Transcript Gene-Environment and Gene

Genes, Environment and Health
Where are the Connections?
Byron C. Jones
The Pennsylvania State
University
The Problem
• The challenge of increases in
greenhouse gasses, toxins and related
stress on ALL organisms, including
humans presents a particularly
compelling case for studying individual
differences in response to
environmental perturbations.
• Alternatively, we are getting a unique
chance to see evolution in action!
The Premise
• Most of health related biological
processes are influenced by multiple
genes, their interaction with the
environment and with each other.
• This includes:
–
–
–
–
Etiology of degenerative diseases
Etiology and course of infectious diseases
Source and course of vector-borne diseases
Etiology and course of psychiatric disorders
The Promise
• A more thorough understanding of
diseases through the study of genegene and gene-environment interactions
• Better understanding of vector-borne
diseases
• New treatments for disease through
pharmacogenomics
• New prevention strategies – to amplify
Dr. Sapego’s presentation
Why Study Interactions?
• Genes and environment work together
• Genes also influence other genes
(epistasis)
• Therefore:
• Not everyone is equally susceptible to
stressors, toxins, etc.
• This is the way it really works – I did
not say that life is fair!
How do we define GXE?
• In the same sense that we can show non
additive effects in any factorial design,
we can show that in some cases, genes
and environment, when accounted for
experimentally do not cover the totality
of phenotypic variance.
• Thus Vp=Vg+Ve+(Vgxe)+V
Are there other types of genotype
environment associations?
• Genotype-environment correlation – how
the genetic makeup of individuals leads
them into specific environments.
– Passive -- shy children placed into state
hospitals
– Reactive – response of individuals to
actions of others -- interactive
– Active – “Niche Picking” – selecting or
creating environments to match genetic
propensities
Evidence for GXE
• Discordant identical twins – the work of
Irving Gottesman on genetics of
schizophrenia.
• The seminal work of Robert Cloninger on
alcohol typologies – one has genetic
predisposition and is triggered by the
environment
• New research on depression, the serotonin
transporter gene and stressful environments
Some Experimental Evidence
• Gariepy, Rodriguiz and Jones, 2002
– Study of experimentally administered
different environments during development
in lines of mice selected for high and low
aggression.
– Handling vs undisturbed
– Group vs Isolate housing
Spontaneous Activity
• Open field ambulation
• Unsupported rearings
Corticosterone Response to Testing
• Serum collected 20 min after
introduction into the open field
• Corticosterone measured by RIA
• Baseline corticosterone values obtained
in separate animals, nonhandled, not
isolated.
Dopamine D1 receptor densities
• After open-field testing animals were
killed by halothane overdose, and the
brains removed with caudate-putamen
and nucleus accumbens dissected.
• Maximum binding for 3H-SCH 23390 in
membrane fragments
• No effects of handling or isolation in
the caudate-putamen
• Nucleus accumbens….
Isolate Housed
Group Housed
Aggressive/Fear-like Behaviors
•
•
•
•
Latency to attack an intruder..
Latency to freeze..
Attacks
Freezing episodes
Conclusions
• HPA system seems to be a major target
of GXE sensitivity
• Aggression also seems to be sensitive
• Dopamine system seems to be
refractory
• Moral of the story – not all systems in
an organism are equally susceptible
Gene-Environment – Human Studies
• The seminal work of Robert Cloninger, type 1
and type 2 alcoholics
– Type 2 – gender limited (no longer holds)
– Type 1 – environmentally limited
• The exciting new work from Avshalom Caspi
and Terrie Moffitt on the effect of the 5HTT gene on stressful situation-depression.
• Serotonin transporter blockers are used to
treat depression
Practical Considerations
• New ammunition for predicting and
possibly preventing psychiatric and
other disorders?
• New ammunition for treating some
psychiatric disorders?
OK, So What About Other
Health Issues?
• Host-parasite relationships
• Pharmacogenetics/toxicogenetics and
genomics
Host-Parasite Interactions
• Mosquitoes and their (and human) parasites:
–
–
–
–
–
–
Plasmodium
Filaria
Dengue
West Nile
Equine encephalitis
Etc.
• How will the balance be changed by global
warming?
Host Resistance to Filaria
• Aedes egypti and Brugia pahangi
– filarial parasite that in turn carries
Wolbachia bacteria –affects fecundity, etc
– acid hydrolase enzymes linked to host
susceptibility in Aedes
Toxicogenetics
• Follows same principles as
pharmacogenetics – understanding basis
of individual differences in response to
environmental toxins
What Have We Learned?
• Most of our health issues fit within the framework of
“complex trait analysis”
– Multiple genes/alleles are involved
• Networks of genes may be players
– Environmental factors vary in importance
– Genes can alter the environment as well as vice versa
• New analytical techniques in bioinformatics will aid in
identifying individuals who are sensitive to
environmental hazards
• The ultimate goal is to tailor prevention and
treatments based on genetically-based individual
differences
SO WHAT?
• Global warming, greenhouse gasses, new sources of
energy all have probable impact on biological and
ecosystems.
• The exact course of the effects on health and
environment cannot be precisely predicted.
• Take for example the change in electromagnetic
radiation incident on the oceans and impact on the
thousands of species of phytoplankton. Like humans,
all species show genetic-based individual differences
in susceptibility to environmental perturbations…..
Commentary
• In terms of baseball:
– It’s the top of the 9th inning and we are at
bat – ergo have a chance of winning the
game
– However, nature bats last.