test for
all the
mutations?
Finding the causative
mutation of Joubert
Syndrome
(In collaboration with Hadassah
Medical Center and Dor Yeshorim)
What is Joubert Syndrome?
•  The disease affects the entire body:
- Pyschomotor retardation and hyptonia
- Extra digits in upper and lower limbs (sometimes)
- Lazy eye
- Renal insufficiency
The cases
• 
Dor-Yeshorim identified 13 cases in 8 Ashkenazi families
•  Three families are part of the same clan.
•  Founder mutation
•  Social implications
The scale of the problem
3 billion
2 billion
300 million
100 million
3 million
The question
quickly
How to find a serial murderer in a country of 3 billion people?
Intro.
Human genetics
Pooling
Bacteria Experiment
Human Experiment
Huge throughput sequencing
Sequencing costs
10 cents / million bp!
Introduction
Joubert syndrome
Genetic investigation
Success!
Future directions
Investigation – initial steps
Check known ex-convicts
9 genes are known to cause Joubert. All of them where
normal in the affected children.
Narrow down the geographical location
Hadassah suspected the mutation is in chr. 11
Investigation – cont
Prepare a list of suspects from the region and interrogate
them
Sequence gene by gene in the region and check for
mutations
Problem: it takes A LOT OF TIME
Our approach
•  We will sequence every possible gene in the
genome.
•  A process that takes two weeks and $1000 per sample
•  Sequencing a mother (carrier) and affected daughter
Looking for: Recessive & Harmful & Rare mutation
Elimination of suspects:
# suspects
Mutation in:
Mother
49,515
Child
48,142
Shared mutations
23,986
Recessive pattern
2,541
And not in previous databases (rare)
Changing the gene
And are in Chr. 11
A single base substitution in TMEM216
105
39
1
Where is the mutation?
Chromosome 11
Amino-acid change: Arg -> Leu
(CGC>CTC)
Single mutation!
G
G is the normal DNA
The individual
has a mutation in
the position
Joubert syndrome
Additional lines of evidence
• Hadassah found the same mutation (double blind)
- Found in all 13 cases and parents found as carriers.
- Carrier rate in Ashkenazi is 1:92
From: Elpeleg Orly
Sent: Sun 12/6/2009 11:56 PM
To: Erlich, Yaniv
Subject: RE: Preliminary analysis
BINGO
________________________________________
From: Erlich, Yaniv [[email protected]]
Sent: Sun 12/6/2009 23:32
To: Elpeleg Orly
Subject: Preliminary analysis
Hi Orly,
The only potential homozygous SNP mutation we found on chr11 between 59.5M-62M that
is not in dbSNP and has an affect on the protein (missense, nonsense, splice) is
TMEM216 Arg12->Leu (chr11:60918013).
Are we right?
Thanks,
Yaniv
Impact
The Israeli Ministry of Health include the
Joubert mutation in the recommended panel
of pre-natal screens.
“Happy families are all
alike; every unhappy
family is unhappy in its
own way”(Leo Tolstoy)
Outline
Mendelian
disorders
Complex
traits
Complex traits
How to map complex
traits?
The architecture of complex traits
How can genes create such phenotypes?
1 gene
Height
2 genes
Many genes
3 genes
Plomin et al, 2009
How to find mutations of complex traits?
Phenotype
A – Wild Type
B – Mutation
Genome-wide association
studies
AA
AB
BB
Genotype
Linear regression on each mutation:
Null hypothesis: slope = 0
Alternative hypothesis: slope ≠ 0
Results of Genome Wide Association Study of Systemic
Scleroderma
Radstake et al, 2010
On a search for common genetic variants
•  Genome Wide Association Studies (GWAS) aim to scan common variants.
•  Almost 1000 studies have conducted on every possible major condition
NIH/NHGRI catalog of GWAS studies
A long way to go…
A study with 200,000 participants
Common genetic variants
explain only 10% of height
variability