Early Environmental Stress and Epigenetics

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Annu. Rev. Anthropol. 2016.45:233-249. Downloaded from www.annualreviews.org
Connie J. Mulligan
Department of Anthropology, Genetics Institute, University of Florida, Gainesville,
Florida 32610-3610; email: cmulligan@ufl.edu
Annu. Rev. Anthropol. 2016. 45:233–49 Keywords

First published online as a Review in Advance on DNA, genetic, DOHaD, developmental plasticity, adaptation
July 22, 2016
The Annual Review of Anthropology is online at Abstract

anthro.annualreviews.org
The field of social and behavioral epigenetics examines the role of epige-
This article’s doi: netic modifications to mediate the effect of psychosocial stressors on an
10.1146/annurev-anthro-102215-095954
individual’s health and well-being. Epigenetic modifications influence gene
Copyright c 2016 by Annual Reviews. expression, which can lead to changes in an individual’s phenotype. DNA
All rights reserved
methylation is an important epigenetic modification that varies throughout
the lifespan and appears to respond to a wide range of psychosocial and bio-
logical stressors. The effects of early-life adversity impact future health and
may be passed on to future generations. The underlying model proposes that
stress influences health via an epigenetic mechanism involving altered DNA
methylation and gene expression. This review summarizes a range of studies
that have identified DNA methylation at specific genes and throughout the
genome in association with multiple psychosocial stressors, including psy-
chiatric disorders, sexual and physical abuse, and war trauma. Future studies
should test a comprehensive list of epigenetic modifications in association
with psychosocial stressors and multiple health outcomes.
233
INTRODUCTION
Our ability to successfully adapt to a constantly changing environment and respond to increasingly
Stressor: a stimulus complex stressors is one of the traits that make us profoundly human. Developmental plasticity,
that triggers the stress as the foundational concept from which adaptation emerges, has long been studied by anthro-
response or, more pologists (Boas 1912, Frisancho 1993, Lasker 1969). Fetal developmental plasticity is focused on
generally, an event
the postnatal effects of adaptive responses to in utero conditions (Kuzawa & Pike 2005, Pluess &
that we do not feel
capable of dealing with Belsky 2011). Of particular interest is the fetal response to stressful conditions, such as nutrient
limitation (a biological stressor) or maternal depression (a psychosocial stressor).
Psychosocial:
stressors, and aspects As a consequence of fetal plasticity and adaptation, the possibility has emerged that the effects
of the environment, of early-life events may be passed to future generations, i.e., intergenerational or transgenerational
that involve both inheritance (e.g., Drake & Liu 2010, Kuzawa & Thayer 2011, Painter et al. 2008, Seckl & Meaney
psychological and 2006, Siklenka et al. 2015, Thayer & Non 2015). An evolutionary perspective proposes a selective
social components
advantage for the fetus to accurately predict the postgestational environment based on intrauterine
Intergenerational: cues (Kuzawa 2005, Kuzawa & Quinn 2009, Kuzawa & Thayer 2011). In contrast, the possibility
transmission of
of maladaptive responses and an explicit focus on adult health and disease influenced by early-life
information to
individuals who share experiences are articulated in the developmental origins of health and disease (DOHaD) hypothesis
an environmental (Barker 1990, Benyshek 2013, Gluckman et al. 2008, Gluckman & Hanson 2006, Seckl & Meaney
exposure, i.e., a 2006).
pregnant woman, her According to the DOHaD hypothesis, the potential impact of early-life experiences on future
fetus, and the fetus’
health and disease risk is thought to be particularly salient (Barker et al. 2012, Benyshek 2013).
germ line
The underlying assumption is that there is a critical period of developmental plasticity in utero
Transgenerational:
when many fetal tissues are especially plastic and sensitive to the maternal environment (Davis
transmission of
information to & Sandman 2010, Gluckman et al. 2008, Kuzawa & Pike 2005, Kuzawa & Quinn 2009). During
individuals who do not this period, the phenotype that is most appropriately adapted to the intrauterine environment is
share an selected and expressed. However, if the intrauterine environment is unusually stressful or non-
environmental representative of the postgestational environment, the selected phenotype may be maladaptive in
exposure, i.e., the
later life and may result in increased disease risk (Bateson et al. 2004, Kuzawa 2005). The specific
great-grandchildren of
a pregnant woman disease that emerges in adulthood may reflect the timing of adverse events during gestational
development (Barker et al. 2012, Roseboom et al. 2011).
Phenotype:
the observable In addition to later-life effects of prenatal trauma, the effects of prenatal stress might be passed
characteristics of an to future generations. Some of the most compelling evidence implicating the effects of prenatal
organism, including stress on intergenerational health comes from the Dutch famine of the mid-1940s (Roseboom
