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Early Environments, Stress,and the Epigenetics ofHuman HealthConnie J. MulliganDepartment of Anthropology, Genetics Institute, University of Florida, Gainesville,Florida 32610-3610; email: [email protected]

Annu. Rev. Anthropol. 2016. 45:233–49

First published online as a Review in Advance onJuly 22, 2016

The Annual Review of Anthropology is online atanthro.annualreviews.org

This article’s doi:10.1146/annurev-anthro-102215-095954

Copyright c© 2016 by Annual Reviews.All rights reserved

Keywords

DNA, genetic, DOHaD, developmental plasticity, adaptation

Abstract

The field of social and behavioral epigenetics examines the role of epige-netic modifications to mediate the effect of psychosocial stressors on anindividual’s health and well-being. Epigenetic modifications influence geneexpression, which can lead to changes in an individual’s phenotype. DNAmethylation is an important epigenetic modification that varies throughoutthe lifespan and appears to respond to a wide range of psychosocial and bio-logical stressors. The effects of early-life adversity impact future health andmay be passed on to future generations. The underlying model proposes thatstress influences health via an epigenetic mechanism involving altered DNAmethylation and gene expression. This review summarizes a range of studiesthat have identified DNA methylation at specific genes and throughout thegenome in association with multiple psychosocial stressors, including psy-chiatric disorders, sexual and physical abuse, and war trauma. Future studiesshould test a comprehensive list of epigenetic modifications in associationwith psychosocial stressors and multiple health outcomes.

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ANNUAL REVIEWS Further

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Stressor: a stimulusthat triggers the stressresponse or, moregenerally, an eventthat we do not feelcapable of dealing with

Psychosocial:stressors, and aspectsof the environment,that involve bothpsychological andsocial components

Intergenerational:transmission ofinformation toindividuals who sharean environmentalexposure, i.e., apregnant woman, herfetus, and the fetus’germ line

Transgenerational:transmission ofinformation toindividuals who do notshare anenvironmentalexposure, i.e., thegreat-grandchildren ofa pregnant woman

Phenotype:the observablecharacteristics of anorganism, includingmorphology,development,physiology, andbehavior

Gene: a segment ofDNA that codes for afunctional proteinproduct. Humans have∼20,000 genes

Gene expression:the process by which agene is translated intoa functional geneproduct, usually aprotein

INTRODUCTION

Our ability to successfully adapt to a constantly changing environment and respond to increasinglycomplex stressors is one of the traits that make us profoundly human. Developmental plasticity,as the foundational concept from which adaptation emerges, has long been studied by anthro-pologists (Boas 1912, Frisancho 1993, Lasker 1969). Fetal developmental plasticity is focused onthe postnatal effects of adaptive responses to in utero conditions (Kuzawa & Pike 2005, Pluess &Belsky 2011). Of particular interest is the fetal response to stressful conditions, such as nutrientlimitation (a biological stressor) or maternal depression (a psychosocial stressor).

As a consequence of fetal plasticity and adaptation, the possibility has emerged that the effectsof early-life events may be passed to future generations, i.e., intergenerational or transgenerationalinheritance (e.g., Drake & Liu 2010, Kuzawa & Thayer 2011, Painter et al. 2008, Seckl & Meaney2006, Siklenka et al. 2015, Thayer & Non 2015). An evolutionary perspective proposes a selectiveadvantage for the fetus to accurately predict the postgestational environment based on intrauterinecues (Kuzawa 2005, Kuzawa & Quinn 2009, Kuzawa & Thayer 2011). In contrast, the possibilityof maladaptive responses and an explicit focus on adult health and disease influenced by early-lifeexperiences are articulated in the developmental origins of health and disease (DOHaD) hypothesis(Barker 1990, Benyshek 2013, Gluckman et al. 2008, Gluckman & Hanson 2006, Seckl & Meaney2006).

