Transcript Development and Behavioral Genetics

Development and Behavioral
Genetics
PSC 113
Jeff Schank
Outline
• Unifactorial Methods
– Vasopressin Deficiency Behavioral Example
• Multi factorial Methods (Quantitative Genetics)
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Heritability
The IQ Controversy
What are Intelligent Tests?
Are Intelligence Tests Valid?
Norm of Reaction vs Reaction Range
Is IQ heritable?
Unifactorial Methods
• Unifactorial genetic analyses focus on single gene
effects whereas multi factorial (Quantitative Genetic)
approaches focus on multiple gene effects
• Unifactorial methods typically use inbred strains of
animals with a singe-gene mutation and compare them
to out bred strains
• Problems
– Not all aspects of an organism’s environment are easily
controlled, e.g., intrauterine, birth, and maternal effects
– Genes can have pleiotropic effects, which means that one
gene may affect multiple, often unrelated, phenotypic
traits
A Single Gene Effect: PKU
(Phenylketonuria)
• Is a condition that leads to severe intellectual impairment
of human functioning
• The condition occurs when there is a single recessive gene
present in both sister chromosomes that play a role in the
liver’s production of the enzyme phenylalanine hydroxylase
• Without this enzyme, the amino acid phenylalanine is not
converted to tyrosine
• The consequence of building up phenylalanine is structural
malformations of the brain, resulting in children that are
mentally retarded and irritable
• However, by modifying diet, to greatly lower the intake of
phenylalanine, this condition can be largely avoided
Transgenic Organisms
• A knockout organism is created by disabling a
specific gene
• A Knockin organism is created by inserting a
specific gene into the genome
Part I
Part II
Issues with Transgenic Organisms
• Typically produced in inbred animals
• As we would predict, genes expressed earlier in
development, when knocked out (in), are often lethal
• Knocking out (in) a gene is somewhat analogous to making
a part of a machine non-functional
– It is relatively easy to see how the machine breaks down, but
not as easy to identify the functional role in a complex
regulatory system.
• This type of genetic engineering has often been more
focused on creating organisms that have some
technological use such as
– Roundup ready plants
– Human insulin
– GMO Corn
Clustered regularly interspaced short
palindromic repeats (CRISPR)
• The CRISPR/Cas system is a bacterial immune
system that allows bacteria to cutup phage DNA
• Researchers recently discovered how CRISPR
works and how to co-opt this system to precisely
edit DNA in any organism
• Potential applications include editing faulty genes
in vitro, altering the germline of animals,
introducing gene edits for food crops
• Issues: considerable uncertainty regarding the
general application to animals and humans
A Natural Knockout of a Single Gene: An
Example of an Analysis of Behavioral Effects
• The Brattleboro, di/di, rat strain was discovered in the
laboratory of Henry A. Schroeder in Brattleboro, VT,
USA in 1964 (Valtin Ann New York Acad Sci, 1982; 394: 1-9)
• It turned out to be a single base deletion at nucleotide
1552 in a conserved region of exon B resulting in a
frame shift mutation that produces an altered amino
acid sequence (Schmale , Richter Nature, 1984; 308: 705-709)
• Immunohistochemical and in situ hybridization studies
showed that the vasopressin gene is transcribed and
translated in di/di rats, but with an impaired response
to physiological stimulation (McCabe, Morrell, Ivell, Schmale, Richter, Pfafp
Neuroendocrinology, 1986; 44:361-364)
Brattleboro Rat continued
• Brattleboro rats develop diabetes insipidus at
least by the time of weaning with indications
of AVP deficiency even earlier in development
(Dlouha, Nrecek, Sicha Annuls of the New York Academy of Science, 1982; 394: 1020)
• AVP deficiency also affects social behavior by
modulating
– aggression
– pair bonding
– social recognition (Caldwell, Lee, Macbeth, Young Prog Neurobiol, 2008; 84:124)
Autism Spectrum Disorder (ASD)
• What Is Autism Spectrum Disorder?
