Developmental Plasticity and Human Nature: Implications for … · 2011-07-29 · Developmental Plasticity and Human Nature: Implications for Health and Disease ... Nurturing Nature

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Developmental Plasticity and Human Nature:

Implications for Health and Disease

Karola Stotz ARC Research Fellow

ISHPSSB Meeting SLC July 2011

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Tour Guide •  New insights into Human Nature

•  Contingent Development (Epigenesis) •  Extended inheritance

•  New insights into Health and Dis ease •  Developmental plasticity •  Developmental Origin of Health and Disease •  Predictive Adaptive Reponses •  Environmental Mismatch Hypothesis •  Cases of Behavioral Epigenetics and

environmental epigenomics

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Reconstructing Human Nature •  Non-essentialist process view of human nature

•  Transcends features of universality/fixity to integrate plasticity/diversity

•  Prerequisite: developmental plasticity •  Framework:

•  Epigenesis of the developmental system even at molecular level •  DS: Extended organism - environment system

•  Extended Inheritance •  Allows for evolutionary significance of devo-environment

interplay •  Transcends the inherited- acquired distinction

•  Extended aspects of acquisition beyond ‘learning’ (‘Experience’)

•  Developmental Niche construction •  Construction of ontogenetic niche nurtures our nature

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Extended Inheritance

•  Allows for the reliable transmission of crucial information from parents to offspring

•  Provides reliability, but also plasticity in the provision of these resources

•  Adaptive and context-dependent transgenerational transmission of phenotypic strategies

•  A range of strategies to manage aspects of one’s offspring’s developmental environment to guide the developmental process

•  Enables “evolution by natural selection by reliably transferring developmental resources needed to reconstruct, maintain and modify genetically inherited components of the phenotype” (Badyaev & Uller 2009)

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Inherited, but still acquired

•  Developmental systems are often designed to be as ecologically open as possible

•  Evolution has trusted developmental niche to transmit extragenetic information vital for reproduction of life-cycle.

•  Devo niche as an information centre that exposes the young to stimuli of future relevance

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Nurturing Nature •  Organisms deploy a range of strategies to manage

aspects of their own or their offspring’s developmental environment to guide the developmental process.

•  Many of these processes can be understood as the adaptive and context-dependent transgenerational transmission of phenotypic strategies.

These biological advances •  call into question the coherence of the opposition

between ‘biological nature’ and ‘environmental influences/nurture’, and

•  subvert the nature/nurture dichotomy by relocating nurture at the molecular-level

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Developmental Plasticity = The real stuff of evolution

•  Development with built-in flexible responsiveness to both gene products and environment

•  Flexible development, rather than being an alternative to selection in the evolution of form, mediates the production of variable and condition-sensitive phenotypes of organisms, and hence selectable variation

•  Evolvability is the ability of particular features of systems to facilitate change through the generation of non-lethal phenotypic variation

•  Epigenetic information enables the interpretation of genetic information in response to a given environment through changes in gene expression

M.-J. West-Eberhard, Scott Gilbert, P. Bateson, M. Pigliucci,

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Peter Gluckman & Mark Hanson

•  Adoption of developmental perspective on human nature and the human life-cycle can inform efforts to reduce the burden of non-communicable disease, particularly in populations in rapid environmental

(e.g. nutritional) transitions.

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•  Developmental origin of Health and Disease •  Environmental influences affect cellular pathways during gestation,

enabling production of a broad range of adult phenotypes •  Epidemiological, clinical and experimental evidence links

early development to later risk of non-communicable diseases: •  The metabolic complex: obesity, insulin resistance/ type II diabetes,

cardiovascular disease •  Cognition (learning ability, attention) •  Mood disorders (e.g. anxiety, depression) •  Longevity/aging

•  Developmental Plasticity is adaptive phenomenon •  In adverse circumstances, alternative phenotypes that come with

costs can facilitate survival •  Gives advantage in environments that change of several

generations

DOHaD

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Predictive Adaptive Response (PAR) •  Early environmental cues shift developmental pathways

to modify phenotype in expectation of later environment •  Fetus treats nutrient supply through placenta a forecast

for the availability of food after birth, and prepares for this with a modified developmental trajectory

•  PARs: 1.  Induced by early environmental factors 2.  Respond to wide range of developmental environments 3.  Mediated by permanent changes of gene expression,

physiology and anatomy 4.  Result in effects that often manifest later in life

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Epigenetic mechanisms as mediator between genome and environment

•  During gestation and early postnatal life an individual becomes programmed for nutritional thrift in order to adapt to and survive in an environment of limited resources and poor nutrition.