morphology, et al. 2011). Painter and Roseboom have documented reduced birth length and poor health in
development,
later life in the grandchildren of women pregnant during the famine, suggesting that the stress of
physiology, and
behavior starvation has intergenerational effects (Painter et al. 2008). Heijmans et al. (2008) showed that
individuals who were prenatally exposed to the famine had reduced methylation of the imprinted
Gene: a segment of
DNA that codes for a IGF2 gene six decades later, suggesting that methylation may mediate the intergenerational effect
functional protein of prenatal stress exposure.
product. Humans have Both biological and psychosocial stressors can impact health, and they are mediated by the
∼20,000 genes psychobiological stress response. The stress response is a multisystem process in which the
Gene expression: hypothalamic-pituitary-adrenocortical (HPA) axis and the sympathetic-adrenomedullary (SAM)
the process by which a system coordinate to provide proper biological and behavioral responses to stress (Gunnar &
gene is translated into
Quevedo 2007). The HPA system produces glucocorticoids (GCs) (cortisol in humans), with the
a functional gene
product, usually a brain as a major target. GC production is a cascade process, and many of the effects of GCs are
protein carried out by modified gene expression such that the HPA system is relatively slow to respond to
a stressful event. In contrast, the SAM system releases epinephrine to mobilize resources and more
234 Mulligan
directly acts on the target organs to facilitate a rapid stress response, known as the fight-or-flight
response.
In this review, I focus on the effects of stress on health, with an emphasis on psychosocial
Epigenetics:
stressors. Psychosocial stressors include a wide range of stressors including (but not limited to, chemical modifications
and in no particular order) childhood abuse, drug addiction, poverty, poor education, lack of to the genome that do
family support, war trauma, racial discrimination, and depression and other psychiatric disorders. not alter the DNA
These stressors have been studied across multiple academic fields including cultural anthropology, sequence but can
influence expression of
psychology, psychiatry, sociology, and economics. Isolating the influence of a psychosocial stressor
the encoded genes
on health can be challenging for a number of reasons. It can be difficult to define the temporal
DNA methylation:
range of psychosocial stressors because some of them are isolated events (e.g., a single sexual
attachment of a methyl
assault), some are chronic events (multiple suicide attempts), and some are long-term situations group, usually to a
(poverty). Stressors in real life often overlap and it may be impossible to isolate psychosocial-only cytosine base in the
stressors when biological stressors, e.g., nutrition or toxin exposure, may also be relevant in certain DNA, is a common
situations. Many stressors exist on a continuum, i.e., more or less depressed, and it is important type of epigenetic
modification
to consider the entire range of effects because both negative and positive events have important
influences on health. DNA: the genetic
instructions used in
In this review, I focus on the effects of early-life events because these events are particularly
the development and
salient in the programming processes with which the body interprets cues from the environment functioning of all
to predict the response, or phenotype, with the best chance for future survival. This programming, known living
or early-life prediction and planning, involves gathering information from a wide range of inputs organisms
and then processing that information to identify, select, and express the optimal phenotype. All Genome: the genetic
these steps require exquisite coordination of multiple systems within the body. material of an
Thus, the final piece of this review introduces epigenetics as a mechanism by which the multiple organism that includes
both the genes and the
processes of stress response, fetal programming, adaptation, and transgenerational effects among
noncoding (nongenic)
others, may be integrated. Epigenetic modifications have the potential to produce a response to sequences
psychosocial stressors that results in a condition or phenotype that may then feedback to influence
DNA seqnuence:
the process in a circular fashion; e.g., poverty may create epigenetic modifications that increase the order of nucleotide
the risk of depression, which then further entrenches the individual in poverty. Although much bases (adenine,
important work on epigenetics and stress has been performed in animal models, in this review, I guanine, cytosine,
focus almost exclusively on human studies. Furthermore, I focus on one type of epigenetic mod- thymine) in a molecule
of DNA
ification, DNA methylation, because virtually all current studies on epigenetics and psychosocial
stress have assayed DNA methylation variation and because the full range of epigenetic modifi-
cations is beyond the scope of this review (for a review of epigenetic modifications, particularly
those responsible for reprogramming cells, see Brix et al. 2015).
SOCIAL AND BEHAVIORAL EPIGENETICS