According to the DOHaD hypothesis, the potential impact of early-life experiences on futurehealth and disease risk is thought to be particularly salient (Barker et al. 2012, Benyshek 2013).The underlying assumption is that there is a critical period of developmental plasticity in uterowhen many fetal tissues are especially plastic and sensitive to the maternal environment (Davis& Sandman 2010, Gluckman et al. 2008, Kuzawa & Pike 2005, Kuzawa & Quinn 2009). Duringthis period, the phenotype that is most appropriately adapted to the intrauterine environment isselected and expressed. However, if the intrauterine environment is unusually stressful or non-representative of the postgestational environment, the selected phenotype may be maladaptive inlater life and may result in increased disease risk (Bateson et al. 2004, Kuzawa 2005). The specificdisease that emerges in adulthood may reflect the timing of adverse events during gestationaldevelopment (Barker et al. 2012, Roseboom et al. 2011).

In addition to later-life effects of prenatal trauma, the effects of prenatal stress might be passedto future generations. Some of the most compelling evidence implicating the effects of prenatalstress on intergenerational health comes from the Dutch famine of the mid-1940s (Roseboomet al. 2011). Painter and Roseboom have documented reduced birth length and poor health inlater life in the grandchildren of women pregnant during the famine, suggesting that the stress ofstarvation has intergenerational effects (Painter et al. 2008). Heijmans et al. (2008) showed thatindividuals who were prenatally exposed to the famine had reduced methylation of the imprintedIGF2 gene six decades later, suggesting that methylation may mediate the intergenerational effectof prenatal stress exposure.

Both biological and psychosocial stressors can impact health, and they are mediated by thepsychobiological stress response. The stress response is a multisystem process in which thehypothalamic-pituitary-adrenocortical (HPA) axis and the sympathetic-adrenomedullary (SAM)system coordinate to provide proper biological and behavioral responses to stress (Gunnar &Quevedo 2007). The HPA system produces glucocorticoids (GCs) (cortisol in humans), with thebrain as a major target. GC production is a cascade process, and many of the effects of GCs arecarried out by modified gene expression such that the HPA system is relatively slow to respond toa stressful event. In contrast, the SAM system releases epinephrine to mobilize resources and more

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Epigenetics:chemical modificationsto the genome that donot alter the DNAsequence but caninfluence expression ofthe encoded genes

DNA methylation:attachment of a methylgroup, usually to acytosine base in theDNA, is a commontype of epigeneticmodification

DNA: the geneticinstructions used inthe development andfunctioning of allknown livingorganisms

Genome: the geneticmaterial of anorganism that includesboth the genes and thenoncoding (nongenic)sequences

DNA seqnuence:the order of nucleotidebases (adenine,guanine, cytosine,thymine) in a moleculeof DNA

directly acts on the target organs to facilitate a rapid stress response, known as the fight-or-flightresponse.

In this review, I focus on the effects of stress on health, with an emphasis on psychosocialstressors. Psychosocial stressors include a wide range of stressors including (but not limited to,and in no particular order) childhood abuse, drug addiction, poverty, poor education, lack offamily support, war trauma, racial discrimination, and depression and other psychiatric disorders.These stressors have been studied across multiple academic fields including cultural anthropology,psychology, psychiatry, sociology, and economics. Isolating the influence of a psychosocial stressoron health can be challenging for a number of reasons. It can be difficult to define the temporalrange of psychosocial stressors because some of them are isolated events (e.g., a single sexualassault), some are chronic events (multiple suicide attempts), and some are long-term situations(poverty). Stressors in real life often overlap and it may be impossible to isolate psychosocial-onlystressors when biological stressors, e.g., nutrition or toxin exposure, may also be relevant in certainsituations. Many stressors exist on a continuum, i.e., more or less depressed, and it is importantto consider the entire range of effects because both negative and positive events have importantinfluences on health.

In this review, I focus on the effects of early-life events because these events are particularlysalient in the programming processes with which the body interprets cues from the environmentto predict the response, or phenotype, with the best chance for future survival. This programming,or early-life prediction and planning, involves gathering information from a wide range of inputsand then processing that information to identify, select, and express the optimal phenotype. Allthese steps require exquisite coordination of multiple systems within the body.

