John Merck Fund Summer Institute on the Biology of Developmental Disabilities Genetics Workshop
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John Merck Fund Summer Institute on the Biology of Developmental Disabilities Genetics Workshop John Fossella, PhD Sackler Institute
description
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. - PowerPoint PPT Presentation
Transcript of John Merck Fund Summer Institute on the Biology of Developmental Disabilities Genetics Workshop
John Merck Fund Summer Instituteon the Biology of Developmental Disabilities
Genetics Workshop
John Fossella, PhDSackler Institute
The Human Genome Project
TIGR: 1 microbe per day:Sargasso Sea
Tool #1: Genome Sequence DatabasesTool #1: Genome Sequence Databases
Tool #2: Human Genome Variation DatabasesTool #2: Human Genome Variation Databases
….AGTGTTCGATAGCTGTTGACATGATCGCTGTCGCTAATCTCGCTACACACACCACAGAATGACAATGATCGCTGTCGCTAATCTCTTTTCATAGACCACAGATTGACC ATGATCGCAGTCGCAGATCTCTCTTCATAGAGCACAGATCGACT ATGATCGCTGTCTCTAATCTCTTTCACATAGATCGAGATGGACA ATGATCGCTGAAGCTAATCTCTCGGCTTAGATCACAGATTGACA GTGATCGCTGTTGCTAATCTCTCTACCATAGATCACAGACTGAA GATCGCTCGATAGAAGAT…….
….AGTGTTCGATAGCTGTTGACATGATCGCTGTCGCTAATCTCGCTTCATAGATCACAGAATGACAATGATCGCTGTCGCTAATCTCTTTTCATAGACCACAGATTGACC ATGATCGCAGTCGCTAATCTCTCTTCATAGAGCACAGATCGACT ATGATCGCTGTCTCTAATCTCTTTCACATAGATCGAGATGGACA ATGATCGCTGAAGCTAATCTCTCGGCATAGATCACAGATTGACA GTGATCGCTGTTGCTAATCTCTCTACCATAGATCACAGACTGAA GATCGCTCGATAGAAGAT…….
Patient Group Control Group
Neuregulin –SchizophreniaRGS4 -SchizophreniaNeuroligin -Autism5HTT -Anxiety, DepressionCalcineurin -SchizophreniaDYX1C1 –Reading disorderDRD4 –ADHDFMRP -Fragile XMAOA –AggressionGPR56 -Frontal cortex structure
Tool #3: Genetic Origins of PsychopathologyTool #3: Genetic Origins of Psychopathology
Tool #4: Brain Gene Expression DatabasesTool #4: Brain Gene Expression Databases
Tool #5: Mouse Models of Tool #5: Mouse Models of Brain Development and BehaviorBrain Development and Behavior
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“The LIM-homeobox 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
The ScientistVolume 17, June 2003
Whole-Genome SNP Genotyping
Four highly parallel approaches make the technically intractable a reality
Tool #6: High Throughput GenotypingTool #6: High Throughput Genotyping
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There are many issues to consider There are many issues to consider When designing a behavioral or imaging-genetics study:When designing a behavioral or imaging-genetics study:
What phenotype(s) ?What phenotype(s) ?a chance to integrate multiple levels of analysisa chance to integrate multiple levels of analysis
Population Structure & Study design ?Population Structure & Study design ?families, volunteers & patientsfamilies, volunteers & patients
What genetic markers or candidate genes ?What genetic markers or candidate genes ?biological pathwaysbiological pathways
Genotyping technologyGenotyping technologycost & conveniencecost & convenience
Statistical analysis and reporting of dataStatistical analysis and reporting of datastatistical nightmare, biology can light the waystatistical nightmare, biology can light the way
A few grant writing and IRB issuesA few grant writing and IRB issues
Goal of the Genetics Workshop:
Impart an understanding of:
1. The molecular nature of DNA2. Of the structure of a gene & genome3. Of variation in the genome4. Of the historical origins of variation5. 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. The molecular nature of DNA2. Of the structure of a gene & genome3. Of variation in the genome4. Of the historical origins of variation5. 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. The molecular nature of DNA2. Of the structure of a gene & genome3. Of variation in the genome4. Of the historical origins of variation5. How 1-5 are used in the design of studies
Single Nucleotide Polymorphisms (SNPs) …AGTTCGATTGCTCGATAGCACGAT……AGTTCAATTGCTTGATAGCACGAT……AGTTCGATTGCTTGATAGCTCGAT…
Repeats…AGTTCAATTGCTTGATAGCGCGAT…
…AGTTCAATTGCTTGCTTGCTTGATAGCGCGAT…
Deletions…AGTTCAATTGATAGCGCGAT…
3 million polymorphic sites
Protein Structure PolymorphismsPolymorphisms in the DRD4 gene
DRD4
DA facilitatesNMDA and Ca++ influx
(permits weight change)
DA
Glu
CB1, BDNF
mGlu
D2short
MAOA
MAOA
COMT
DA Receptor
G-protein Beta-arrestin
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Protein StructureProtein StructureValine / Methionine Polymorphisms in the COMT gene
Gene Regulation Polymorphisms
5HTT “long” allele lower 5HT
5HTT “short” allelehigher 5HT
Why are carriers of the 5HTT “short” allele more susceptible to affective disorders ?