Adaptive and maladaptive responses to early-life experiences can impact immediate mental and
physical health as well as influence later-life disease risk. However, the underlying molecular mech-
anism(s) to mediate this process, specifically the translation of lived experiences and responses
into potentially heritable changes in phenotypes related to adaptation and health, is not known. In
recent years, epigenetic changes have been proposed as a possible mechanism by which psychoso-
cial stressors are incorporated into a biological reality and, in terms of DOHaD, the mechanism
by which the most adaptive phenotype based on early-life experiences is selected and expressed
(Essex et al. 2011, Kinnally et al. 2011).
Epigenetic changes are chemical modifications to the genome that do not alter the DNA
sequence but do influence expression of the encoded genes (Figure 1). Specifically, epigenetically
www.annualreviews.org • Early Environment, Stress, and Epigenetics 235

Cytosine
Guanine
Thymine
Adenine
Methyl
group
Figure 1
Depiction of a DNA molecule showing the methylation of some, but not all, cytosine bases, as often occurs in the cell.
determined changes in gene expression may identify a particular phenotype to be expressed in

response to a psychosocial stressor (Figure 2). Originally, DNA methylation was proposed to
silence genes, i.e., to turn off gene expression, but recent research suggests that DNA methylation
correlates both positively and negatively with gene expression depending on the specific gene and
part of the gene, as well as the cell and tissue type ( Jones 2012, Plongthongkum et al. 2014) From
the perspective of social and behavioral epigenetics, methylation at enhancers may be particularly
variable over the lifespan and may be more sensitive, or responsive, to environmental stimuli (e.g.,
Johansson et al. 2013).
The term epigenetic has evolved since its first mention in the 1940s, when it was used to
explain how genes create certain phenotypes [Waddington 2012 (1942)], to its current definition,
i.e., changes in phenotype or gene expression caused by mechanisms other than changes in the
underlying DNA sequence. One of the most important types of epigenetic modifications is the
attachment of a methyl group to a DNA molecule, i.e., DNA methylation (Handel et al. 2009).
Epigenetic alterations were first studied in imprinting diseases, such as Prader-Willi and Angelman
syndromes, in which different diseases are caused by genetic defects in the same part of the
genome depending on which parent carries the defect; i.e., inheriting the genetic defect from the
father causes Prader-Willi syndrome, but inheriting the defect from the mother causes Angelman
syndrome. More recently, epigenetic abnormalities have been associated with the development of
cancer through hypermethylation of promoter CpG islands, leading to the inactivation of tumor
suppressor genes and aberrant histone modifications (Choi & Lee 2013, Esteller 2007, Herman
& Baylin 2003).
CpG islands: More speculative is the idea that epigenetic alterations may play a broad role in trans-
a cluster of lating changes in the social and behavioral environment into changes in gene expression,
cytosine-guanine which is the focus of the emerging field of social and behavioral epigenetics (Mulligan 2015)
dinucleotides that are (Figure 3). The term social and behavioral epigenetics focuses on the effect of psychosocial
often the focus of
DNA methylation
stressors on a phenotype and is intended to stimulate study within the social sciences be-
cause much work on epigenetics has already been conducted in the biological sciences; this
Stress Methylation Gene expression Phenotype
Figure 2
Proposed model of stress influencing a phenotype via an epigenetic mechanism that alters gene expression.
236 Mulligan
Figure 3
A wide range of psychosocial factors (both positive and negative) influence our lives, including (top right,
continuing clockwise) personal finances, our mood, psychiatric disorders such as depression or anxiety,
parenthood and family, our neighborhoods and homes, nutrition and physical activity, and poverty and
homelessness. These factors impact our mental and physical health and may affect the expression of our
genes and genome through epigenetic modifications. In turn, epigenetic modifications to specific genes and
our genome may impact psychosocial factors in our lives, e.g., poverty may create epigenetic modifications
that increase the risk of depression that then further entrenches the individual in poverty. Figure provided
courtesy of Buster O’Connor.

term was established during a 2014 workshop sponsored by the National Science Foundation,
the National Institute of Child Health and Human Development, Research Councils United
Kingdom, and the UK Science and Innovation Network in Potomac, Maryland (see workshop re-
port at http://www.nichd.nih.gov/about/meetings/2014/Documents/ExecSocialBehavEpi
genetics_Sum.pdf ).
Over the past decade, much progress has been made to establish the field of social and behavioral
epigenetics and begin to identify foundational questions. In 2004, Szyf, Meaney, and colleagues
published one of the most highly cited papers ever published in Nature Neuroscience (Weaver
et al. 2004). They reported changes in newborn methylation patterns in the promoter of the GC
receptor (which is involved in the HPA response to stress) that correlated with differences in
nurturing behaviors of mother rats to their offspring (Weaver et al. 2004). Specifically, Weaver
et al. (2004) found that rat pups raised by mothers who showed high levels of nurturing behaviors
(pup licking and grooming, arched-back nursing) exhibited lower levels of DNA methylation at the
GC receptor promoter and more moderate HPA responses when compared with pups raised by
mothers with low levels of nurturing behaviors. These differences in methylation patterns emerged
during the first week of life and persisted into adulthood. Treatment with a chemical that interfered
with DNA methylation removed the between-group differences in methylation patterns, GC
receptor expressions, and HPA responses, which suggests a causal relationship between maternal
and offspring behavior, GC receptor methylation, and GC receptor gene expression. Furthermore,
the DNA methylation differences were reversible if rat pups were cross-fostered, which implies
possible reversibility of the maternal behavior–driven, epigenetic-induced changes. This study
has enormous implications for the possibility that our psychosocial environment impacts us at the
level of the genome and influences behavior.
GENETIC LOCI INVOLVED IN AN EPIGENETIC RESPONSE

TO THE PSYCHOSOCIAL ENVIRONMENT
Epigenetically determined responses to psychosocial stressors may have evolved in higher-order
organisms as a mechanism to provide rapid, short-term responses to changes in the psychosocial
environment. In contrast, genetic changes to the DNA sequence of the genome would provide
long-term adaptations. The number of genes involved in an epigenetic response to the psychosocial
environment, i.e., the number of genes that are epigenetically sensitive to the environment, would
likely be relatively small because the majority of genes must continue to function regardless of
changes in the environment. For instance, in our study of prenatal exposure to maternal stress
in mother–infant dyads in the Democratic Republic of Congo (DRC), we found that only 212
CpG sites out of 431,048 studied sites correlated with maternal stress (false discovery rate = 5%),
suggesting a very small number of environmentally sensitive CpG sites (Rodney & Mulligan 2014).
Glucocorticoids and Additional Studies of NR3C1 Methylation