Thus, the final piece of this review introduces epigenetics as a mechanism by which the multipleprocesses of stress response, fetal programming, adaptation, and transgenerational effects amongothers, may be integrated. Epigenetic modifications have the potential to produce a response topsychosocial stressors that results in a condition or phenotype that may then feedback to influencethe process in a circular fashion; e.g., poverty may create epigenetic modifications that increasethe risk of depression, which then further entrenches the individual in poverty. Although muchimportant work on epigenetics and stress has been performed in animal models, in this review, Ifocus almost exclusively on human studies. Furthermore, I focus on one type of epigenetic mod-ification, DNA methylation, because virtually all current studies on epigenetics and psychosocialstress 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, particularlythose 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 andphysical 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 responsesinto potentially heritable changes in phenotypes related to adaptation and health, is not known. Inrecent 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 mechanismby 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 DNAsequence but do influence expression of the encoded genes (Figure 1). Specifically, epigenetically

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

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CytosineGuanineThymineAdenine

Methylgroup

Figure 1Depiction of a DNA molecule showing the methylation of some, but not all, cytosine bases, as often occurs in the cell.

CpG islands:a cluster ofcytosine-guaninedinucleotides that areoften the focus ofDNA methylation

determined changes in gene expression may identify a particular phenotype to be expressed inresponse to a psychosocial stressor (Figure 2). Originally, DNA methylation was proposed tosilence genes, i.e., to turn off gene expression, but recent research suggests that DNA methylationcorrelates both positively and negatively with gene expression depending on the specific gene andpart of the gene, as well as the cell and tissue type ( Jones 2012, Plongthongkum et al. 2014) Fromthe perspective of social and behavioral epigenetics, methylation at enhancers may be particularlyvariable 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 toexplain 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 theunderlying DNA sequence. One of the most important types of epigenetic modifications is theattachment 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 Angelmansyndromes, in which different diseases are caused by genetic defects in the same part of thegenome depending on which parent carries the defect; i.e., inheriting the genetic defect from thefather causes Prader-Willi syndrome, but inheriting the defect from the mother causes Angelmansyndrome. More recently, epigenetic abnormalities have been associated with the development ofcancer through hypermethylation of promoter CpG islands, leading to the inactivation of tumorsuppressor genes and aberrant histone modifications (Choi & Lee 2013, Esteller 2007, Herman& Baylin 2003).

More speculative is the idea that epigenetic alterations may play a broad role in trans-lating changes in the social and behavioral environment into changes in gene expression,which is the focus of the emerging field of social and behavioral epigenetics (Mulligan 2015)(Figure 3). The term social and behavioral epigenetics focuses on the effect of psychosocialstressors 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 2Proposed model of stress influencing a phenotype via an epigenetic mechanism that alters gene expression.

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Figure 3A 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 andhomelessness. These factors impact our mental and physical health and may affect the expression of ourgenes and genome through epigenetic modifications. In turn, epigenetic modifications to specific genes andour genome may impact psychosocial factors in our lives, e.g., poverty may create epigenetic modificationsthat increase the risk of depression that then further entrenches the individual in poverty. Figure providedcourtesy of Buster O’Connor.


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term was established during a 2014 workshop sponsored by the National Science Foundation,the National Institute of Child Health and Human Development, Research Councils UnitedKingdom, and the UK Science and Innovation Network in Potomac, Maryland (see workshop re-port at http://www.nichd.nih.gov/about/meetings/2014/Documents/ExecSocialBehavEpigenetics_Sum.pdf ).

Over the past decade, much progress has been made to establish the field of social and behavioralepigenetics and begin to identify foundational questions. In 2004, Szyf, Meaney, and colleaguespublished one of the most highly cited papers ever published in Nature Neuroscience (Weaveret al. 2004). They reported changes in newborn methylation patterns in the promoter of the GCreceptor (which is involved in the HPA response to stress) that correlated with differences innurturing behaviors of mother rats to their offspring (Weaver et al. 2004). Specifically, Weaveret 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 theGC receptor promoter and more moderate HPA responses when compared with pups raised bymothers with low levels of nurturing behaviors. These differences in methylation patterns emergedduring the first week of life and persisted into adulthood. Treatment with a chemical that interferedwith DNA methylation removed the between-group differences in methylation patterns, GCreceptor expressions, and HPA responses, which suggests a causal relationship between maternaland offspring behavior, GC receptor methylation, and GC receptor gene expression. Furthermore,the DNA methylation differences were reversible if rat pups were cross-fostered, which impliespossible reversibility of the maternal behavior–driven, epigenetic-induced changes. This studyhas enormous implications for the possibility that our psychosocial environment impacts us at thelevel of the genome and influences behavior.

