John Merck Fund Summer Institute

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John Merck Fund Summer Institute on the Biology
of Developmental Disabilities Genetics
Workshop John Fossella, PhD Sackler Institute
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Tool 1 Genome Sequence Databases
The Human Genome Project
TIGR 1 microbe per day Sargasso Sea
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Tool 2 Human Genome Variation Databases
Patient Group
Control Group
.AGTGTTCGATAGCTGTTGAC ATGATCGCTGTCGCTAATCTCG CTAC
ACACACCACAGAATGACA ATGATCGCTGTCGCTAATCTCT TTTCATAG
ACCACAGATTGACC ATGATCGCAGTCGCAGATCTCT CTTCATAGAGC
ACAGATCGACT ATGATCGCTGTCTCTAATCTCT TTCACATAGATCGA
GATGGACA ATGATCGCTGAAGCTAATCTCT CGGCTTAGATCACAGAT
TGACA GTGATCGCTGTTGCTAATCTCT CTACCATAGATCACAGACTG
AA GATCGCTCGATAGAAGAT.
.AGTGTTCGATAGCTGTTGAC ATGATCGCTGTCGCTAATCTCG CTTC
ATAGATCACAGAATGACA ATGATCGCTGTCGCTAATCTCT TTTCATAG
ACCACAGATTGACC ATGATCGCAGTCGCTAATCTCT CTTCATAGAGC
ACAGATCGACT ATGATCGCTGTCTCTAATCTCT TTCACATAGATCGA
GATGGACA ATGATCGCTGAAGCTAATCTCT CGGCATAGATCACAGAT
TGACA GTGATCGCTGTTGCTAATCTCT CTACCATAGATCACAGACTG
AA GATCGCTCGATAGAAGAT.
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Tool 3 Genetic Origins of Psychopathology
Neuregulin Schizophrenia RGS4
-Schizophrenia Neuroligin -Autism 5HTT -Anxiety
, Depression Calcineurin -Schizophrenia DYX1C1
Reading disorder DRD4 ADHD FMRP -Fragile
X MAOA Aggression GPR56 -Frontal cortex
structure
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Tool 4 Brain Gene Expression Databases
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Tool 5 Mouse Models of Brain Development and
Behavior
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
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Tool 6 High Throughput Genotyping
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(No Transcript)
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(No Transcript)
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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
?
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• Goal of the Genetics Workshop
• Impart an understanding of
• 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

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The molecular structure of DNA
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How many bases ? How many genes ? How many
variable sites ?
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• Goal of the Genetics Workshop
• Impart an understanding of
• 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

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What is a gene ?
The Central Dogma
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• Goal of the Genetics Workshop
• Impart an understanding of
• 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

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3 million polymorphic sites
Single Nucleotide Polymorphisms (SNPs)
AGTTCGATTGCTCGATAGCACGAT AGTTCAATTGCTTGATAGCAC
GAT AGTTCGATTGCTTGATAGCTCGAT
Repeats AGTTCAATTGCTTGATAGCGCGAT AGTTCAATTGCTTG
CTTGCTTGATAGCGCGAT Deletions AGTTCAATTGATAGCGCG
AT
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Protein Structure Polymorphisms Polymorphisms in
the DRD4 gene
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Glu
CB1, BDNF
D2short
DRD4
mGlu
MAOA
DA
MAOA
DA facilitates NMDA and Ca influx (permits
weight change)
COMT
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DA Receptor
G-protein
Beta-arrestin
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Protein Structure Valine / Methionine
Polymorphisms in the COMT gene
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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 ?
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• Goal of the Genetics Workshop
• Impart an understanding of
• 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

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3 million polymorphic sites
Single Nucleotide Polymorphisms (SNPs)
AGTTCGATTGCTCGATAGCACGAT AGTTCAATTGCTTGATAGCAC
GAT AGTTCGATTGCTTGATAGCTCGAT
Repeats AGTTCAATTGCTTGATAGCGCGAT AGTTCAATTGCTTG
CTTGCTTGATAGCGCGAT Deletions AGTTCAATTGATAGCGCG
AT
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DNA Replication
Mistakes
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(No Transcript)
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The collection of mistakes is an history book
of evolution
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Mitochondrial Eve Y-chromosomal Adam
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?
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?
?
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?
?
?
?
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• Goal of the Genetics Workshop
• Impart an understanding of
• 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

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Efficient Executive Attention Group
Poor Executive Attention Group
.AGTGTTCGATAGCTGTTGAC ATGATCGCTGTCGCTAATCTCG CTAC
ACACACCACAGAATGACA ATGATCGCTGTCGCTAATCTCT TTTCATAG
ACCACAGATTGACC ATGATCGCAGTCGCAGATCTCT CTTCATAGAGC
ACAGATCGACT ATGATCGCTGTCTCTAATCTCT TTCACATAGATCGA
GATGGACA ATGATCGCTGAAGCTAATCTCT CGGCTTAGATCACAGAT
TGACA GTGATCGCTGTTGCTAATCTCT CTACCATAGATCACAGACTG
AA GATCGCTCGATAGAAGAT.
.AGTGTTCGATAGCTGTTGAC ATGATCGCTGTCGCTAATCTCG CTTC
ATAGATCACAGAATGACA ATGATCGCTGTCGCTAATCTCT TTTCATAG
ACCACAGATTGACC ATGATCGCAGTCGCTAATCTCT CTTCATAGAGC
ACAGATCGACT ATGATCGCTGTCTCTAATCTCT TTCACATAGATCGA
GATGGACA ATGATCGCTGAAGCTAATCTCT CGGCATAGATCACAGAT
TGACA GTGATCGCTGTTGCTAATCTCT CTACCATAGATCACAGACTG
AA GATCGCTCGATAGAAGAT.
How do we know that the yellow T influences
variation in executive attention ?
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Pedigree, family-based design
T
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Case-control design Qualitative trait
5 T
60 T
Efficient Executive Attention Group
Poor Executive Attention Group
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Case-control design Qualitative trait
5 T
60 T
Efficient Executive Attention Group
Poor Executive Attention Group
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Case-control design Qualitative trait
5 T
60 T
Efficient Chopstick Dexterity Group
Poor Chopstick Dexterity Group
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Case-control design Quantitative trait
Allele T
Allele 1
Attentional Efficiency
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Case-control design Quantitative trait
Allele T
Allele 1
Dexterity with chopsticks
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(rare) between group vs. (abundant) within group
variation
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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
?
41
Roche Genetics Education Online Course
http//www.roche.com/home/science/sci_gengen/sci_g
engen_cdrom/sci_gengen_cdrom_online.htm
National Genographics Genographic Project
https//www5.nationalgeographic.com/genographic/at
las.html