GCs are a class of steroid hormones with a wide range of effects on immunologic, cardiovascular,
and metabolic functions. GCs also act on various parts of the brain and are involved in memory
formation, particularly memories associated with strong emotions. GCs influence the function-
ing and levels of other hormones, such as insulin, leptin, and sex steroids, although the exact
mechanisms are not well understood. Cortisol is the most important GC in humans and, like all
GCs its effect is expressed by binding to the GC receptor. GCs have been proposed as a primary
candidate for fetal programming, in part because they have multiple effects on fetal development,
most notably on lung maturation, and because elevated GC levels during pregnancy are correlated
238 Mulligan
with low birthweight (Cottrell & Seckl 2009, Davis & Sandman 2010, Seckl & Meaney 2006).
In epigenetic studies, methylation of the NR3C1 gene, which encodes the GC receptor, has been
widely studied in relation to early-life stress because of its important role in the HPA axis response
to stress (Turecki & Meaney 2016).
Oberlander et al. conducted one of the first studies of GC receptor NR3C1 methylation in
humans by investigating the effect of maternal stress on a developing fetus. They found increased
methylation of the NR3C1 promoter in newborns that was associated with prenatal exposure
to third-trimester maternal depressed or anxious mood (Oberlander et al. 2008). Furthermore,
they found increased salivary cortisol stress reactivity in infants at three months that correlated
with prenatal exposure to maternal stress and increased NR3C1 methylation, suggesting that a
stress phenotype may emerge very rapidly in exposed infants and may be mediated by NR3C1
methylation and expression.
We focused initially on NR3C1 methylation in our study of prenatal exposure to maternal stress,
newborn birthweight, and DNA methylation in mother–infant dyads in the DRC (Mulligan et al.
2012, Rodney & Mulligan 2014). We found a strong correlation between three models of maternal
stress (material deprivation, mundane stressors, and war stress) and birthweight. War stress had
the strongest effect and accounted for 35% of the variance in birthweight. The association between
maternal stress and newborn birthweight provided the foundation upon which to investigate the
role of DNA methylation at the NR3C1 promoter. We found an association in which increased
maternal stress, increased NR3C1 promoter methylation in newborns, and decreased newborn
birthweight were correlated. In this context, increased newborn methylation may have occurred
as a short-term response to increased maternal stress, but it may have long-term repercussions
if increased methylation constrains plasticity in expression of stress-related genes later in life.
Significantly, altered NR3C1 promoter methylation in association with maternal stress was found
only in newborns, not in mothers, which is consistent with the tenets of the DOHaD hypothesis
that maternal stress modifies offspring biology. Furthermore, there were no identically methylated
sequences between mothers and their infants, suggesting that methylation marks at NR3C1 may
be more susceptible to environmental influences than to genetic influences.
Other studies have found evidence of a significant role for NR3C1 promoter methylation
and a range of psychosocial stressors. McGowan et al. (2009) were the first to study NR3C1 in
brain tissue and found increased promoter methylation and decreased gene expression in suicide
victims with a history of childhood abuse in comparison to suicide victims with no history of
abuse and nonsuicide controls. Radtke et al. (2011) found altered NR3C1 promoter methylation
in children aged 10–19 years old that correlated with maternal retrospective recall of intimate
partner violence. No correlation was found between intimate partner violence and methylation
in the mothers, similar to our results with maternal war exposure in the DRC and consistent
with the tenets of the DOHaD hypothesis. Yehuda et al. (2014) found lower NR3C1 promoter
methylation in combat veterans with post-traumatic stress disorder (PTSD), which is consistent
with a model in which increased NR3C1 expression leads to the enhanced GC receptor sensitivity
seen in PTSD patients. Building on this result, Vukojevic et al. (2014) found that increased NR3C1
promoter methylation and reduced NR3C1 expression were associated with less intrusive memory
of a traumatic event and reduced PTSD risk in male, but not female, survivors of the Rwandan
genocide. This result is consistent with the role of GC receptor signaling in the regulation of
emotional memory processes in which the memory-enhancing effects of stress-induced elevations
of glucocorticoids are increased in men (Andreano & Cahill 2006).
Two meta-analyses of dozens of studies of early-life stress and NR3C1 promoter methylation
found that both hyper- and hypomethylation may be maladaptive and that the level and timing
of NR3C1 promoter methylation may be critically important for health and future disease risk

(Palma-Gudiel et al. 2015b, Turecki & Meaney 2016). Palma-Gudiel et al. (2015b) found that
hypermethylation at select CpG sites generally associates with early-life stress, including sexual
or physical abuse, suicide, eating disorders, psychiatric disorders, and prenatal stress, whereas a
more global, promoter-wide pattern of hypomethylation was associated with PTSD. The authors
suggest a possible mechanism in which the timing of the stress exposure creates an epigenetically
controlled modification of HPA function that ultimately determines the specific disease pheno-
type; specifically, early-life stress may increase NR3C1 methylation, which decreases GC receptor
expression, promotes GC resistance, and increases the risk for psychiatric disorders in adulthood.
In contrast, later exposure to trauma may induce demethylation in the same regions of the NR3C1
promoter, thus increasing GC expression and increased sensitivity of the HPA axis. Moreover,
prior hypomethylation of the NR3C1 promoter may increase susceptibility to develop PTSD via
increased recall of negative memories in early life and adulthood.
Methylation at Other Genes and Throughout the Genome