GENETIC LOCI INVOLVED IN AN EPIGENETIC RESPONSETO THE PSYCHOSOCIAL ENVIRONMENT

Epigenetically determined responses to psychosocial stressors may have evolved in higher-orderorganisms as a mechanism to provide rapid, short-term responses to changes in the psychosocialenvironment. In contrast, genetic changes to the DNA sequence of the genome would providelong-term adaptations. The number of genes involved in an epigenetic response to the psychosocialenvironment, i.e., the number of genes that are epigenetically sensitive to the environment, wouldlikely be relatively small because the majority of genes must continue to function regardless ofchanges in the environment. For instance, in our study of prenatal exposure to maternal stressin mother–infant dyads in the Democratic Republic of Congo (DRC), we found that only 212CpG 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 memoryformation, 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 exactmechanisms are not well understood. Cortisol is the most important GC in humans and, like allGCs its effect is expressed by binding to the GC receptor. GCs have been proposed as a primarycandidate 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

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http://www.nichd.nih.gov/about/meetings/2014/Documents/ExecSocialBehavEpigenetics_Sum.pdf

http://www.nichd.nih.gov/about/meetings/2014/Documents/ExecSocialBehavEpigenetics_Sum.pdf


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 beenwidely studied in relation to early-life stress because of its important role in the HPA axis responseto stress (Turecki & Meaney 2016).

Oberlander et al. conducted one of the first studies of GC receptor NR3C1 methylation inhumans by investigating the effect of maternal stress on a developing fetus. They found increasedmethylation of the NR3C1 promoter in newborns that was associated with prenatal exposureto 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 correlatedwith prenatal exposure to maternal stress and increased NR3C1 methylation, suggesting that astress phenotype may emerge very rapidly in exposed infants and may be mediated by NR3C1methylation 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 maternalstress (material deprivation, mundane stressors, and war stress) and birthweight. War stress hadthe strongest effect and accounted for 35% of the variance in birthweight. The association betweenmaternal stress and newborn birthweight provided the foundation upon which to investigate therole of DNA methylation at the NR3C1 promoter. We found an association in which increasedmaternal stress, increased NR3C1 promoter methylation in newborns, and decreased newbornbirthweight were correlated. In this context, increased newborn methylation may have occurredas a short-term response to increased maternal stress, but it may have long-term repercussionsif increased methylation constrains plasticity in expression of stress-related genes later in life.Significantly, altered NR3C1 promoter methylation in association with maternal stress was foundonly in newborns, not in mothers, which is consistent with the tenets of the DOHaD hypothesisthat maternal stress modifies offspring biology. Furthermore, there were no identically methylatedsequences between mothers and their infants, suggesting that methylation marks at NR3C1 maybe more susceptible to environmental influences than to genetic influences.

Other studies have found evidence of a significant role for NR3C1 promoter methylationand a range of psychosocial stressors. McGowan et al. (2009) were the first to study NR3C1 inbrain tissue and found increased promoter methylation and decreased gene expression in suicidevictims with a history of childhood abuse in comparison to suicide victims with no history ofabuse and nonsuicide controls. Radtke et al. (2011) found altered NR3C1 promoter methylationin children aged 10–19 years old that correlated with maternal retrospective recall of intimatepartner violence. No correlation was found between intimate partner violence and methylationin the mothers, similar to our results with maternal war exposure in the DRC and consistentwith the tenets of the DOHaD hypothesis. Yehuda et al. (2014) found lower NR3C1 promotermethylation in combat veterans with post-traumatic stress disorder (PTSD), which is consistentwith a model in which increased NR3C1 expression leads to the enhanced GC receptor sensitivityseen in PTSD patients. Building on this result, Vukojevic et al. (2014) found that increased NR3C1promoter methylation and reduced NR3C1 expression were associated with less intrusive memoryof a traumatic event and reduced PTSD risk in male, but not female, survivors of the Rwandangenocide. This result is consistent with the role of GC receptor signaling in the regulation ofemotional memory processes in which the memory-enhancing effects of stress-induced elevationsof glucocorticoids are increased in men (Andreano & Cahill 2006).

