Genetics and Prenatal
Development
D. Messinger, Ph.D.
Messinger
Quantitative and molecular genetics
Quantitative genetics:
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Quantifies the strength of genetic and non-genetic factors
Genetics believed to play role in all traits
non-genetic influences also important
in gene-environment interactions, environment may have
more/less impact on those who are/are not genetically susceptible
Molecular genetics:
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Identification of specific genes involved in susceptibility
Some individual genes have been identified in liability to
mental disorders; some also associated with variations in
response to environmental hazards or medication
Gangi
Basics
Genes
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Bits of DNA in each cell
information on cell functioning & reproduction
Chromosomes
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Larger groupings of DNA
All non-gamete cells have 23 pairs of chromosomes
Half of each pair came from each parent
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Chromosomes
Ordered by karotyping
In vitro
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Human genome project
identify the ~30,000 genes in human DNA,
determine the sequences of the 3 billion
chemical base pairs that make up human
DNA,
99% (of nucleotide bases) are the same in
all people
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Detailed description
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Disadvantages of the genes-asblueprint metaphor
Genes are in a primarily liquid nucleus in a
primarily liquid cell surrounded by other
cells in a primarily liquid uterine
environment
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Without an “environment,” genes are just
wound up nucleic acid
From a lump of jelly to an organism
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How do genes actually work?
What is the role of “junk” DNA?
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Genomes to Life Project - Proteomics
Identify the
protein
machines that
carry out
critical life
functions and
the gene
regulatory
networks that
control these
machines
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Terms
Phenotype
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Observable trait
“Phenotyping”
The
broader phenotype (autism)
Genotype
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Genetic pattern associated with the phenotype
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Polygenic inheritance – not blueprint inheritance - is the rule
Multiple genes influence most traits
Sign of polygenic inheritance is range in
phenotype rather than either/or
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skin/eye/hair color, height, baldness, personality
Reaction Range
Potential variability in expression of a trait
Such traits may also be susceptible to
environmental influence
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How are genes a blueprint?
“The DNA sequence (e.g., ATTCCGGA) . .
. spells out the exact instructions required to
create a particular organism with its own
unique traits.”
A metaphor which describes cases in which
there is a specific correspondence between
genotype and phenotype
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Blueprint-like
modes of genetic transmission
Dominant-recessive
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Single gene or Mendellian
Specific
genetic defects can be deadly or disabling
sickle cell, phenylkitenuria (but see Knox &
Messinger, 1958), etc.
Sex-linked (23rd chromosome)
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Dominant-Recessive Inheritance
Traits are transmitted as separate units
Autosomes - 22 pairs
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Non-sex chromosomes
One pair from each parent
When 2 competing traits are inherited
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Only 1 trait is expressed
Dominant
trait
Recessive trait
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Dominant-Recessive Inheritance
C a rrie r F a th e r (N r)
+
C a rrie r M o th e r (N r)
N o rm a l
(N N )
C a rrier
(N r )
C a rrier
(N r )
Affe c te d
(rr )
Traits are transmitted as separate units
•25% risk of inheriting a “double-dose” of r genes
•which may cause a serious birth defect
•25% chance of inheriting two N’s
•thus being unaffected
•50% chance of being aMessinger
carrier as both parents are
Sex-linked inheritance
23rd chromosomal pair
Male = XY (Missing an
arm)
– one Y branch not
matched
– so allele on
corresponding X
branch is expressed
Female = XX
– each branch is matched
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Sex-linked inheritance
Male’s “x” inherited from mother
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Women are carriers
Males represented disproportionately in sex linked
disorders
Color-blindness, hemophilia
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Behavioral genetics
The influence of genetic and environmental
factors be distinguished and the influence of
each can be quanitified using behavioral
genetic methods (Plomin)
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Twin Studies
Monozygotic vs Dizygotic: human studies of
genetic versus environment
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Twin studies
Identical (MZ) twins share 100% of their genes
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Fraternal (DZ) twins share 50% of their genes
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genetic duplicates.
on average
Both types of twins have similar environments . . .
Greater behavioral similarity of identical twins
indexes greater genetic influence
•
http://www.psych.umn.edu/psylabs/mtfs/special.htm
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Modeling differences between
correlations
A (additive genetics) C (common environment) and E (unique environment); ACE Model.
The correlation we observe between MZ twins provides an estimate of A + C .
Dizygous (DZ) twins have a common shared environment, and share on average 50% of their genes:
so the correlation between DZ twins is a direct estimate of ½A + C .
rmz = A + C rdz = ½A + C Where rmz and rdz are simply the correlations of the trait in MZ and DZ
twins respectively.