Studies of methylation at other genes in association with early-life stress are more infrequent, in
part because it is difficult to identify good candidate genes. As stated previously, the percentage
of the ∼20,000 human genes that may have evolved to respond epigenetically to the psychosocial
environment is likely to be quite small. Likely candidates include genes involved in serotonin and
dopamine release, e.g., SLC6A4 and SLC6A3, as well as genes involved in placenta function, such
as 11ß-HSD2, which shields the fetus from excess maternal GC. Jawahar et al. (2015) provide an
excellent review of genes with altered epigenetic signatures in response to early-life adversity.
In addition to NR3C1, three other genes are known to regulate the HPA axis (i.e., CRH, CRHBP,
and FKBP5) and are good candidates to mediate an epigenetic response to psychosocial stress. We
found widespread effects on HPA axis gene methylation with significant methylation changes at
transcription factor binding sites in all three genes in association with chronic stress and war trauma
in mothers and newborns in our DRC study (Kertes et al. 2015). Methylation at FKBP5 has also
been associated with childhood trauma–dependent psychiatric disorders in adulthood (Klengel
et al. 2013), with Holocaust survivors and their offspring, with some cases of childhood physical
and sexual abuse (Yehuda et al. 2015), with low socioeconomic status (SES) during childhood
(Needham et al. 2015), and with severe social deprivation, such as early-life institutionalization
in Romanian orphans (A.L. Non, B.M. Hollister, K.L. Humphreys, A. Childebayeva, K. Esteves
et al., manuscript under review).
Brain-derived neurotrophic factor (BDNF ) is another good candidate gene because it is
affected by the HPA axis response; i.e., stress-induced increase of GCs increases anxiety and
impairs BDNF signaling, and evidence indicates that BDNF and NR3C1 interact in stress-related
disorders (Braithwaite et al. 2015, Chiba et al. 2012). Multiple studies have shown that BDNF pro-
moter methylation associates with early-life stress and may explain later adult psychopathology;
specifically, BDNF methylation has been associated with depression (Kang et al. 2015), suicide
(Keller et al. 2010, Kim et al. 2015), and eating disorders, especially when co-occurring with child-
hood abuse or borderline personality disorder (Thaler et al. 2014) or Alzheimer’s disease (Chang
et al. 2014) and with response to treatment such as psychotherapy (Perroud et al. 2013). BDNF is
well known to be involved in the pathophysiology of depression, and BDNF methylation has been
suggested as a biomarker to diagnose depression (Fuchikami et al. 2011). Furthermore, Gassen
et al. (2015) found that treatment of cells isolated from depressed patients with the antidepressant
paroxetine correlated with BDNF abundance and clinical treatment outcomes, suggesting that
BDNF expression may help modulate the action of antidepressants.
Furthermore, the genes that regulate DNA methylation may also be involved in an epigenetic
response to psychosocial stress; i.e., the genes in charge of DNA methylation may themselves be
240 Mulligan
differentially methylated and expressed as part of an orchestrated response to psychosocial stress.

Laget et al. (2014) found that DNMT1 and MBD4 (genes involved in methylation) proteins are
recruited to sites of DNA damage caused by oxidative stress (a biological stressor caused by the
toxic effects of reactive oxygen molecules known to damage DNA), which is a clear example of
methylation genes responding to environmental stressors. In our DRC study, we found that ma-
ternal stress correlated with a genome-wide decrease in methylation in mothers but not in their
offspring, which suggests that the individual who directly experiences the stressor may be most
likely to experience a genome-wide epigenetic response (Rodney & Mulligan 2014). In terms of
an underlying molecular mechanism, we found a correlation between maternal stress, maternal
genome-wide mean methylation, and methylation at DNMT3A, which may reflect DNMT3A’s
role in maintaining somatic cell methylation (Clukay et al. 2016). We also saw a correlation
between genome-wide mean methylation and methylation at three methylation complex genes
(i.e., DNMT3A, DNMT3B, and DNMT3L) in newborns, which is consistent with a well-
characterized feedback loop among these genes to establish methylation profiles in utero (Clukay
et al. 2016). These results suggest that altered methylation of the methylation genes may be part
of a molecular mechanism underlying the biological response to stress.
Scholars have also begun investigating the effect of psychosocial stressors on genome-wide
changes in methylation. For example, Cao-Lei et al. (2014) found altered genomic methylation
patterns in 13-year-old children of women who had been pregnant during the 1998 Quebec ice
storm; specifically, prenatal maternal stress was correlated with offspring methylation at 1675
CpG sites in 957 genes primarily related to immune function, which provided evidence of long-
term and genome-wide effects of prenatal stress exposures. Fisher et al. (2015) found site-specific
methylation differences throughout the genome at age 10 in 24 monozygotic twin pairs who
were discordant for age-12 psychotic symptoms, and the top-ranked differentially methylated
site was also hypomethylated in postmortem prefrontal cortex brain tissue from schizophrenic
patients. These results suggest that epigenetic variation identified in peripheral tissue, like blood,
may correlate well with potentially causative changes in the brain and may indicate susceptibility
to schizophrenia and other mental health disorders. Non et al. (2014) found a small number of
CpG sites with different DNA methylation levels (42 out of 453,857) that associated with prena-
tal exposure to maternal depression or anxiety relative to selective serotonin reuptake inhibitor
(SSRI)-medicated maternal depression/anxiety or unexposed neonates.
Two studies of genome-wide methylation levels have leveraged the power of animal models
to investigate, and manipulate, dominance rank and the stress associated with one’s position in
the social environment. Tung et al. (2012) showed that gene expression data could predict social
status with 80% accuracy in 10 social groups of female rhesus macaques, even in cases where the
individual’s rank changed during the study. They also found that differences in cell type composi-
tion between samples, variation in GC signaling, and DNA methylation patterns all contributed
to the association between dominance rank and gene expression, which demonstrates the impor-
tance of the molecular response to social conditions (Tung et al. 2012). Lenkov et al. (2015) tested
DNA methylation as a mechanism to mediate changes in dominance rank. Using African cich-
lid fish, they could manipulate social status by injecting low-status individuals with methylating
agents (those individuals were statistically likely to increase in rank) and demethylating agents
(statistically unlikely to increase in rank).
OTHER PSYCHOSOCIAL STRESSORS UNDER STUDY

The majority of stressors discussed in this review thus far are stressors that most people in the
United States may experience. However, additional stressors are also worthy of study either
because a large proportion of people do experience them, even if the stressor is nonrandomly
distributed across the United States, or because the stressor represents an extreme that may elicit
a more easily detectable biological or molecular signal. For instance, war often creates multiple
extreme stressors (e.g., witnessing the death of a loved one, becoming a refugee, or experienc-
ing multiple sexual assaults) in the same study population that, while statistically confounded,
arguably create one of the most stressful situations possible in a study organism, such as humans,
that cannot be experimentally manipulated. For instance, our study in the DRC showed a signifi-
cant correlation only between maternal genome-wide methylation and war-related stress but not
with mundane stress or material deprivation (Rodney & Mulligan 2014). Moreover, it is difficult
to identify candidate genes, so it may be necessary to study individuals in an extremely stressful
environment to identify the relevant genes, and those genes can then be targeted in future studies
with more moderate stressors.
War and Violence

