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Cambridge University, NST Psychology Part II, Section C, Genetics of Individual Differences
Genetics of Individual Differences
Lecture 1 - Personality
Summary
1
...
Selective breeding in animals
...
Belyaev, in 40 generations, transformed a wild species of fox into a tame
one
...
The adult animals retain juvenile traits (neoteny)
not only of behaviour but also of anatomy
...
DeFries (1978) selected for open-field behaviour in mice
...
Twin studies in man
...
Examples, extraversion-introversion,
preference for fairness, neuroticism
...
47 for the heritability of
personality
...
It is assumed that genes are additive
...
Similarly, the effect of a
particular allele at one genetic locus may depend on the allele present at a different
locus ('epistasis')
...
Epigenetics: Random X-chromosome inactivation in female twins
...

c
...

However, this may not be true
...
Similarity of personality may be secondary to morphological similarity
...
The values of a trait may not be identically distributed in the population of MZ twins
and the population of DZ twins
...

f
...
The DZ twins could average more or less than 50% shared genes
if their parents are positively or negatively correlated in the relevant trait
...
Selective breeding in animals
...

Cross-fostering (or transplanting of embryos) showed that the changes were uninfluenced
by the mother's behaviour
...

The Belyaev-Trut hypothesis is that the selection acts on the timing of ontogenetic
processes
...
However,
the age of sexual maturity has been reduced, and some females breed twice in the year
...
vulpes, found an association with a region of chromosome 12
that is homologous to a region of canine chromosome 5 that has been implicated in the
domestication of dogs from grey wolves (Kukekova, 2014)
...
Rodents are typically reluctant to
explore a well-lit open area, and will have less locomotor activity and defecate more - signs
of anxiety
...
For 30 generations, mice were selected for either high activity or low activity in
an open field
...

2
...
The heritability of personality is often estimated by comparison of
monozygotic (MZ) and same-sex dizygotic (DZ) twins
...
Heritability is a statement about variance - not what proportion of a trait is due to
genes
...
It is a statement about a population at a given time - it varies as the environment
varies
...
It is not a statement about resemblance to parents
...
So –
in the simplest model – the difference between MZ and DZ correlations is accounted for by
50% of the genes, thus twice this difference has been taken as a measure of heritability
...
It is assumed that genes are additive
...
There may be a particular
advantage or disadvantage in being heterozygous
...
Similarly, the effect of a particular allele at one genetic
locus may depend on the allele present at a different locus ('epistasis')
...
Epigenetics: Random X-chromosome inactivation in female twins
...
And
there are disproportionately many X-linked genes that affect the CNS
...
g
...
Thus random X-chromosome
inactivation in females will lead to an underestimate of the genetic contribution
...

c
...

However, identical twins often have a particularly close relationship and they
develop together their attitudes to the world
...
Conversely, parents and peers may exaggerate
differences between MZ twins in order to distinguish them
...
Similarity of personality may be secondary to morphological similarity
...
g
...

e
...
Neuroticism and smoking behaviour are two traits
reported to be lower absolutely in MZ twins than in DZ twins
...
Assortative mating
...
In
general, people are more likely to be attracted to those similar to themselves,
suggesting that DZ twins might average more than 50% shared genes
...
g
...
33 between spouses has been reported
...
Examples:








‘Preference for fairness’
...
In this game, there are two participants, the proposer and the
receiver, who are required to bargain over a sum of money
...
If the receiver accepts the offer, the players are paid accordingly;
and if the offer is rejected, then both players receive a zero pay-off
...
However, there are large individual differences in the
acceptance threshold
...
39 (95% confidence interval
0
...
49); for DZ: -0
...
25–0
...

Introversion-extraversion
...

Neuroticism
...
46, and for DZ twins reared together, 0
...
For twins reared apart the
corresponding values are 0
...
23
...
47 for the heritability of personality
...
5 is typical
...
The for gene in Drosophila melanogaster - individuals with the dominant 'rover' allele (forR)
move greater distances when feeding than do those homozygous for the 'sitter' allele (forS)
...
Reaume et al (2011) showed that rovers but not sitters exhibit retrospective inhibition
...