•  Once established, this acquired metabolic phenotype is maintained throughout the lifetime of the individual, and does not change.

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Mismatch and Disease •  Mismatch between prediction and

real environment •  Developmental influences acting in

early life set the developmental trajectory for a phenotype better adapted for a low energy environment

•  This phenotype places individual at greater risk in a high energy environment

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NIH Genes, Environment and Health Initiative (GEI)

•  Mediators of the stress response are key locus for gene-environment interactions in the shared biology of depression and obesity

•  This diagram shows groups of cytokines, neuropeptides and neurotransmitters implicated in both obesity and depression

•  These substances interact with the HPA axis.

•  Owing to early epigenetic programming, chronic stress and differential gene expression, individuals may develop isolated or combined forms of depression and obesity.

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Mothering imprints •  Mothering characterized by high levels

of licking and grooming produces two interacting pathways of changes in the pup:

1.  Increased serotonin tone in the hippocampus leads to increased expression of the transcription factor NGF1-A.

2.  The first exon of the glucocorticoid receptor gene in the hippocampus is demethylated, and the histones surrounding it are acetylated.

•  The result is a glucocorticoid receptor gene that is permanently more open to transcriptional activation by NGF1-A.

•  This produces higher numbers of glucocorticoid receptors in the hippocampus of the rat as an adult, which gives rise to other distinctive endocrine and behavioral features.

transcription factor nerve growth factor–inducible protein A

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CIHR program in Maternal Adversity,

Vulnerability and Neurodevelopment (Mavan) •  Over five years, Michael Meaney and colleagues examine aspects of

parental care and their effect on the DNA of human babies. •  Being depressed during pregnancy is a form of stress, which can

render children more vulnerable to certain health and developmental problems.

•  Mothers with severe depression also tend to touch and caress their babies less than others.

•  The project will follow a group of depressed mothers throughout pregnancy.

•  Babies will be tested for 22 genes known to be related to aggressive or antisocial behaviour and learning difficulties (e.g. ADHD). The cognitive and social development of these children will be followed.

•  Given the link between glucocorticoids, brain development, and memory, they will also perform brain scans and measure stress hormones levels throughout the study.

•  PAR: In dangerous environments higher stress levels may make one more fearful and less likely to get into trouble.

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Stress-induced epigenetic inheritence

A.  Low stress conditions: dATF-2 specifically binds to its recognition sequence CRE (cyclic AMP response element) and likely cooperates with HP1 and chromatin-modifying complexes containing a histone methyltransferase to nucleate and spread heterochromatin assembly

B.  Heat shock or osmotic stress: dATF-2 is phosphorylated by stress-activated protein kinases including p38, which leads to release of phosphorylated dATF-2 from the heterochromatin region. Heterochromatin is disrupted, which increases the expression of genes located in the region. This epigenetic change is heritable and occurs by transcommunication between chromosomes.

•  The results suggest a mechanism by which the effects of stress are inherited epigenetically via the regulation of a tight chromatin structure.

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Acknowledgments

Collaborators:

Paul Griffiths (Sydney University) Maureen O’Malley (Sydney University)

This work is supported by ARC Grant DP0878650

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The Nurturing of Health and Disease

Developmental Plasticity Developmental origin of health

and disease Predictive Adaptive Reponses

Mismatch Pathways and Disease

Behavioral epigenetics

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Experience and Heredity: Epigenetically inherited adaptive response

•  Transference of essential developmental resources •  Transgenerational transmission of effects of experience

•  = intergenerational impact of environmental events •  = Acquired information passed on to progeny

•  Environmental cues experienced by previous generations shift the offspring’s developmental pathways to modify the phenotype in expectation of later environment

•  Transgenerational Developmental plasticity: •  = environmental cues are utilized to fine-tune phenotype to current

environment and to forecast future environment

•  Undermines distinction between innate and acquired

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In the News

The Seductive Allure of Behavioral Epigenetics Could chemical changes to DNA underlie some of society’s more vexing problems? Or is this hot new field getting ahead of itself?