• Animal model Issues
– No communication analog
– Difficult to compare social deficits
– Difficult to compare patterns of behavior
• Possible bases for comparison
– General social deficits
– Behavior: stereotypical behavior, hyper activity,
sleep problems
ASD, Animal Models, and Vassopressin
• ASD may be associated with vasopressin
resistance due to hyporesponsiveness of AVP V1a
receptors (Boso, et al, 2007)
• Knockout mice lacking V1a receptors have deficits
in social recognition resembling aspects of ASD
(Bielsky, Hu, Ren, Terwilliger, Young Neuron, 2005; 47:503-513)
• Brattleboro rats exhibit social deficits in
recognition (Engelmann, Landgraf Physiol Behav, 1994;55:145-9)
• Brattleboro rats exhibit abnormalities in
emotional reactivity (Williams, Carey, Miller 1985; 6(Suppl. 1): 69-76)
Is AVP Deficiency Detectable in Rat
Pups?
• Fifteen-day-old di /di pups exhibit reduced social
attachment as measured by odor preference and
approach latency learning (Nelson, Panksepp. Neuroscience & Biobehavioral
Reviews, 1998; 22: 437-452)
• By day 10, di/di pups have an impaired
adrenocorticotropin stress response to
separation from their mother (Zelena D et al Endocrinology, 2008)
• These results indicate that AVP deficiency is
behaviorally detectable early in life and they are
related to abnormalities detected in adult di/di
rats
Development in Rat Pups
Figure 1. Locomotor neural development in rats has four stages. During the fetal stage, motor neurons become
excitable, the CPG begins to function, and the first projections from the brainstem develop. During the immature stage,
infant rats crawl, maturation ofposture in locomotion proceeds cephalocaudally, the cotricospinal tract begins to
develop around day 7 after birth, and by day 10 (the end of the immature stage) coupled activity in groups can be
detected. During the transitory period, the eyes and ears open and walking begins. By the beginning of the adult
period, adult locomotion begins.
Social Behavior of Brattleboro Rats in a
Temperature Controlled Arena
Measuring Behavior: Metrics
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Activity: change in position or orientation between each time interval;
Distance: if active, the distance moved over a time interval as measured from the
tip-of-the snout
Orientation: if active, the change in body orientation over a time interval as
measured in degrees
Wall contact: body contact with a wall of the arena at each time interval
Corners: the number of corners visited by a pup during an experimental session
Inner cells: the arena was divided into an array of 6 X 9 cells of equal size with
inner cells defined as the number of cells not adjacent to a wall that the tip-of-thesnout entered
Outer cells: the total number of cells adjacent to a wall that the tip-of-the-snout
entered
Total cells: the proportion of the total number of cells that the tip-of-the-snout
entered. For group trials, there was one additional metric
Subgroups: the number of different contact groups that formed out of eight pups
at each time interval, which ranged from 8 (no pups in contact with each other) to
1 (all pups in direct or indirect contact)
Were there Effects?
Effects of Sex?
7-Day Old Pups
10-Day Old Pups
Individual Metrics
Individual Movement
Figure 3. Trajectory plots of 145 tip-of-snout points for a 12-minute session. The two
plots on the left are from two di/di, 10-day-old pups that visited four corners. The two
on the right are typical one-corner visits by +/+ (top right) and +/di pups (bottom
right).
Group Metrics
Activity/Inactivity
+/+
+/di
di/di
Main Results
• Ten-day-old di/di pups moved over twice the distance
moved by either +/+ or +/di pups in group trials
• Pups often repeatedly circled the arena, a behavior
rarely observed in either +/+ and +/di pups.
• Informal observations of 10-day-old di/di pups
revealed that they were often able to lift their bodies
off the surface of the arena and walk or run across the
surface.
– Walking or running on the surface of the arena was never
observed for either day-10 +/+ or +/di pups
• Another interesting behavior observed in 10-day-old
di/di pups was a large degree of turning
Conclusions
• Accelerated motor development also seen in
ASD
• High degree of change in orientation a
stereotypic behavior?
• Increase activity with contact indicates social
deficits
• Lower aggregation indicates social deficits
• Failure of activity to decrease over time may
be related to sleep disturbances
Problems
• There were no sex differences. Autism, however, occurs
in males in about a 4:1 ratio.
– If Vasopressin is involved in autism, it is far from the whole
story
– Genetically, untangling the mechanisms of autism likely
will involve understanding complex genetic networks
• Autism is not associated with diabetes insipidus, but if
vasopressin is somehow involved, it may be at the
receptor level and/or at the gene regulatory level
• How do we know we have an animal model of autism?