Goal of the Genetics Workshop:
Impart an understanding of:
1. The molecular nature of DNA2. Of the structure of a gene & genome3. Of variation in the genome4. Of the historical origins of variation5. How 1-5 are used in the design of studies
Single Nucleotide Polymorphisms (SNPs) …AGTTCGATTGCTCGATAGCACGAT……AGTTCAATTGCTTGATAGCACGAT……AGTTCGATTGCTTGATAGCTCGAT…
Repeats…AGTTCAATTGCTTGATAGCGCGAT…
…AGTTCAATTGCTTGCTTGCTTGATAGCGCGAT…
Deletions…AGTTCAATTGATAGCGCGAT…
3 million polymorphic sites
DNA ReplicationDNA Replication
“Mistakes”
HumanGTGATGAC
BonoboGTGCTGAC
ChimpanzeeGTGCTGAC
GorillaGTGCTGAT
OrangutanATGCTGAT
A to G change
T to C change
C to Achange
The collection of “mistakes” is an history book of evolution
“Mitochondrial Eve”& Y-chromosomal Adam
Goal of the Genetics Workshop:
Impart an understanding of:
1. The molecular nature of DNA2. Of the structure of a gene & genome3. Of variation in the genome4. Of the historical origins of variation5. How 1-5 are used in the design of studies
….AGTGTTCGATAGCTGTTGACATGATCGCTGTCGCTAATCTCGCTACACACACCACAGAATGACAATGATCGCTGTCGCTAATCTCTTTTCATAGACCACAGATTGACC ATGATCGCAGTCGCAGATCTCTCTTCATAGAGCACAGATCGACT ATGATCGCTGTCTCTAATCTCTTTCACATAGATCGAGATGGACA ATGATCGCTGAAGCTAATCTCT
CGGCTTAGATCACAGATTGACA GTGATCGCTGTTGCTAATCTCTCTACCATAGATCACAGACTGAA GATCGCTCGATAGAAGAT…….
….AGTGTTCGATAGCTGTTGACATGATCGCTGTCGCTAATCTCGCTTCATAGATCACAGAATGACAATGATCGCTGTCGCTAATCTCTTTTCATAGACCACAGATTGACC ATGATCGCAGTCGCTAATCTCTCTTCATAGAGCACAGATCGACT ATGATCGCTGTCTCTAATCTCTTTCACATAGATCGAGATGGACA ATGATCGCTGAAGCTAATCTCTCGGCATAGATCACAGATTGACA GTGATCGCTGTTGCTAATCTCTCTACCATAGATCACAGACTGAA GATCGCTCGATAGAAGAT…….
Efficient Executive Attention Group Poor Executive Attention Group
How do we know that the yellow T influences variation in executive attention ?
“T”
Pedigree, family-based design
Efficient Executive Attention Group Poor Executive Attention Group
60% “T”
5% “T”
Case-control design: Qualitative trait
Efficient Executive Attention Group Poor Executive Attention Group
60% “T”
5% “T”
Case-control design: Qualitative trait
Efficient Chopstick Dexterity Group Poor Chopstick Dexterity Group
60% “T”
5% “T”
Case-control design: Qualitative trait
All
ele
1A
llel
e “T
”
Attentional Efficiency
Asian
Non-asian
Case-control design: Quantitative trait
All
ele
1A
llel
e “T
”
Dexterity with chopsticks
Asian
Non-asian
Case-control design: Quantitative trait
(rare) between group vs. (abundant) within group variation
There are many issues to consider There are many issues to consider When designing a behavioral or imaging-genetics study:When designing a behavioral or imaging-genetics study:
What phenotype(s) ?What phenotype(s) ?a chance to integrate multiple levels of analysisa chance to integrate multiple levels of analysis
Population Structure & Study design ?Population Structure & Study design ?twins, families, volunteers & patientstwins, families, volunteers & patients
What genetic markers or candidate genes ?What genetic markers or candidate genes ?biological pathwaysbiological pathways
Genotyping technologyGenotyping technologycost & conveniencecost & convenience
Statistical analysis and reporting of dataStatistical analysis and reporting of datastatistical nightmare, biology can light the waystatistical nightmare, biology can light the way
A few grant writing and IRB issuesA few grant writing and IRB issues
http://www.roche.com/home/science/sci_gengen/sci_gengen_cdrom/sci_gengen_cdrom_online.htm
Roche Genetics Education Online Course
https://www5.nationalgeographic.com/genographic/atlas.html
National Genographic’s Genographic Project
