Transcript Presentation Slides

Gene-Environment Interplay on Behaviour
Marla B. Sokolowski, PhD, FRSC
University Professor
Canada Research Chair in Genetics and Behavioural Neurology,
Academic Director Institute for the Fraser Mustard Human Development.
Co-director of Canadian Institutes for Advanced Research (CIFAR)
Experience Based Brain and Biological Development Programme (EBBD),
Funding for our Research
Early adversity sets developmental
trajectories for health, learning and social
functioning across the life-time.
How?
a) Gene-Environment Interactions
b) Epigenetics
For most traits:
• It’s not just nature (genes)
• It’s not just nurture
(environment)
• It’s not nature plus nature
(genes + environment).
It is their interaction!
GxE
Sokolowski and Wahlsten 2001
Example of Gene by Environment Interaction
in Human Mothering Behavior
(serotonin transporter gene variants LL, SS and LS)
Mileva-Seitz et al 2011
Candidate Genes
Model Organisms to Humans
Why?
 Conservation of DNA Sequence
 Conservation of a Gene’s
Behavioural Function
Example 2: G x E: The foraging (for) gene

Almost all organisms have the gene including humans!

The gene affects energy balance: food intake, food related
movement, fat, learning and memory

Different individuals have different forms of the gene –rover
or sitter

The gene makes an enzyme found in the brain called PKG.
Rovers have more of it than sitters