Two meta-analyses of dozens of studies of early-life stress and NR3C1 promoter methylationfound that both hyper- and hypomethylation may be maladaptive and that the level and timingof NR3C1 promoter methylation may be critically important for health and future disease risk


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(Palma-Gudiel et al. 2015b, Turecki & Meaney 2016). Palma-Gudiel et al. (2015b) found thathypermethylation at select CpG sites generally associates with early-life stress, including sexualor physical abuse, suicide, eating disorders, psychiatric disorders, and prenatal stress, whereas amore global, promoter-wide pattern of hypomethylation was associated with PTSD. The authorssuggest a possible mechanism in which the timing of the stress exposure creates an epigeneticallycontrolled modification of HPA function that ultimately determines the specific disease pheno-type; specifically, early-life stress may increase NR3C1 methylation, which decreases GC receptorexpression, 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 NR3C1promoter, thus increasing GC expression and increased sensitivity of the HPA axis. Moreover,prior hypomethylation of the NR3C1 promoter may increase susceptibility to develop PTSD viaincreased 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, inpart because it is difficult to identify good candidate genes. As stated previously, the percentageof the ∼20,000 human genes that may have evolved to respond epigenetically to the psychosocialenvironment is likely to be quite small. Likely candidates include genes involved in serotonin anddopamine release, e.g., SLC6A4 and SLC6A3, as well as genes involved in placenta function, suchas 11ß-HSD2, which shields the fetus from excess maternal GC. Jawahar et al. (2015) provide anexcellent 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. Wefound widespread effects on HPA axis gene methylation with significant methylation changes attranscription factor binding sites in all three genes in association with chronic stress and war traumain mothers and newborns in our DRC study (Kertes et al. 2015). Methylation at FKBP5 has alsobeen associated with childhood trauma–dependent psychiatric disorders in adulthood (Klengelet al. 2013), with Holocaust survivors and their offspring, with some cases of childhood physicaland 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 institutionalizationin Romanian orphans (A.L. Non, B.M. Hollister, K.L. Humphreys, A. Childebayeva, K. Esteveset al., manuscript under review).

Brain-derived neurotrophic factor (BDNF ) is another good candidate gene because it isaffected by the HPA axis response; i.e., stress-induced increase of GCs increases anxiety andimpairs BDNF signaling, and evidence indicates that BDNF and NR3C1 interact in stress-relateddisorders (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 (Changet al. 2014) and with response to treatment such as psychotherapy (Perroud et al. 2013). BDNF iswell known to be involved in the pathophysiology of depression, and BDNF methylation has beensuggested as a biomarker to diagnose depression (Fuchikami et al. 2011). Furthermore, Gassenet al. (2015) found that treatment of cells isolated from depressed patients with the antidepressantparoxetine correlated with BDNF abundance and clinical treatment outcomes, suggesting thatBDNF expression may help modulate the action of antidepressants.

Furthermore, the genes that regulate DNA methylation may also be involved in an epigeneticresponse to psychosocial stress; i.e., the genes in charge of DNA methylation may themselves be

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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 arerecruited to sites of DNA damage caused by oxidative stress (a biological stressor caused by thetoxic effects of reactive oxygen molecules known to damage DNA), which is a clear example ofmethylation 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 theiroffspring, which suggests that the individual who directly experiences the stressor may be mostlikely to experience a genome-wide epigenetic response (Rodney & Mulligan 2014). In terms ofan underlying molecular mechanism, we found a correlation between maternal stress, maternalgenome-wide mean methylation, and methylation at DNMT3A, which may reflect DNMT3A’srole in maintaining somatic cell methylation (Clukay et al. 2016). We also saw a correlationbetween 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 (Clukayet al. 2016). These results suggest that altered methylation of the methylation genes may be partof a molecular mechanism underlying the biological response to stress.