War, and more generally violent conflict, has long been a focus of medical anthropologists. Pike
and collaborators (2010) combine ethnographic methods and stress biomarkers to study violent
conflict, and psychosocial stressors more generally, in a range of African communities to document
the varied effects of conflict and stress on health (Pike et al. 2010, Pike & Williams 2006, Straight
et al. 2014). Panter-Brick and colleagues study war stress and a wide range of mental health
issues, including post-traumatic distress, depression, and refugee resettlement among others, in
Afghanistan to learn more about resilience and vulnerability and to better inform public and
international health policy (Panter-Brick 2010, Panter-Brick et al. 2015, Reed et al. 2012). Studies
such as these represent excellent opportunities for collaboration between medical and molecular
anthropologists to add genetic and epigenetic components to existing projects to better understand
the underlying mechanisms that mediate the effects of psychosocial stressors on health.
Our study in the DRC has shown that war stressors leave a more substantial imprint on the
epigenome than do other stressors (Rodney & Mulligan 2014), confirming the lasting effect of war
trauma and the potential for such effects to be passed to the next generation. Furthermore, personal
experience of rape (past rape, rape resulting in pregnancy, rape during pregnancy) accounted for
31% of birthweight variance and eclipsed the effect of other war stress variables (e.g., refugee
status, family member killed, past kidnapping, parents or self a result of rape). This result has
implications close to home because studies show that nearly 1 in 5 US undergraduate women
have experienced completed or attempted sexual assault while in college (Krebs et al. 2009), 1 in
4 college women have reported completed or attempted rape since the age of 14 (Koss et al. 1987),
and nearly 1 in 2 women (44.6%) experience sexual violence other than rape at some time in their
lives (Black et al. 2010). As the studies in this section demonstrate, medical anthropology has much
to offer to better inform public mental and physical health policies around the world.
Slavery and Racial Discrimination

Another relevant stressor is the impact of racial discrimination on mental and physical health.
The history of slavery shared by virtually all African Americans provides a framework in which to
investigate multigenerational effects of racism and oppression. Jasienska (2009) proposed that the
well-known reduced birthweight among African Americans relative to European Americans is due
to current exposure to population-specific stressors and also reflects conditions and experiences
from the period of slavery. The fact that enslavement of African Americans persisted in the United
States for many generations means that this history of adversity is well-positioned for an epigenetic
study of the potential transgenerational effects of slavery. However, to my knowledge, no one has
242 Mulligan
published such a study. Saban et al. (2014) proposed a theoretical model in which early-life adversity
and social stressors, such as perceived discrimination, neighborhood violence, subjective social
status, and low SES, create an epigenetic signature that increases risk for inflammatory diseases
with racial disparities, such as coronary heart disease and ischemic stroke. African Americans are
more likely to have low SES, and a few studies have investigated DNA methylation and SES (Lam
et al. 2012, Needham et al. 2015). Borghol et al. (2012) find that adult DNA methylation profiles
correlate more strongly with childhood SES than with adult SES, suggesting that a persistent
epigenetic pattern is linked to early-life adversity.
Many studies have investigated the genetic variants that underlie complex diseases with in-
creased prevalence in African Americans in an attempt to explain racial health disparities. Freel
et al. (2008) investigated an interesting intersection between HPA axis activity, corticosteroid
phenotype, and blood pressure by assaying genetic variants in CYP11B1 and CYP11B2, genes that
encode the enzymes that help regulate cortisol and aldosterol production; the authors speculate
that specific variants in these genes may upregulate HPA axis activity and also lead to the devel-
opment of hypertension. Some of these variants may be present at higher frequencies in African
Americans (Nguyen et al. 2013), although all African populations exhibit higher levels of genetic
variation, which reflects the deep time depth of humans in Africa.
Very few studies have tested theories to explain the multiple health disparities that plague
African Americans, particularly studies that include the unique stressors shared by African Ameri-
cans and other minorities. In our study of African Americans living in Tallahassee, Florida (Boulter
et al. 2015), we found that a novel measure of unfair treatment of individuals close to the study par-
ticipant showed a threshold effect on blood pressure consistent with the “weathering hypothesis,”
which proposes that a threshold of experienced discrimination must be met before effects on phys-
ical and biological health are observed (Geronimus et al. 2006). Furthermore, unfair treatment
to others acted in conjunction with other genetic variants to reveal a new class of genes involved
in psychosocial stress and mood disorders (Boulter et al. 2015; J.A. Quinlan, L.N. Pearson, C.J.
Clukay, C.C. Gravlee, C.J. Mulligan, manuscript under review). These results demonstrate the
necessity of integrating cultural and genetic data when studying the effects of psychosocial stres-
sors that are unique to minorities and suggest that the biological consequences of discrimination
are complex and not yet well understood.
FUTURE DIRECTIONS
Recent technological advances in assaying genetic and epigenetic diversity across the genome
(for a review of epigenetic methods, see Non & Thayer 2015) have greatly accelerated the pace
of epigenetic investigations into the impact of stress on health and disease risk. However, it is
important to note that the field of social and behavioral epigenetics is not sufficiently mature
to rely solely on hypothesis-testing perspectives; instead, we need broad, unbiased collection of
samples and data to develop the appropriate questions and hypotheses. For instance, although we
have known for decades that increased DNA methylation at gene promoters is generally associated
with reduced gene expression, there is no consensus on how DNA methylation is measured or
interpreted in the cell; i.e., must a critical number of sites be methylated to affect gene expression,
are there key sites that must be methylated, or is there an average level of methylation that is
necessary? Palma-Gudiel et al. (2015b) argue that particular sites (at NR3C1) should be analyzed
rather than mean methylation measures; they found that NR3C1 CpG site 36 strongly associates
with prenatal stress and they recommend that future studies should focus on this site (Palma-
Gudiel et al. 2015a). However, Palma-Gudiel and colleagues’ meta-analysis required data from
almost two dozen studies, which do not currently exist for any gene except NR3C1. Furthermore,