How much enzyme the gene makes depends on the
environment. (G x E)
(Osborne et al 1997 Science; Ben Shahar et al 2002 Science; Mery et al 2007 PNAS; Fitzpatrick et al 2007 Nature;
Kaun et al 2007 J Exp Biol; Lucas and Sokolowski 2009 PNAS; Sokolowski 2010 Neuron).
Rover and sitter foraging behaviour
Sokolowski 2001 Nature Review Genetics
The rover/sitter natural variants
are due to variation in a single
gene called foraging which makes a
cGMP-dependent protein kinase (PKG)
enzyme
Rover heads and larval CNSs have
more foraging enzyme than sitter
heads and larval CNSs.
Osborne et al. 1997 Science 277:
roof of cloning the DNA of the foraging gene
“Gene Therapy”
he
foraging gene responds to the environmen
Fruit Flies
Rover or sitter
Osborne et al 1997
Science
Honey Bee
Nurse or forager
BenShahar et al
2002 Science
Nematode Worm
Roamer or dweller
Fujiwara et al.
2002 Neuron
Sokolowski 2010 Neuron
Ant
Forager or
defender
Lucas & Sokolowski
2009 PNAS
Gene-Environment Interaction
in response to the nutritional environment
Example 2: Rovers change into sitters when chronically food
deprived (the gene is responsive to the early rearing
environment)
Rover
Sitter
Enzyme Activity
Rover
Sitter
Food Intake
15
10
*
5
12
8
4
100%
15%
Food Quality
100%
15%
Food Quality
Kaun et al 2007 J Exp Biol
Chronic nutritional deprivation in the larval
period affects adult exploratory behaviour
Burns et al 2012 PNAS
Darting Exploration (darting is stop and go motion)
High ‘darting exploration’
Low ‘darting exploration’
G-E interplay:
sitter adults exhibit a more plastic response to modifications
in the larval nutritional environment
***
*** p<0.001
Burns et 2012 PNS
Cost of darting exploration
www.chickencrap.com
Dworkin, Michigan State
Increasing foraging gene expression in the mushroom bodies changes
exploratory behavior from sitter to rover (reared in 100% food)
***
UAS-forT1a
Gal4
+ 30Y
+ 201Y
+ 739Y
None
*** p<0.001, ** p<0.01, * p<0.05
Burns et al 2012 PNAS
Chronic food deprivation early in life effects
adult fitness (fecundity)
Burns et al 2012 PNAS
foraging affects learning and memory:
the gene is responsive to the environment
Rovers have better short term memory. foraging acts in the mushroom
bodies for olfactory based aversive learning and memory
Mery et al 2007 PNAS
Example 3: Gene-Environment interplay
in response to social context
STM: sitters are sensitive to the learning context
(rovers and sitters are trained alone or in groups)
P = 0.20
P = 0.005
Kohn, Reaume, Burns, Sokolowski, Mery (submitted)
Increasing foraging enables sitter to learn when
alone
PKG activator (8-Bromo-cGMP) on flies trained and tested alone
P = 0.01
0.75
Proportion making the correct choice
0.7
P < 0.001
0.65
Sham Control
8-Bromo-cGMP
0.6
0.55
141
120
162
154
150
154
0.5
Rover
Sitter
Treatment
SS22
Decreasing PKG decreases learning in rovers
PKG inhibitor (KT5823) on individuals trained and tested alone
P = 0.01
0.75
Sham Control
Proportion making the correct choice
0.7
KT5823
0.65
0.6
0.55
111
112
135
136
139
139
0.5
Rover
Sitter
0.45
Treatment
S2
S2
Early adversity sets developmental trajectories
for health and behaviour across the life-time.
How?
a) Gene-Environment Interactions
b) Epigenetics
DNA is like books in a library. Limitless potential to inform
and inspire…….But they need to be read.
Health Risks Associated with Early Adversity and Low SES
Early Experience
Abuse
Family strife
Emotional neglect
Harsh discipline
Prevention
Health Risks
Depression
Drug abuse
Anxiety
Diabetes
Heart disease
Obesity
Individual differences
in neural and endocrine
responses to stress brain development,
Immune system
A New Science = EPIGENETICS
Epigenetics
the study of those
environmental factors that
alter whether DNA will be
“expressed” without
altering the DNA sequence
Factors that change the likelihood that a
book will be read.
Champagne and Mashoodh, 2009
What factors induce epigenetic changes?
Epigenetic
Variation
nutrition
stress
drug use
Environmental
toxins
social
interactions
hormones
smoking
When the DNA is read it is said to be “expressed”
hard to read
epigenetics
easier to read
Early adversity makes some genes difficult to read. Those
involved in: 1) how we cope with stress, 2) how our brain
develops and works and, 3) how we fight disease.
Social Interactions: Natural Variations in Maternal
Care in the Rat: High and Low Lickers and
Groomers. Differential Methylation of
Glucocorticoid Receptor in rats (and humans)
Michael Meaney, McGill University
Low licking and grooming
High licking and grooming
Cross fostering
Epigenetics: Cross-fostering shows direct effects
of maternal care on the expression of genes in the brain
(i.e. glucocorticoid receptor) involved with coping with stress!
0.8
GRir (ROD)
0.6
*
*
0.4
0.2
0.0
High/High
High/Low
Low/High
Low/Low
Biological Mom / Foster Mom
60
*
40
20
0
Control
Suicide Suicide
- Abuse + Abuse
GR-1F mRNA/GAPDH (log conc.)
GR 1-F CpG Methylation (%)
Early Abuse in Victims of Suicide
1.5
*
1.0
0.5
0.0
Control
Suicide Suicide
- Abuse + Abuse
McGowan et al 2009 Nature Neuroscience
Changes to the epigenome
are a cellular memory of an
environmental event
New Era of Research on the Origins
of our “Uniqueness”
Consequences?
• The mom’s behaviour (social context) affects the
lifelong health of the infants via later stress
reactivity
• The mom’s behaviour is transferred to the pups in
an epigenetic manner
• Is this epigenetic effect is reversible, how?
Early adversity sets developmental trajectories for
health and behaviour across the life-time.
How: mechanisms?
Gene by Environment Interaction and Epigenetics
When: sensitive periods?
What: early adversities?
(individual differences)
Drosophila foraging gene project:
Amsale Belay
Ralph Greenspan
Kate Osborne
Joel Levine
Mark Fitzpatrick
Chris Reaume
Locke Rowe
Tony So
Karla Kaun
Tad Kawecki
Craig Riedl
Bertam Gerber
Clement Kent
Thomas Hendel
Bryon Hughson
Aaron Allen
Hiwote Belay
Bee foraging gene project:
Yehuda Ben-Shahar
Alain Robichon
Gene Robinson
Ant foraging gene project:
Christophe Lucas
Human foraging gene project James Kennedy
Robert Levitan Hiwote Belay Sam Bidnur
Roger Ferreira
Torry Higgins
Learning and Memory
Fred Mery
Nancy Kohn
Epigenetic by Genetic
Interactions
How does the foraging gene respond to
food deprivation?
Hypothesis: Epigenetic modification of foraging by EHMT
euchromatin histone methyltransferases a
family of evolutionarily conserved proteins that write part of the
epigenetic code through methylation of histone 3 at lysine 9
(H3K9).
EHMT is a a key epigenetic regulator of neuronal genes and
processes.
EHMT in the transcriptional control of foraging
(Mutations in EHMT affect larval foraging behaviour and adult cognition)
foraging
gene
transcripts
Loss of methylation peak in EHMT mutants
USCS genome browser “LOMB” track
Kramer et al in prep
FORAGING protein levels are reduced in response to
food deprivation. This does not occur in EHMT
mutants EHMT(-)
Kramer et al in prep
EHMT modulates food dependent plasticity in
rover and sitter larval foraging behaviour
12
10
Pathlength (cm)
8
6
Fed
Food Deprived
4
2
0
forR
fors
wild type EHMT
fors2
forR
fors
fors2
EHMT mutants
I. Anreiter, J. Kramer, M.B. Soko
Adult Foraging Behaviour:
Number of drops consumed in 10 min
3
no of drops consumed in 10 min
2.5
2
1.5
1
0.5
0
forR
fors
wild type EHMT
forR
fors
EHMT mutants
I. Anreiter, B. Hughson, J. Kramer, M.B. Sokolowski
foraging’s behavioural plasticity may be
regulated via epigenetic modifications
through EHMT.
-foraging allele specific?
-food deprivation specific?
-other organisms? bees, ants, flies, humans?