Download 5% “T” - The Sackler Institutes

John Merck Fund Summer Institute
on the Biology of Developmental Disabilities
Genetics Workshop
John Fossella, PhD
Sackler Institute
Tool #1: Genome Sequence Databases
The Human Genome Project
TIGR: 1 microbe per day:
Sargasso Sea
Tool #2: Human Genome Variation Databases
Patient Group
….AGTGTTCGATAGCTGTTGAC
ATGATCGCTGTCGCTAATCTCG
CTACACACACCACAGAATGACA
ATGATCGCTGTCGCTAATCTCT
TTTCATAGACCACAGATTGACC
ATGATCGCAGTCGCAGATCTCT
CTTCATAGAGCACAGATCGACT
ATGATCGCTGTCTCTAATCTCT
TTCACATAGATCGAGATGGACA
ATGATCGCTGAAGCTAATCTCT
CGGCTTAGATCACAGATTGACA
GTGATCGCTGTTGCTAATCTCT
CTACCATAGATCACAGACTGAA
GATCGCTCGATAGAAGAT…….
Control Group
….AGTGTTCGATAGCTGTTGAC
ATGATCGCTGTCGCTAATCTCG
CTTCATAGATCACAGAATGACA
ATGATCGCTGTCGCTAATCTCT
TTTCATAGACCACAGATTGACC
ATGATCGCAGTCGCTAATCTCT
CTTCATAGAGCACAGATCGACT
ATGATCGCTGTCTCTAATCTCT
TTCACATAGATCGAGATGGACA
ATGATCGCTGAAGCTAATCTCT
CGGCATAGATCACAGATTGACA
GTGATCGCTGTTGCTAATCTCT
CTACCATAGATCACAGACTGAA
GATCGCTCGATAGAAGAT…….
Tool #3: Genetic Origins of Psychopathology
Neuregulin
RGS4
Neuroligin
5HTT
Calcineurin
DYX1C1
DRD4
FMRP
MAOA
GPR56
–Schizophrenia
-Schizophrenia
-Autism
-Anxiety, Depression
-Schizophrenia
–Reading disorder
–ADHD
-Fragile X
–Aggression
-Frontal cortex structure
Tool #4: Brain Gene Expression Databases
Tool #5: Mouse Models of
Brain Development and Behavior
QuickTime™ and a
Photo - JPEG decompressor
are needed to see this picture.
“The LIMhomeobox gene
Lhx8 is required
for the
development of
many cholinergic
neurons in the
mouse forebrain”
Zhao et al. (2003)
PNAS 100 (15) pp.
9005-9010
Tool #6: High Throughput Genotyping
The Scientist
Volume 17, June 2003
Whole-Genome
SNP Genotyping
Four highly parallel approaches make
the technically intractable a reality
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
Hariri et al., (2002) Science
QuickTi me™ and a
TIFF ( Uncompressed) decompressor
are needed to see thi s pi ctur e.
There are many issues to consider
When designing a behavioral or imaging-genetics study:
What phenotype(s) ?
a chance to integrate multiple levels of analysis
 Population Structure & Study design ?
families, volunteers & patients
What genetic markers or candidate genes ?
biological pathways
Genotyping technology
cost & convenience
Statistical analysis and reporting of data
statistical nightmare, biology can light the way
A few grant writing and IRB issues
Goal of the Genetics Workshop:
Impart an understanding of:
1.
2.
3.
4.
5.
The molecular nature of DNA
Of the structure of a gene & genome
Of variation in the genome
Of the historical origins of variation
How 1-5 are used in the design of studies
The molecular structure of DNA
How many bases ?
How many genes ?
How many variable sites ?
Goal of the Genetics Workshop:
Impart an understanding of:
1.
2.
3.
4.
5.
The molecular nature of DNA
Of the structure of a gene & genome
Of variation in the genome
Of the historical origins of variation
How 1-5 are used in the design of studies
What is a gene ?
The Central Dogma
Goal of the Genetics Workshop:
Impart an understanding of:
1.
2.
3.
4.
5.
The molecular nature of DNA
Of the structure of a gene & genome
Of variation in the genome
Of the historical origins of variation
How 1-5 are used in the design of studies
3 million polymorphic sites
Single Nucleotide Polymorphisms (SNPs)
…AGTTCGATTGCTCGATAGCACGAT…
…AGTTCAATTGCTTGATAGCACGAT…
…AGTTCGATTGCTTGATAGCTCGAT…
Repeats
…AGTTCAATTGCTTGATAGCGCGAT…
…AGTTCAATTGCTTGCTTGCTTGATAGCGCGAT…
Deletions
…AGTTCAATTGATAGCGCGAT…
Protein Structure Polymorphisms
Polymorphisms in the DRD4 gene
Glu
CB1, BDNF
D2short
DRD4
mGlu
MAOA
DA
MAOA
COMT
DA facilitates
NMDA and
Ca++ influx
(permits weight change)
DA Receptor
G-protein
Beta-arrestin
Protein Structure
Valine / Methionine Polymorphisms in the COMT gene
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Gene Regulation Polymorphisms
5HTT “long” allele
lower 5HT
5HTT “short” allele
higher 5HT
Why are carriers of the 5HTT “short” allele
more susceptible to affective disorders ?
