Transcript teach-eng-mod2

Twin Studies
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Dissecting Genetic Vs
Environmental Effects
• Identical twins have identical
DNA, while dizygotic twins share
50% of their DNA
• If schizophrenia were completely
genetic, concordance rates in
MZ:DZ twins would be 100:50%,
or 2:1
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Twins: Summary of Nine
Studies
• MZ twins have a 53% concordance
rate, as compared to 15% in DZ
twins
• Approximately 70% of the liability
to develop schizophrenia is due to
nongenetic factors
• Environmental factors play a
crucial role in etiology
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Adoption Studies
• Unconfound genes and
environment by measuring
prevalence in adopted offspring
of schizophrenic mothers, as
compared to normal mothers
• Both groups are raised by
normal parents
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Adoption Studies:
Results
• Heston: 16.6% schizophrenia in
children of ill mothers, 0% for
normal mothers
• Kety: 32% schizophrenia in
children of ill mothers, 18% for
normal mothers (this study used
a relatively broader definition of
illness)
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A
st
21
Century View of
Genetics
• No longer sees “genes” as static or simple
phenomena
• Genes interact dynamically with one
another and with cellular and extracellular
components to regulate body and brain
functions
• Genes turn on and off (“are expressed”)
• Regulation of gene expression may be as
important a contributor to disease risk as
genes alone
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Genes: Some Simple
Concepts
• Gene: a section of DNA that codes for the
RNA that produces protein products
• Regulatory genes: genes that determine
when proteins will be produced
• Gene expression: the process of turning
on genes so that they will become active
• Disease risk genes: genes that contain a
variation in DNA that leads to a change in
gene function that contributes to disease
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The Six Steps in
Understanding Disease Genes
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Finding or locating
Cloning
Sequencing
Identifying the product
Identifying the function
Identifying how DNA variation in
the gene contributes to disease
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Linkage Studies
• Also called “reverse genetics,” since
they assume no prior knowledge of
disease mechanism
• DNA from affected families is used
to identify genetic markers (I.e.,
relatively large chromosomal
regions) that segregate in ill family
members
• The linkage points to the locations of
a disease genes (chromosomal
susceptibility loci)
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Some Chromosomal
Susceptibility Loci with
Several Replications
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1q21-q22
6q21-q22
8q21-q22
However, findings come and go
as larger samples are studied
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Candidate Gene Approaches
• “Forward genetics”
• Begin with genes hypothesized to be
related to the disease mechanism
(e.g., neurotransmitters, receptors,
regulators of brain development)
• Can be studied either in affected
families or in transgenic mice
(“knockout” or “knock-in”)
• Method is handicapped by the large
number of possible candidates that
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can be studied
The Human Genome Project
• Provides a reference sequence of 3 billion
base pairs
• Has identified important markers of genetic
diversity that may have relevance for
finding disease markers: SNPs
• SNPs (“snips”): single nucleotide
polymorphisms, or mutations in a single
nucleotide, which may be associated with
predisposition to a given disease (e.g., the
APOe4 allele and Alzheimer’s disease)
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Gene Mutations
• Occur spontaneously during the
process of DNA replication
• May also be induced by exogenous
sources (e.g., radiation)
• Most are corrected (eliminated) when
they occur
• Some persist and may lead to disease
(e.g., cancer)
• Some may persist and serve as markers
of genetic variation (e.g. SNPS)
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Genes and Environment
• A false dichotomy
• Environmental factors influence genes
– mutations, stress and endocrine
regulation, viruses, etc
• Genes create a blueprint, but a gene
must be “turned on” (I.e., be
“expressed”) to exert its influence
• We can potentially prevent diseases by
stopping the expression of “bad
genes”
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A Genetically Complex Illness
• A “complex” disorder, probably caused
by multiple genes, each of which has a
small effect
• A genetic predisposition may be
released by nongenetic
(environmental) triggers, such as
difficult labor, infections, subtle brain
injuries, toxins, etc
• “Multiple hits” are probably required,
with those affecting adolescent brain
development being most important WPA
How Do We Define the
Phenotype?
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Clinical symptoms?
Characteristic course and outcome?
Cognitive deficits?
Endophenotypic markers
This (clinical!) question is perhaps
the most important issue in 21st
century genetics
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Can We Find a
Pathological Marker?
• Should it be present in all cases?
• The majority of cases?
• Only present as a group
difference?
• Specific to schizophrenia?
• Also present in unaffected family
members?
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What Does the Marker
Mark?
• Vulnerability to develop the
disorder?
• Subthreshold forms of the
disorder?
• The endophenotype?
• The expressed phenotype?
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Some Candidate Markers
• Eye tracking abnormalities
• Impaired prepulse inhibition
• Backward masking
abnormalities
• Eyeblink conditioning
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