Download 17 Greenough-Behavior Genetics 2006

Behavioral Genetics
A bridge between the Neuro and Genetics
courses
Behavioral Genetics
Many news sources are filled of late with
evidence (some of it pretty good, but
needing careful interpretation) for genes that
determine or affect certain behavioral
abilities.
It is clear that aspects of many
behaviors and behavioral abilities
are influenced by one’s genetic
makeup. One sees this in a broad
array of aspects of life: often,
when presented with
extraordinary talent, we just
assume “it must be genetic!”
In addition, as our knowledge of
molecular genetics has grown,
possibly so has our ability to
attribute differences in behavior
to genetic influences
Scientists create a genetically engineered 'smart mouse'
September 1, 1999
PRINCETON, New Jersey (CNN) -- Can intelligence and memory be genetically
enhanced? Princeton University scientists say the answer is yes, at least in mice.
Research published in this week's edition of the journal Nature suggests similar
processes may one day be used to boost human intelligence and memory, though
such applications are still far from reality.
Princeton neurobiologist Joe Tsien and colleagues genetically engineered a single
gene into a strain of mice they then named "Doogie" -- after the child genius
doctor from the television show "Doogie Howser, MD."
"This points to the possibility that enhancement of learning and memory or even
IQ is feasible through genetic means, through genetic engineering," said Tsien.
The gene in question, called NR2B, controls the production of a brain chemical
called NMDA, a neurotransmitter that has been identified in previous studies as a
key player in learning and memory.
Gene expression tied to social behavior in honey bees
CHAMPAIGN, Ill. -- Genes and behavior go together in honey bees so
strongly that an individual bee's occupation can be predicted by knowing a
profile of its gene expression in the brain, say researchers at the University
of Illinois at Urbana-Champaign.
This strong relationship surfaced in a complex molecular study of 6,878
different genes replicated with 72 cDNA microarrays that captured the
essence of brain gene activity within the natural world of the honey bee
(Apis mellifera). Even though most of the differences in gene expression
were small, the changes were observable in 40 percent of the genes
studied, the scientists report in the Oct. 10 issue of the journal Science.
"We have discovered a clear molecular signature in the bee brain that is
robustly associated with behavior," said principal researcher Gene E.
Robinson, a professor of entomology and director of the Neuroscience
Program at Illinois. "This provides a striking picture of the genome as a
dynamic entity, more actively involved in modulating behavior in the
adult brain than we previously thought."
And, of course, the ability to
manipulate genetic outcomes to
our benefit is far older than our
knowledge of how this works at a
molecular genetic level. Consider
the behavior of human bred pit
bull dogs vs. cocker spaniels.
Thus insights of Behavioral Genetics
should not really surprise anyone
Behavioral-psychiatric disorders with a
genetic component (select examples)
• Major depression
• Schizophrenia
• Alcoholism
• Personality disorders
• Autism
(Lecture notes closely linked to Fadem
Board Review Series textbook)
Sources of evidence regarding
genetic components
• Pedigree - family tree (good for single-gene
disorders--pattern of inheritance can be evident)
• Relatedness and risk (degree of relationship; first
degree: parent, sibling, DZ twin)
• Twin studies, especially concordance in
monozygotic (isogenetic) vs. dizygotic (typically
genetic siblings) twins. (Twins maximize
environmental similarities.)
• MZ > DZ concordance indicates genetic
component
Relatedness and Risk of
Developing Schizophrenia
• No relationship: 1%
• First degree relative (child, sibling, DZ
twin): 10%
• Child of 2 parents with schizophrenia: 40%
• Monozygotic twin of patient with
schizophrenia: 50%
• Not a simple single-gene disorder
Symptoms of schizophrenia
• Positive: Delusions, hallucinations,
disorganized speech, grossly disorganized
or catatonic behavior
• Negative: Reduced expression of emotion,
impoverished speech, impaired initiation of
goal-directed behavior
• Categories, e.g., paranoid (multiple
delusions of persecution)
Relatedness and Risk of
Developing Bipolar Disorder
Higher heritibility:
• No relationship: 1%
• First degree relative (child, sibling, DZ
twin): 20%
• Child of 2 parents with bipolar disorder:
60%
• Monozygotic twin of patient with bipolar
disorder : 75%
How might defective gene expression
relate to mental disorder?