there is always the chance that different CpG sites might be important in a different population
with a different psychosocial stressor; thus the field will benefit from the collection of methylation
data across many CpG sites.
Additional foundational questions abound. For example, most scholars believe there is a critical
window of time in which stressful experiences are most impactful on biology and presumably on
the genome, but the limits and characteristics of the critical window are not known. When does the
critical time period start and end? Does the critical period differ for different stressors? Does the
impact of a stressor slowly diminish during this time period? Do some stressors have more impact
than others and, if so, how does this increased impact manifest?
Investigators are also concerned about the samples and types of epigenetic variation that are
assayed. Most studies use samples from peripheral tissues, such as blood and saliva, even though
we know that much of the HPA axis functioning relevant to the stress process occurs in the brain.
Epigenetically determined differences in gene expression are part of the differentiation process by
which cells with the same genome sequence become different types of cells. Therefore, epigenetic
differences are expected to exist between different cell types. For social and behavioral epigenetics,
the questions focus on the part of the genome that contains epigenetic variation that is sensitive
to psychosocial stressors: Is that variation similarly reflected in the nervous system and peripheral
tissues?
The vast majority of DNA methylation studies thus far have focused on the presence of a
methyl group at the fifth position of a cytosine base (5-mC) when the cytosine is followed
by a guanine base (a CpG site). However, there are additional products that are derived from
5-mC, e.g., 5-hydroxymethylcytosine (5-hmC) and 5-formylcytosine (5-fC), as well as cytosine
methylation at non-CpG sites. Some of these additional methylation products, such as 5-hmC, are
present at high frequencies in the brain and primordial germ cells (Pastor et al. 2013), but they are
less frequently studied because they are generally more difficult to assay and occur in samples that
are difficult to collect. Furthermore, other classes of epigenetic modifications do exist, including
multiple types of histone modifications, chromatin modifiers, and noncoding RNAs. Ultimately,
all types of epigenetic modifications must be assayed to determine their significance with respect
to epigenetically determined responses to psychosocial stressors. Some progress has been made in
determining which aspects of the genome are more epigenetically sensitive to psychosocial stres-
sors. Substantial evidence is emerging that gene enhancers are more variable over the lifespan than
are promoters (Johansson et al. 2013, Reynolds et al. 2014); thus, Illumina’s (San Diego, Califor-
nia) new methylation assay platform (Infinium MethylationEPIC BeadChip) includes ∼350,000
CpG sites in enhancer regions.
Finally, we know that DNA methylation is erased and new DNA methylation profiles are
generated twice during gamete formation and development of the new embryo (i.e., germ line
reprogramming), which would seem to limit the possibility of heritable changes in DNA meth-
ylation (Smallwood & Kelsey 2012). However, not all DNA methylation is removed; i.e., DNA
methylation is <10% in mouse sperm and egg germ cells (Popp et al. 2010), which is entirely
consistent with transgenerational epigenetic inheritance at a small number of genes. However,
we do not know how sites across the genome differ in their methylation: Is methylation at some
sites genetically determined and methylation at other sites environmentally determined? Can one
site be influenced by both genetics and the environment? If a site is environmentally sensitive,
does a methylation change in response to the environment persist for a few cell divisions or for
generations? Does it depend on the stressor and the strength of the stressor? Anthropology, with
its multidisciplinary approach that integrates social and biological perspectives, is well positioned
to address these questions.
244 Mulligan
SUMMARY POINTS
1. Anthropology has a long history of investigation into adaptation, development plasticity,
and psychobiological stress. Adaptive responses to early-life stress can influence future
health and disease risk.
2. An evolutionary perspective combines fetal development plasticity and transgenerational
inheritance to propose an epigenetic mechanism that allows short-term adaptation to
environmental changes in contrast with long-term adaptation based on genetic change.
3. Epigenetic modifications, specifically DNA methylation, may mediate the translation of
early-life events into altered health outcomes, possibly transgenerationally.

4. The number of genes, or parts of the genome, that are environmentally sensitive and epi-
genetically modifiable is likely small relative to the total number of ∼20,000 human genes.
5. Social and behavioral epigenetics is the study of epigenetic changes in response to the
social and behavioral environment that alter gene expression and phenotype.
6. Multiple studies have found associations between DNA methylation (at genes such as
NR3C1, BDNF, and other HPA axis genes as well as genome-wide) and a wide range of
psychosocial stressors (including prenatal exposure to maternal depression, anxiety, war
stress, or intimate partner violence; childhood presence of sexual and physical abuse, low
socioeconomic status, or psychotic disorder; and adult presence of depression, PTSD,
eating disorders, or suicidality).
7. Future studies should continue a broad perspective on the impact of a wide range of
psychosocial stressors and multiple health outcomes by assaying an increasingly compre-
hensive catalog of epigenetic effects across multiple genes and the genome.
DISCLOSURE STATEMENT
The author is not aware of any affiliations, memberships, funding, or financial holdings that might
be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
Sincere gratitude is due to the study participants from the Democratic Republic of Congo (DRC)
and Tallahassee, Florida, and to colleagues at HEAL Africa hospital, Goma, DRC, without whom
my research would not be possible. Appreciation goes to current and past Mulligan lab members,
with particular thanks to Amy Non for constructive comments on the present manuscript. Funding
was provided by National Science Foundation grants BCS 1231264 and 0820687 and grants from
the University of Florida (UF) Clinical and Translational Science Institute, UF College of Liberal
Arts and Science, and a UF Research Opportunity Seed Fund award.
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AN45-FrontMatter ARI 28 September 2016 9:1
Annual Review of
Anthropology
Volume 45, 2016 Contents