Science 2 Jul 2010 329(5987):24-7

Can epigenetics underlie the enduring effects of a mother's love? Lizzie Buchen investigates the criticisms of a landmark study and the controversial field to which it gave birth. Nature 8 Sept 2010 467 (7312): 146-148

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Developmental Causes of Obesity •  Malnutrition

•  Famine •  Dieting •  Imbalanced nutrition (low protein; high sugar/fat diet)

•  Increased placental constraint •  First pregnancy •  Adolescent or late pregnancy •  Under/Overweight mothers •  Pregnancy diabetes •  Assisted reproduction: In vitro fertilization, cloning

•  Psychological/chemical Stressors •  High glucocorticoid exposure of fetus •  Exposure to toxins or endocrine disruptors (e.g. BPA)

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Mismatched phenotype •  Metabolism

•  Obesity •  Fatty liver •  Insulin resistance •  Leptin resistance •  Hyperphagia •  Fat preference in diet •  Impaired thermogenesis

•  Cognition •  Altered HPA axis •  Increased anxiety •  Reduced voluntary movement

•  Cardiovascular phenotype •  Hypertension •  Endothelial/cardiovascular

dysfunction

•  Aging •  Premature puberty

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Prenatal–postnatal interaction

1.0

1.5 2.0 2.5 3.0 3.5 4.0

Ret

rope

riton

eal f

at (%

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AD UN AD UN AD UN AD UN Control High Fat Control High Fat

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Leptin (ng/ml)

Fat pad Plasma leptin

Programming, diet p<0.001 Programming x diet interaction p<0.001

Normal mother Normal postnatal

diet (control)

From Vickers et al, Am J Physiol 2000; 279: E83-7

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1.0

1.5 2.0 2.5 3.0 3.5 4.0

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Leptin (ng/ml)



Undernourished mother

Normal postnatal diet


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1.0

1.5 2.0 2.5 3.0 3.5 4.0

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rope

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Normal mother High fat postnatal

diet


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1.0

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Leptin (ng/ml)



Undernourished mother

High fat postnatal diet


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Nurture goes Molecular: How the environment

effects gene expression

Epigenetics Parental Effects

Reductionism and Integration

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DNA does not exist as naked molecules in the cell: it is wrapped around nucleosomes (complex of 8 histone proteins) to form a substance known as chromatin.

Epigenetics comprises the heritable changes in gene expression in the absence of changes to the DNA sequence = Lifelong molecular memory storage mechanism put into place during development.

Epigenetics constitutes the main and previously missing link among genetics, [phenotype of health and] disease, and the environment.�

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DNA does not exist as naked molecules in the cell: it is wrapped around nucleosomes (complex of 8 histone proteins) to form a substance known as chromatin.

DNA methylation is a chemical modification of the DNA molecule itself. Methylation can directly switch off gene expression by preventing transcription factors binding to promoters.

Combination of Histone modification (histone code of de/acetylation, methylation, phosphorylation) causes the de/condensation of chromatin, making DNA in/accessible to transcription factors --> genes are activated/ silenced

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The Histone Code

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•  Genomic Imprinting (Parent-of-origin allelic effect) •  ‘differentially methylated regions (DMR)’ are expressed either

only from the allele inherited from the mother or from the father (insects, mammals, and flowering plants). More than 200 genes are imprinted in humans (H19 and NGF2)

•  Following DNA demethylation in germ cells, the genome is de novo DNA methylated in a sex-specific manner.

•  ‘Meta-stable alleles’: •  Methylation-variable positions (MVPs) are not uniformly

distributed throughout our genome, but are concentrated among genes that regulate transcription, growth, metabolism, differentiation, and oncogenesis.

•  Alterations in MVP methylation status create epigenetic patterns that appear to regulate gene expression profiles during cell differentiation, growth, and development, as well as in cancer.

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Examples •  Imprinting

•  Mule and hinny •  Human Growth factors (H19,

CDKN1C, IGF2) •  Prader-Willy/Angelman Syndrome

(methylated genes on CH15) •  Meta-stable epi-alleles

•  Agouti mice •  Daphnia water fleas •  Rat behavior •  Dutch hunger winter •  Memory formation (silencing of memory inhibitor PP1)

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Human Epigenome Project

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Epi-mutations and obesity •  Plasticity through altered expression of key regulatory genes

for cell number and differentiation early in development, permanently reset activity of many homeostatic mechanisms

•  Insulin-like Growth Factor 2 (IGF2) •  Maternally imprinted; Dutch Hunger Winter

•  Glucocorticoid receptor (GR) / hypothalamic-pituitary-adrenal (HPA) axis •  Rat stress reactivity; human depression and suicide risk

•  Agouti viable yellow (Avy) /Melanocortin Receptor (MC4R) •  regulation of eating and metabolism, sexual behaviour

•  Peroxisome proliferator-activated receptor alpha (PPARa) •  fatty acid b-oxidation, adipocytes differentiation, improves insulin

sensitivity

•  Serotonin receptor (5-HT2A)

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Reductionism and Integration •  Epigenetics of obesity highlights important step for the

study of ‘environmental contribution to development’ (‘nurture’) to turn reductionist and scientifically tractable.