• Dopamine hypothesis of schizophrenia:
postulates overactivity of mesolimbic and
mesocortical dopamine neurons that project
from the ventral tegmental area to the basal
forebrain, limbic cortex and neocortex
• Postulates that D2 dopamine receptors of
schizophrenic patients are hyperactive or
hypersensitive to the neurotransmitter
dopamine
Origins of Dopamine Hypothesis
• Chlorpromazine, haloperidol (neuroleptics)
remarkably effective in treating schizophrenia
symptoms
• Chlorpromazine blocks D2 dopamine receptors
(Parkinson like symptoms can arise with longterm use: rigidity, tremor, movement initiation
difficulty; tardive dyskinesia: involuntary
movements of face and jaw)
• Atypical neuroleptics (clozapine, risperidone)
don’t directly block D2 receptors
Reduced neuropil hypothesis of
schizophrenia (P. Goldman-Rakic)
• Neurons in prefrontal cortical areas (9,10) more
densely packed
• Loss of synapses in prefrontal cortex (David
Lewis)
• Premorbid period/onset often occurs in or
following adolescence, a period of prefrontal
cortical synapse elimination (J. Geidd)
• Synapse elimination is a normal developmental
process (P. Huttenlocher)
1997
Visual
Prefrontal
<= Prefrontal
Ctx
Auditory
Losses of synapses correspond to
gains in development
Simple inheritance: Phenylketonurea
• Autosomal recessive genetic disorder;
phenyalanine hydroxylase, which converts
phenyalanine to tyrosine.
• Excess phenylalanine (some is converted to
a ketone form excreted via urine) builds up,
alters amino acid transport => amino acid
insufficiencies in the brain => mental
retardation.
Simple inheritance: Phenylketonurea
• Each parent of a child with PKU carries at
least one defective gene. In a recessive
condition, both genes must be defective in
order to have the disorder.
• Individuals with only one defective gene are
"carriers," show no symptoms, and may be
unaware of their status until they have an
affected child.
Simple inheritance: Phenylketonurea
• For a child to inherit PKU, both parents must be
PKU carriers. When this occurs, there is a one in
four chance of their producing an affected child
with each pregnancy.
• Until the 1960s, most infants born with PKU
developed mental retardation and cerebral palsy.
Now, postnatal detection and institution of a low
phenylalanine diet are routine and usually
sufficient to prevent symptom development.
PKU and gene-environment interactions
• Phenylketonurea (PKU) provides a simple model
for understanding how genes and their
environment may interact.
• If a child with PKU comes into a dietary
environment with normal (or at least typical)
levels of phenylalanine, disordered
neurobehavioral development will occur.
• If the same child receives a diet low in
phenylalanine (tolerance may increase with age),
essentially normal mental development is typical.
Medicine is replete with geneenvironment interactions
• In genetically-susceptible individuals,
consumption of excess saturated fats leads
to a predisposition towards coronary artery
disease.
• Genetic bases of susceptibility are less
clear, but negative impacts of smoking,
excess alcohol consumption, excess caloric
intake, etc., on health are widespread, but
not universal.
Fragile X Syndrome
• Single gene disorder located on the X
chromosome
• Nucleotide triplet (CGG) repeat disorder
• Unaffected individuals approx 50 repeats
• Carriers >50, <200 repeats
• Affected >200 repeats, hypermethylation,
silencing gene (no transcription)
Fragile X Syndrome
Absence of functional FMRP
• Affects 1:2000 males and 1:4000 females
• Behavioral Manifestations:
–
–
–
–
Mental Retardation
Hyperactivity
Autistic-like behaviors
Seizures
Griffiths et al. (2000)
• Physical profile
– Macro-orchidism
– Large forehead
– Elongated ears
• Cognitive Deficits
– Spatial Processing, Math skills
– Executive function
– Visual-Motor impairment
Warren S.T. (1997) Trinucleotide Repetition and fragile X Syndrome. Hospital Practice.
Fragile X Syndrome illustrates the
value of animal models of disorders
• Simple gene knockout: insertion of “stop”
codon at an early point in the sequence.
• Conditional knockouts that allow
transcription to be turned on or off at
specific points in development or maturity
• Is development without the gene
irreversibly harmed? Can behavioral
function be restored by the presence of the
protein in adulthood?
Some uses of animal models of FXS
• Assess “behavioral phenotype” to develop
basis for evaluation of drugs and other
therapeutic treatments
• Study brain anatomy and cell biology to
assess nature of functional damage
• Determine “cargo” mRNAs bound by
FMRP and which are differentially
expressed in absence of FMRP
Current models for
biological basis of
Fragile X
• FMRP regulator of synaptic protein
synthesis
• mRNA translation at synapses impaired
in absence of FMRP
• The mRNAs that FMRP binds and
helps translate at synapses may be
important for synaptic plasticity
Single-gene  multiple gene disorder;
Gene disorder that interacts with other
(possibly some defective) genes
Dendritic spine abnormalities
(common in MR syndromes)
(Hinton et al., 1991)
Summary
• Many medically important conditions involve
defective genes that influence behavior.
• Inheritance patterns for behavioral effects follow
the same rules as for somatic effects.
• Behavioral syndromes with important genetic
contributions include major depression,
schizophrenia, alcoholism, personality disorders,
mental retardation and autism.
Summary
• Risk-relatedness comparisons can identify
genetic contributions and lead to novel
hypotheses regarding cellular mechanisms.
• Phenylketonurea, an autosomal recessive
disorder, illustrates the inheritance of
behavioral characteristics and the
importance of environment in determining
gene effects.
Summary
• Gene-environment interactions are very
commonly addressed in medicine and much
less commonly viewed this way.
• Fragile X syndrome illustrates gene-gene
interactions that affect neural development
and behavior.