2
...
In exon 3 of the D4 dopamine receptor gene are 1-, 2-, 4-, 5- or 7-fold repeats of a 48
base-pair sequence
...
Ebstein
et al (1996) found that the 7-repeat allele was significantly associated with high scores for

Cambridge University, NST Psychology Part II, Section C, Genetics of Individual Differences
Cloninger's trait of 'Novelty seeking'
...
g
...

Associations between DRD4 polymorphisms and promiscuity and sexual desire and function
have also been found
...

3
...
The monoamine oxidase A gene is on the X-chromosome
...

There is a polymorphism in the promoter region of the MAOA gene, whereby there are
variable numbers of tandem repeats of a 30-base pair region, resulting in differences in
expression
...

4
...
The COMT (catechol-O-methyltransferase) gene on chromosome 22q11
...
The presence of either one or two Met-alleles is associated with
higher negative emotionality and lower activity of the enzyme
...
The for gene in Drosophila melanogaster - individuals with the dominant 'rover' allele (forR)
move greater distances when feeding than do those homozygous for the 'sitter' allele (forS)
...
Typically
a wild population may have 70% rovers and 30% sitters, which is beneficial for the whole
population, as sitters use existing patches while rovers are free to explore new feeding
patches
...

The for gene is known to encode a protein kinase (PKG) that is activated by cyclic GMP and
alters the action of other proteins by phosphorylation
...

The for gene also causes a natural polymorphism of memory in Drosophila
...
Flies were tested either 15 minutes or 24 hours later: air streams
containing the alternative odorants were presented at the choice point of a T-maze and the
numbers of flies entering each arm was counted
...

Reaume et al (2011) showed that rovers but not sitters exhibit retrospective inhibition
...
Thus rover
responses are biased towards more recent learning events
...
In other words, they
are both able to use public and private information, but sitters either use or display more
public information than rovers, and tend to rely more on the transfer of social information
...
DRD4
...
In
exon 3 there are 1-, 2-, 4-, 5- or 7-fold repeats of a 48 base-pair sequence
...
The DRD4
...
7 receptor does not show this salt dependence
...

Several other polymorphisms have also been identified for this gene, e
...
the C-521T SNP
(single nucleotide polymorphism) is also associated with novelty seeking
...
Zion et al (2006) report associations between DRD4
polymorphisms and sexual desire and function
...
Settle et al (2010) found that those with DRD4-7R and
a large number of friends were more likely to be liberal in their politics (however, this may
be a result of selective analysis)
...
Women show greater cognitive empathy if they have the
7R+ allele instead of the 7R- allele, whereas men show less cognitive empathy if they are
7R+
...
Fidler et al (2007) suggest that wild-caught great tits, Parus major, have
a significant genetic component of novelty-seeking behaviour
...
MAOA
...
The gene is on the X-chromosome
...
Since the gene is on the X-chromosome, these men are
effectively human knock-outs for the gene
...
The female carriers
were normal, suggesting the point mutation is recessive
...
Increased aggression has also been
found in mice MAOA knock-outs
...
3
...
Allele 3 is twice as common as Allele 1 in White/Nonhispanics, whereas Allele 1 is more common than Allele 3 in Asians
...
The score for anti-social behaviour was derived from (a)
Adolescent conduct disorder assessed by DSM-IV (b) convictions for violent crime (c)
psychological assessment at age 26 and (d) ratings by peers at age 26
...
Not all
studies have replicated Caspi
...
COMT
...
21 has a
Val158Met polymorphism
...
There are sex differences in
the neurochemistry of COMT and corresponding variations have been reported in its
association with neuroticism
...
Genes that have been associated with personality include:
a
...

b
...
A highly significant relationship between the
estimated level of Neuropeptide Y and the fMRI response of the amygdala and
hippocampus to threat stimuli has been reported
...
BDNF
...
Genetically
engineered mice that were Met/Met were more anxious, and some studies in
humans have found similar results
...
AVPR1a
...
Compared to mountain voles, the prairie vole has a 428 basepair sequence inserted in the 5’ flanking region of the gene
...
In
humans, Knafo et al (2008) studied the polymorphism of the microsatellite region
marked RS3
...

e
...
One
particular polymorphism (rs53576) has been much celebrated: Those with the allele
GG are reported to perform better on the “Reading the Mind in the Eyes” test and to
be better at face recognition, and different alleles also alter altruistic behaviour
...