Multifactorial Methods (Quantitative
Genetics)
• Heritability is based on the statistical idea of
variance
• Recall that for natural selection to operate in a
population, there must be variation in
phenotypes
• If we can measure phenotypes (e.g., the height of
corn plants), then we can measure variation using
the statistical concept of variance
Phenotypic Variance
• Phenotypic variance can be partitioned into
components
• The main empirical problem is how to
estimate each component
• The simplest partition is
• where VG is variation due to genetic factors
and VE is variation due to environmental
factors
Heritability
• Heritability in the broad sense used in the IQ
controversy is:
• If components of variance can be estimated for a
population, then h2 heritability can be used to
predict characters in the next generation.
• If E(x) is the mean measure of the character for a
population and xMP = (xi + xj)/2 is the mid parent
value, then the offspring of these parents would
be expected to have a mean value of
Heritability Example
What are Intelligent Tests?
• The first scale for measuring intelligence was
introduced by Binet in Paris for the purpose of testing
children in school
• His test was based on the concept of mental age
introduce by SE Chaillé in 1887
• The basic idea was to first find the average age at
which most children could solve a problem, then
second if say a 3 year old could solve problems solved
by most 4 year olds, then his/her mental age would be
4 and his/her chronological age would be 3:
• Where MA is mental age and CA is chronological age
Tacit Assumptions of IQ Tests
• Intelligence can be measured by problems that do not
take too long to solve.
• Intelligence is “black or white”
– There is only one perspective on a problem
– Are real world problems “black and white”?
• Problem solving can be separated from knowledge
– This is assumption is important for those looking for race
or group differences
– If problem solving is not separable from knowledge, then
one must show no knowledge differences between groups
IQ Distribution
IQ Test Items
Are Intelligence Tests Valid?
• The validity of a test refers to whether the test
really measures what it is intended to measure
• Binet’s aim was to compare the development of
intelligence in children
• This is very different from an absolute measure of
intelligence in adults
• IQ (and IQ equivalent tests) are only mediocre at
predicting
– Job performance (at best about 50% of the variance)
– First year performance at university or college (about
30% of the variance)
Norm of Reaction vs Reaction Range
• For a norm of reaction, if we know the
phenotypic effects of two genotypes in one
environment, we cannot predict their relative
effects in a different environment
Norm of Reaction vs Reaction Range
continued
• The reaction-range presumes that the
genotype imposes a range of effects in the
expression of a phenotype, i.e., phenotype
has upper and lower
bounds that cannot
be transcended
Maze-bright and maze-dull rats
• Cooper and Zubek (1958) raised maze-bright
and maze-dull rats in the usual, deprived, or
enriched environments
and then tested the rats
in a Hebb-Williams maze
• It was expected that they
would find a range of
reaction in ability to
navigate the maze
Prediction
Results
Is IQ Heritable?
• Some people such as J. Philippe Rushton
claims that there are heritable differences in
IQ among groups or races of people
• In this video, he presents his statistical
arguments
• If one doesn’t have a basic understanding
statistics and quantitative genetics, it is
difficult to identify the nonsensical use of
statistics to support his agenda
Why Can’t Heritability be Compared
Between Populations?
• Recall that the basic equation for partitioning
phenotypic variance is
• The VE term for IQ tests will vary between
groups if there are differences in background
knowledge
Heritability and Corn: Two Examples
• Consider two completely inbred lines of corn (one tall strain and one short
strain)
• There is no genetic variation within lines because corn plants within lines
are identical
• Now if we plant them in different pots (one seed to a pot with ordinary
potting soil) and a few weeks after they germinate, we will find variation in
the height of the plants
• The variation will be entirely environmental, thus
VP = 0 + VE
h2 = VG/VP = 0
• But, there will be genetic differences between the two lines
• Trying to estimate heritability across to populations is statistically
meaningless in this case
Second Example
• Now, suppose we take seeds from a sack containing seed of an open
pollinated variety containing lots of genetic variation
• We grow each group of seeds in vermiculite watered with a nutrient called
Knop’s solution, which is used by plant physiologists for controlled growth
experiments
• Suppose however that for one group we twice as much Knop’s solution as
the other
• The results we get would be this:
– Within Knops solution conditions, VE would be very close to 0 and thus h2 =
VG/VP = 1 within groups
– Between groups there would be systematic differences in height, but it would
be entirely environmental
• Thus, again to say that corn height is heritable across groups is statistically
meaningless
• This is exactly analogous to the problem of different background
knowledge across groups or populations