Goal of the Genetics Workshop:
Impart an understanding of:
1.
2.
3.
4.
5.
The molecular nature of DNA
Of the structure of a gene & genome
Of variation in the genome
Of the historical origins of variation
How 1-5 are used in the design of studies
3 million polymorphic sites
Single Nucleotide Polymorphisms (SNPs)
…AGTTCGATTGCTCGATAGCACGAT…
…AGTTCAATTGCTTGATAGCACGAT…
…AGTTCGATTGCTTGATAGCTCGAT…
Repeats
…AGTTCAATTGCTTGATAGCGCGAT…
…AGTTCAATTGCTTGCTTGCTTGATAGCGCGAT…
Deletions
…AGTTCAATTGATAGCGCGAT…
DNA Replication
“Mistakes”
The collection of “mistakes” is an history book of evolution
Human
Bonobo
Chimpanzee
GTGATGAC GTGCTGAC GTGCTGAC
C to A
change
T to C change
A to G change
Gorilla
GTGCTGAT
Orangutan
ATGCTGAT
“Mitochondrial Eve”
& Y-chromosomal Adam








Goal of the Genetics Workshop:
Impart an understanding of:
1.
2.
3.
4.
5.
The molecular nature of DNA
Of the structure of a gene & genome
Of variation in the genome
Of the historical origins of variation
How 1-5 are used in the design of studies
Efficient Executive Attention Group
….AGTGTTCGATAGCTGTTGAC
ATGATCGCTGTCGCTAATCTCG
CTACACACACCACAGAATGACA
ATGATCGCTGTCGCTAATCTCT
TTTCATAGACCACAGATTGACC
ATGATCGCAGTCGCAGATCTCT
CTTCATAGAGCACAGATCGACT
ATGATCGCTGTCTCTAATCTCT
TTCACATAGATCGAGATGGACA
ATGATCGCTGAAGCTAATCTCT
CGGCTTAGATCACAGATTGACA
GTGATCGCTGTTGCTAATCTCT
CTACCATAGATCACAGACTGAA
GATCGCTCGATAGAAGAT…….
Poor Executive Attention Group
….AGTGTTCGATAGCTGTTGAC
ATGATCGCTGTCGCTAATCTCG
CTTCATAGATCACAGAATGACA
ATGATCGCTGTCGCTAATCTCT
TTTCATAGACCACAGATTGACC
ATGATCGCAGTCGCTAATCTCT
CTTCATAGAGCACAGATCGACT
ATGATCGCTGTCTCTAATCTCT
TTCACATAGATCGAGATGGACA
ATGATCGCTGAAGCTAATCTCT
CGGCATAGATCACAGATTGACA
GTGATCGCTGTTGCTAATCTCT
CTACCATAGATCACAGACTGAA
GATCGCTCGATAGAAGAT…….
How do we know that the yellow T influences variation in executive attention ?
Pedigree, family-based design
“T”
Case-control design: Qualitative trait
5% “T”
60% “T”
Efficient Executive Attention Group
Poor Executive Attention Group
Case-control design: Qualitative trait
5% “T”
60% “T”
Efficient Executive Attention Group
Poor Executive Attention Group
Case-control design: Qualitative trait
5% “T”
60% “T”
Efficient Chopstick Dexterity Group
Poor Chopstick Dexterity Group
Allele “T”
Case-control design: Quantitative trait
Allele 1
Asian
Non-asian
Attentional Efficiency
Allele “T”
Case-control design: Quantitative trait
Allele 1
Asian
Non-asian
Dexterity with chopsticks
(rare) between group vs.
(abundant) within group variation
There are many issues to consider
When designing a behavioral or imaging-genetics study:
What phenotype(s) ?
a chance to integrate multiple levels of analysis
 Population Structure & Study design ?
twins, families, volunteers & patients
What genetic markers or candidate genes ?
biological pathways
Genotyping technology
cost & convenience
Statistical analysis and reporting of data
statistical nightmare, biology can light the way
A few grant writing and IRB issues
Roche Genetics Education Online Course
http://www.roche.com/home/science/sci_gengen/sci_gengen_cdrom/sci_gengen_cdrom_online.htm
National Genographic’s Genographic Project
https://www5.nationalgeographic.com/genographic/atlas.html