Perspective
A Life in Evolutionary Anthropology
Clifford J. Jolly p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Archaeology
Archaeological Evidence of Epidemics Can Inform Future Epidemics
Sharon N. DeWitte p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p63
Collaborative Archaeologies and Descendant Communities
Chip Colwell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 113
Reaching the Point of No Return: The Computational Revolution
in Archaeology
Leore Grosman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 129
Archaeologies of Ontology
Benjamin Alberti p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 163
Archaeology and Contemporary Warfare
Susan Pollock p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 215
The Archaeology of Pastoral Nomadism
William Honeychurch and Cheryl A. Makarewicz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 341
Urbanism and Anthropogenic Landscapes
Arlen F. Chase and Diane Z. Chase p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 361
Decolonizing Archaeological Thought in South America
Alejandro Haber p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 469
Biological Anthropology
Out of Asia: Anthropoid Origins and the Colonization of Africa
K. Christopher Beard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 199
Early Environments, Stress, and the Epigenetics of Human Health
Connie J. Mulligan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 233
vi
Native American Genomics and Population Histories

Deborah A. Bolnick, Jennifer A. Raff, Lauren C. Springs, Austin W. Reynolds,
and Aida T. Miró-Herrans p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 319
Disease and Human/Animal Interactions
Michael P. Muehlenbein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 395
Anthropology of Language and Communicative Practices

Intellectual Property, Piracy, and Counterfeiting
Alexander S. Dent p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p17
Science Talk and Scientific Reference

Matthew Wolfgram p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p33
Language, Translation, Trauma

Alex Pillen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p95
(Dis)fluency
Jürgen Jaspers p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 147
Some Recent Trends in the Linguistic Anthropology of Native
North America
Paul V. Kroskrity p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 267
Sociocultural Anthropology
Urban Space and Exclusion in Asia
Erik Harms p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p45
Historicity and Anthropology
Charles Stewart p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p79
Anthropological STS in Asia
Michael M. J. Fischer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 181
Cancer
Juliet McMullin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 251
Affect Theory and the Empirical
Danilyn Rutherford p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 285
Where Have All the Peasants Gone?
Susana Narotzky p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 301
Scripting the Folk: History, Folklore, and the Imagination of Place
in Bengal
Roma Chatterji p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 377
Reproductive Tourism: Through the Anthropological “Reproscope”
Michal Rachel Nahman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 417
Contents vii
Design and Anthropology

Keith M. Murphy p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 433
Unfree Labor
Filipe Calvão p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 451
Time as Technique
Laura Bear p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 487
Indexes
Cumulative Index of Contributing Authors, Volumes 36–45 p p p p p p p p p p p p p p p p p p p p p p p p p p p 503

Cumulative Index of Article Titles, Volumes 36–45 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 507
Errata
An online log of corrections to Annual Review of Anthropology articles may be found at

http://www.annualreviews.org/errata/anthro
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Early Environmental Stress and Epigenetics

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AN45CH15-Mulligan ARI 29 September 2016 10:28

Annu. Rev. Anthropol. 2016. 45:233–49 Keywords

The Annual Review of Anthropology is online at Abstract

SOCIAL AND BEHAVIORAL EPIGENETICS

www.annualreviews.org • Early Environment, Stress, and Epigenetics 235

determined changes in gene expression may identify a particular phenotype to be expressed in

Stress Methylation Gene expression Phenotype

www.annualreviews.org • Early Environment, Stress, and Epigenetics 237

GENETIC LOCI INVOLVED IN AN EPIGENETIC RESPONSE

Glucocorticoids and Additional Studies of NR3C1 Methylation

www.annualreviews.org • Early Environment, Stress, and Epigenetics 239

Methylation at Other Genes and Throughout the Genome

differentially methylated and expressed as part of an orchestrated response to psychosocial stress.

OTHER PSYCHOSOCIAL STRESSORS UNDER STUDY

with more moderate stressors.

War and Violence

Slavery and Racial Discrimination

www.annualreviews.org • Early Environment, Stress, and Epigenetics 243

early-life events into altered health outcomes, possibly transgenerationally.

www.annualreviews.org • Early Environment, Stress, and Epigenetics 245

with prenatal exposure to famine in humans. PNAS 105:17046–49

www.annualreviews.org • Early Environment, Stress, and Epigenetics 247

www.annualreviews.org • Early Environment, Stress, and Epigenetics 249

Volume 45, 2016 Contents

Native American Genomics and Population Histories

Anthropology of Language and Communicative Practices

Science Talk and Scientific Reference

Language, Translation, Trauma

Design and Anthropology

Cumulative Index of Contributing Authors, Volumes 36–45 p p p p p p p p p p p p p p p p p p p p p p p p p p p 503

An online log of corrections to Annual Review of Anthropology articles may be found at

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