2
...
For a large population of
participants (usually >1000), the correlation is found between each SNP and a phenotypic
measure, and a large correlation is needed to take account of multiple testing
...

3
...
de Moor et al (2012) give a meta-analysis for the NEO five-factor inventory of
Neuroticism, Extraversion, Openness to Experience, Agreeableness and Conscientiousness
...
2% of the variance in any of the
phenotypic traits
...
However, the results of a GWAS can be used to obtain a direct estimate of the heritability of
a trait
...
Such an analysis has been performed for neuroticism and extraversion by
Vinkhuyzen et al (2012)
...
For extraversion it was 12%
...
Heritable variation in personality may be due to rare variant effects
and/or a combination of dominance and epistasis
...

5
...
Personality may be affected by genetic variations that are not captured by the SNPs
used in the GWAS array, e
...
repeat sequences, or duplications, or rare SNPs with
minor allele frequencies <1%
...
There may be non-additive genetic effects, either non-additivities at the same allele
('dominance') or between alleles ('epistasis')
...
The values from twin studies may be inflated because, say, monozygotic twins enjoy
a more similar environment than do dizygotic twins
...


1
...
The human serotonin
transporter is encoded by a large gene (SLC6A4) on chromosome 17
...
The short allele exhibits a 44 base-pair
deletion and is associated with decreased transcription of the gene compared with the long
allele
...
Canli and Lesch (2007) draw evidence from behavioural
genetics and cognitive neuroscience and suggest that the impact of the 5-HTT gene on
behaviour is much broader than is commonly appreciated and may have a role in social
cognition, which depends on life stress experience
...
5% of phenotypic variance They found no statistically
significant effects of genotype on either neuroticism or major depression
...
Bastiaansen et al (2014) deny
the long-held believe that carriers of the short version of the promoter polymorphism show
stronger activation of the amygdala in an emotional-face task
...
However, a meta-analysis of such studies (PergaminHight, 2012) does conclude in favour of a positive effect
...
NPY
...
It is
abundantly expressed in the limbic system, is anxiolytic and is released in response to stress
...
The polymorphisms
are not independent
...
Zhou et al (2008) show that different haplotypes are associated with different
levels of expression of NPY and that these variations are modestly correlated with two
subscales of the ‘Tridimensional Personality Questionnaire’: Fear of Uncertainty and
Anticipatory Worry
...
However, Cotton (2009)
finds no relationship between NPY polymorphism and Eysenck’s Neuroticism scale
...
BDNF
...
Mice do not exhibit this polymorphism, but Chen et al
(2006) made knock-in mice that were either heterozygous or homozygous for Met at codon
66
...
The heterozygous animals did not show increased anxiety
...
Johnson (2016)
found that individuals who were homozygous for Met had higher scores on the wellvalidated Behavioural Inhibition System scales
...
AVPR1a
...
Arginine vasopressin is a nonapeptide – a string of nine amino acids – that
controls the water content of the body and is sometimes called ADH (anti-diuretic
hormone)
...
The
receptor for the hormone is the heptahelical receptor V1a and falls into the general class of
G-protein coupled receptors
...

Mountain voles are promiscuous, non-parental and asocial, whereas prairie voles are
monogamous, bi-parental and highly affiliative
...
The insert is
‘microsatellite’ DNA, rich in repetitive di- or tetra nucleotide sequences
...
Young et al (1999) showed that male prairie voles, but not mountain voles,
have raised levels of affiliative behaviour (grooming and olfactory behaviour towards an
oviarectomized female) after micro-injections of vasopressin into a ventricle
...
4 kb of the flanking region containing the micro-satellite DNA)
...

Most interestingly, the male transgenic mice, when given a micro-injection of vasopressin,
exhibited more affiliative behaviour towards a tethered oviariectomized female mouse than
did wild-type males
...