Twice difference between MZ and DZ twins gives us A: the additive genetic effect
C is simply the MZ correlation minus our estimate of A. The random (unique) factor E is estimated
directly by how much the MZ twin correlation deviates from 1.
difference between the MZ and DZ correlations is due to a halving of the genetic similarity…
So additive genetic effect 'A' is simply twice the difference between the MZ and DZ correlations:
A = 2 (rmz – rdz) As the MZ correlation reflects the full effect of A and C, E can be estimated by
subtracting this correlation from 1
E = 1 – rmz Finally, C can be derived:
C = rmz – A = 2 rdz – rmz
http://en.wikipedia.org/wiki/Twin_study
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Sources of Variance in Behavior
Genetic
(heritability)
Environmental
Gene x environment interaction
Error
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No genetic influence
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Genetic influence
Behavior
Similarity
Correlation
60
50
40
30
Twin 1
Twin 2
20
10
0
Dizygotic
Monozygotic
Genetic Relatedness
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“Most, if not all, reliably measured
psychological traits, normal and
abnormal, are substantively
influenced by genetic factors.”
Bouchard, T. J.
(2004). "Genetic Influence on Human Psychological Traits: A Survey." Current Directions in
Psychological Science 13(4): 148-151.
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Estimates of genetic and
environmental influence
Proportional in samples
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Greater environmental variation
Will
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minimize genetic variation
E.g. Poverty
Greater genetic variation
Will
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minimize environmental variation
E.g. Downs Syndrome
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Gene * Environment interactions
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Genetic effects on alcohol use are greater in nonreligious than religious households
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Why?
Genetic effects on seeking specific environments –
Identical twins find similar friends
Identical twins treated more similarly (or differently) than
fraternal twins?
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Questions
Why might adoption studies maximize
estimates of genetic influence?
Can genetic effects increase with time?
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How?
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Transactional perspective on
gene*environment interface
“It is not nature vs. nurture, but the
interaction of nature and nurture that drives
development.” Urie Bronfrenbrenner
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Gene*Environment Interaction
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Gene * environment interactions
Gottlieb, 2003
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“What will it take to make behavioral
genetics truly developmental?”
An analysis of the bi-directional relations
from gene action to the external
environment over the life course, including
the prenatal period. Gottlieb, G. (2003
). Human Development 46(6): 337-355.
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Measured Gene-Environment
Interactions and Mechanisms Promoting
Resilient Development
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(Kim-Cohen & Gold, 2009)
Individuals carrying “protective” allele have
lower levels of psychopathology than those
that posses the “vulnerable” allele
In maltreated children:
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“short” (low) serotonin transporters (5-HTT gene)
only see greater risk for depression in high-stress
conditions.
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No effect in individuals not exposed to risk
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Dunedin Longitudinal Study (Caspi et al., 2003)
(Caspi & Moffitt, 2006)
Replication debate
Fernandez
Contextual Determinants of Gene
Function
Gene = sequence of DNA
Transcription = enzymes “read” DNA
Environment around DNA makes it possible
to “read” DNA
Epigenetic – “in addition to genetic”
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Influences that determine expression without
altering the DNA
Gangi
Messinger
Several epigenetic
mechanisms alter gene
activity in neurons, with
potentially important
effects on brain function
and behavior.
Histone acetylation
tends to promote gene
activity,
whereas histone
methylation and DNA
methylation tend to
inhibit it.
Which is better?
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Environmental Influences on Gene
Activity
In rodents:
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Low maternal care elevated methylation
Prenatal exposure to chronic stress increased
methylation
Less nurturing mothering leads to poorer stress
response in rat pups
Fewer
corticosterone receptors
Linked to DNA methylation
Enzymes reverse methylation, improve receptor
numbers
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Szyf & Meany (2004)
Gangi
Epigenetics in Rodents
Champagne’s extension to later mothering
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Less mothering attention -> Greater methylation
Roth and Sweatt (2009)
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Stressed mothers spend less time nurturing
Lower BDNF hormone -> Greater methylation - > Lower neural
growth
Less mothering attention in the next generation
Linked to anxiety in mice, responds to antidepressants
Miller and Sweatt (2007)- Inhibition of methylation detrimental to memory
Nestler et al. (2010) Cocaine exposure
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Higher acetylation and methylation of histones
Stimulates reward circuitry
Mattson
Methylation can
mask the
transcription of
certain genes
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Epigenetics in Humans
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Antenatal depression and anxiety higher
methylation
Suicide victims elevated methylation in
hippocampus Szyf & McGowan (2009)
More
methyl groups in glucocorticoid receptor
genes of abused
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Umbilical cord blood, higher methylation and higher later cortisol,
increased susceptibility to stress (Oberlander et al., 2008)
Greater discordance in gene expression in older twins –
associated with greater differences in methylation
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The Seductive Allure of Behavioral Epigenetics.
Mattson
Miller (2010)
True or false?
Environmental factors for generation 1 can
influence gene expression in generation 2
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