•  However, while reductionistic investigative strategies are of vital importance, problems of postgenomic biology focus on the mechanisms through which biological function emerges from the interaction of numerous molecular components.

•  These problems can seldom be solved by the reductionist method - they ask for integrative explanatory strategies.

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Systems Biology and Disease a.  Classic genetic association

approaches identify variations in DNA that correlate with disease state. The attraction of this approach is the identification of the genetic causes of disease.

b.  Changes in DNA on their own do not lead to disease but to changes in molecular traits that go on to affect disease risk.

c.  A more realistic model is one in which constellations of genetic and environmental perturbations affect molecular states of networks that in turn affect disease risk.

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Metabolic mismatch affects life history: the timing of puberty

Maternal undernutrition during pregnancy and/or lactation interacts with postnatal high-fat diet to accelerate sexual maturation in female rats.

Sloboda et al, submitted

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Nature meets nurture •  Evo-devo, epigenetics and obesity research •  Development = ‘differential gene expression’ •  Often neglected: complex regulatory network

•  E.g., Environmental signals influence gene expression by triggering expression pathways and controlling the shape and function of regulatory molecules such as transcription factors

•  Very early life experiences cause predictive adaptive responses in the regulation of gene expression which manifest themselves in certain metabolic and psychological phenotypes (e.g. metabolic syndrome; depression)

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Relationship between quality of start to life and longer-term consequences: not a matter of

extremes

From Godfrey, Eur J Obstet Gynecol Reprod Biol 1998;78:141-50

0

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<5.5 6.5 7.5 8.5 9.5 >9.5

Pre

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Birth weight (lbs)

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Education and Diet

Educational level

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60 %

in th

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•  Young Southampton women with a lower level of educational attainment are more likely to eat an unbalanced “imprudent” diet

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Prevalence of diabetes 2003 •  Reunion 13.1 •  Seychelles 12.3 •  Bahrain 14.9 •  Egypt 10 •  Kuweit 12.8 •  Oman 11.4 •  Katar 16 •  Saudi Ara. 9.4 •  U. A. E. 20 •  Cuba 13.2 •  Dominian R 10 •  Fr. Guiana 11 •  Neth Ant. 12.3

•  Austria 9.6 •  Bulgaria 10 •  Bos & Her 9.6 •  Czech 9.5 •  Denmark 9.6 •  Germany 10 •  Latvia 9.9 •  Russia 9.3 •  Slovenia 9.6 •  Spain 9.9 •  Switzerland 9.5 •  Ukraine 9.7 •  North Amer. 9

Puerto Rico 13.3 Naura 30 Singapore 12.3 Tonga 12.4 Brunei 10.7 Mauritius 10.7 Cayman 9.7 Mexico 10.3 China 6-25 India 6-18 Top 10: India, China, USA, Indonesia, Japan, Pakistan, Russia, Brazil, Italy, Bangladesh

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A life history approach to interpreting a poor start to life – two phenotypic extremes

Gluckman et al, 2007. Am J Hum Biol 19: 1-19

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Parental Effects as Adaptations •  Parental (maternal and paternal) effects: •  sustained influences on offspring phenotype derived from

mother or father, apart from nuclear genes •  environmental effects on contemporary phenotypic

expression experienced in previous generations •  mechanisms to enhance offspring’s fitness

•  Spite the mother, fight the offspring •  natural selection has shaped offspring to respond to subtle

variations in parental behaviors as a forecast of the environmental conditions they will ultimately face after independence from the parent

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Systems Biology and disease

•  Tissue-to-tissue coexpression (TTC) networks between genes in heterogeneous tissues.

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Diabetes Worldmap

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Extended Inheritance

•  Allows for the reliable transmission of crucial information from parents to offspring

•  Provides reliability, but also plasticity in the provision of these resources

•  Adaptive and context-dependent transgenerational transmission of phenotypic strategies

•  A range of strategies to manage aspects of one’s offspring’s developmental environment to guide the developmental process

•  Enables “evolution by natural selection by reliably transferring developmental resources needed to reconstruct, maintain and modify genetically inherited components of the phenotype” (Badyaev & Uller 2009)

Developmental Plasticity and Human Nature: Implications for … · 2011-07-29 · Developmental Plasticity and Human Nature: Implications for Health and Disease ... Nurturing Nature

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