However, one weakness of this study is that they did not create transgenics with the

Cambridge University, NST Psychology Part II, Section C, Genetics of Individual Differences
mountain vole form of the flanking region
...
The gene is located at
12q14
...
In addition to
3 polymorphic microsatellite regions in the upstream region, there is a further one (2983
base pairs long) within the intron
...
They
asked whether the polymorphism affects altruism as measured by the ‘Dictator Game’
...
Subjects homozygous for the short
form of the polymorphic region allocated less money to their partner than did those
homozygous for the long form
...

5
...
The role of oxytocin
in parturition and lactation is long established, but recently it has been popularly associated
with a large range of prosocial behaviours
...
One particular
polymorphism (rs53576) has been much celebrated: Those with the allele GG are reported
to perform better on the “Reading the Mind in the Eyes” test and to be better at face
recognition (Skuse, 2014, PNAS)
...
Bakermans-Kranenburg (2014) wrote a
sceptical review where they did a meta-analysis of two single nucleotide polymorphisms
(rs53576 and rs2254298), covering five domains of outcome: biology, personality, social
behaviour, psychopathology and autism
...
Clinical status, age, and sex did not
moderate the effect sizes
...
The
domain of biological functioning seemed most promising, but comprised few studies
...

6
...
Typically 500,000 to 1 million
SNPs are probed
...
Although the number of SNPs tested is
only a fraction of the total SNPs in the genome, the underlying idea is that the unprobed
SNPs will often be genetically linked to the ones that are probed (and software is available to
'impute' the association values for the unprobed SNPs)
...
The exact value depends on the number
of SNPs tested, but typically a probability value of 5 x 10 -8 is required
...
de Moor et al (2012) give a meta-analysis for the NEO five-factor inventory of
Neuroticism, Extraversion, Openness to Experience, Agreeableness and Conscientiousness
...
2% of the variance in any of the
phenotypic traits
...
The entire array of SNPs can be used to estimate the genetic distance between any
two individuals
...
So we can
estimate how much of the phenotypic variance is accounted for by the genetic variance
...
It has been successfully used in the case of height and in the case of
intelligence
...
The combined population comprised ~12,000 unrelated
participants
...

For extraversion it was 12%
...
Verweij et al (2012), too, found a small effect
...
2% on average) is due to the combined effects of common, additive genetic variants
across the genome
...
Furthermore, higher levels
of inbreeding were associated with less socially desirable personality trait levels in three of
the four personality dimensions
...

A study of economic and political preferences came to a similar conclusion
...
Traditional twin analysis had given
heritabilities of ~30% for economic preferences and ~40% for political preferences
...
There was significant heritability when all SNP’s were
taken into account
...
Separate analyses for each chromosome suggested a positive correlation with
chromosome length, confirming that these traits are highly polygenic
...
Personality may be affected by genetic variations that are not captured by the SNPs
used in the GWAS array, e
...
repeat sequences, or duplications, or rare SNPs with
minor allele frequencies <1%
...
There may be non-additive genetic effects, either non-additivities at the same allele
('dominance') or between alleles ('epistasis')
...
The values from twin studies may be inflated because, say, monozygotic twins enjoy
a more similar environment than do dizygotic twins
...

Lecture 4 - Genetics of IQ
Summary
1
...
However, there
is no major gene that accounts for as much as 1% of the variance in IQ scores
...
However, genes that can cause mental retardation may also influence the intelligence of
individuals who fall elsewhere in the distribution:
a
...
Fragile X Tremor/Ataxia Syndrome (FXTAS)
c
...
In a GWAS by Ruano et al (2010) no individual SNP was significantly correlated with
intelligence after the correction for multiple comparisons
...
The
authors also calculated how much variance was accounted for by all the 500000 SNPs that
they tested
...
These are lower-bound estimates, since the
causal factors are likely to not be the measured SNPs themselves, but other genetic
variations with which the test SNPs are in linkage disequalibrium, and since there are other
genetic polymorphisms that are not captured in GWAS
...
Two further interesting results have emerged from GWAS:
a
...

b
...
One interpretation is that children select their own
environments that are correlated with their g-related propensities
...

5
...
Heterozygous advantage: for example, in the case of phenylketonuria, the
heterozygote may enjoy protection against the toxic effects of ochratoxin A
...
Frequency-dependent selection: seen for the for gene in Drosophilia
...
Moreover, estimates suggest that we are each carrying approximately 50 deleterious
mutations, and a number of these probably affect the nervous system
...
A disproportionate number of syndromes are associated with the X-chromosome,
reflecting the fact that the X-chromosome disproportionately carries genes that affect the brain and
the eye
...

The DSM-IV definition for mental retardation is an IQ or 70 or less
...
However, genes that
can cause mental retardation may also influence the intelligence of individuals who fall elsewhere in
the distribution:
1
...
FXS is characterised by intellectual disability, dysmorphism (large
ears, and in adulthood, an elongated face), macro-orchidism and 'cluttering' (rapid,
repetitive or garbled speech)
...
About 20% of hemizygous males who carry the mutation have no clinical expression
b
...
Daughters of normal transmitting males rarely express any symptom, whereas
penetrance is high in sons and daughters of carrier women
...
This gene encodes a protein that binds to
RNA, so it regulates the expression of other genes, particularly those with a role in synaptic
transmission
...
Commonly found in carriers
are 'pre-mutations' - expansions between 50 and 200, which lead to a higher than normal
rate of transcription
...

As is expected for an X-linked condition, fewer females than males exhibit mental
retardation of the FXS type (but not as few as there ought to be)
...
Their average IQ was 82
...
The carriers of pre-mutations (instead of full mutations) differed little
from controls
...

2
...
A distinct syndrome - FXTAS - is found in those
who carry the premutation (55-200 repeats)
...
The patient may present with tremor, ataxia and cognitive impairment,
and he may have recently become irritable and reclusive
...

Females with FXTAS are rare
...
So in this
case, one of the known genes for mental retardation is also contributing to the variance in
the main body of the IQ distribution
...
IQSEC2 and CTNS: IQ is depressed in heterozygotes
...

Kalscheuer et al (2015) report that heterozygous females have learning difficulties
...
The authors hypothesise that in female
carriers, the missense mutation is sufficient to produce symptoms but the mutant protein
has residual function and in addition there is some compensation from the normal allele
...

4
...
Sufferers exhibit intellectual disability, a mousy odour, light
pigmentation, eczema, and peculiarities of gait and stance
...
The effected gene is usually PAH, the gene
that encodes for the enzyme phenylalanine hydrolase, which converts phenylalanine to
tyrosine
...
9% of the gene
...

Globally, the R408W mutation accounts for 30% of cases
...
PKU is a case where genes and environment interact
...
However, the cure doesn't fully work, as treated patients have IQ scores on average
half a standard deviation below controls
...

5
...
However, the authors grouped candidate genes into functional groups, and
one of these groups (G proteins) was strongly related with intelligence when the
probabilities for the individual SNPs were cumulated
...
This approach gave a
heritability of 40% for variation in crystallized intelligence and 51% for variation in fluid
intelligence
...
These are lower-bound estimates,
since the causal factors are likely to not be the measured SNPs themselves, but other genetic
variations with which the test SNPs are in linkage disequalibrium (the variations at one locus
are correlated with variation at another), and since there are other genetic polymorphisms
(such as copy number variation, trinucleotide repeat sequences etc) that are not captured in
GWAS
...

Two further interesting results have emerged from GWAS:
a) The genes that affect intelligence when one is young are different from those that
affect intelligence when one is old (Drury, 2012)
...

b) The heritability of intelligence, estimated from GWAS, increases between the ages of
7 and 12 (Trzaskowsi, 2014)
...
One
interpretation is that children select their own environments that are correlated
with their g-related propensities
...

How is the rich polymorphism of personality and intelligence maintained?




Heterozygous advantage: for example, in the case of phenylketonuria, the heterozygote may
enjoy protection against the toxic effects of ochratoxin A, a mycotoxin, which often infests
stored grains
...
Moreover, these areas have suffered repeated famines during which mouldy food
was eaten
...

Frequency-dependent selection: seen for the for gene is Drosophilia
...




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