Scholars have also begun investigating the effect of psychosocial stressors on genome-widechanges in methylation. For example, Cao-Lei et al. (2014) found altered genomic methylationpatterns in 13-year-old children of women who had been pregnant during the 1998 Quebec icestorm; specifically, prenatal maternal stress was correlated with offspring methylation at 1675CpG 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-specificmethylation differences throughout the genome at age 10 in 24 monozygotic twin pairs whowere discordant for age-12 psychotic symptoms, and the top-ranked differentially methylatedsite was also hypomethylated in postmortem prefrontal cortex brain tissue from schizophrenicpatients. 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 susceptibilityto schizophrenia and other mental health disorders. Non et al. (2014) found a small number ofCpG 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 modelsto investigate, and manipulate, dominance rank and the stress associated with one’s position inthe social environment. Tung et al. (2012) showed that gene expression data could predict socialstatus with 80% accuracy in 10 social groups of female rhesus macaques, even in cases where theindividual’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 contributedto 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) testedDNA 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 methylatingagents (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 theUnited States may experience. However, additional stressors are also worthy of study eitherbecause a large proportion of people do experience them, even if the stressor is nonrandomly


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distributed across the United States, or because the stressor represents an extreme that may elicita more easily detectable biological or molecular signal. For instance, war often creates multipleextreme 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 notwith mundane stress or material deprivation (Rodney & Mulligan 2014). Moreover, it is difficultto identify candidate genes, so it may be necessary to study individuals in an extremely stressfulenvironment to identify the relevant genes, and those genes can then be targeted in future studieswith more moderate stressors.

War and Violence

War, and more generally violent conflict, has long been a focus of medical anthropologists. Pikeand collaborators (2010) combine ethnographic methods and stress biomarkers to study violentconflict, and psychosocial stressors more generally, in a range of African communities to documentthe varied effects of conflict and stress on health (Pike et al. 2010, Pike & Williams 2006, Straightet al. 2014). Panter-Brick and colleagues study war stress and a wide range of mental healthissues, including post-traumatic distress, depression, and refugee resettlement among others, inAfghanistan to learn more about resilience and vulnerability and to better inform public andinternational health policy (Panter-Brick 2010, Panter-Brick et al. 2015, Reed et al. 2012). Studiessuch as these represent excellent opportunities for collaboration between medical and molecularanthropologists to add genetic and epigenetic components to existing projects to better understandthe 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 theepigenome than do other stressors (Rodney & Mulligan 2014), confirming the lasting effect of wartrauma and the potential for such effects to be passed to the next generation. Furthermore, personalexperience of rape (past rape, rape resulting in pregnancy, rape during pregnancy) accounted for31% of birthweight variance and eclipsed the effect of other war stress variables (e.g., refugeestatus, family member killed, past kidnapping, parents or self a result of rape). This result hasimplications close to home because studies show that nearly 1 in 5 US undergraduate womenhave experienced completed or attempted sexual assault while in college (Krebs et al. 2009), 1 in4 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 theirlives (Black et al. 2010). As the studies in this section demonstrate, medical anthropology has muchto 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 toinvestigate multigenerational effects of racism and oppression. Jasienska (2009) proposed that thewell-known reduced birthweight among African Americans relative to European Americans is dueto current exposure to population-specific stressors and also reflects conditions and experiencesfrom the period of slavery. The fact that enslavement of African Americans persisted in the UnitedStates for many generations means that this history of adversity is well-positioned for an epigeneticstudy of the potential transgenerational effects of slavery. However, to my knowledge, no one has

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published such a study. Saban et al. (2014) proposed a theoretical model in which early-life adversityand social stressors, such as perceived discrimination, neighborhood violence, subjective socialstatus, and low SES, create an epigenetic signature that increases risk for inflammatory diseaseswith racial disparities, such as coronary heart disease and ischemic stroke. African Americans aremore likely to have low SES, and a few studies have investigated DNA methylation and SES (Lamet al. 2012, Needham et al. 2015). Borghol et al. (2012) find that adult DNA methylation profilescorrelate more strongly with childhood SES than with adult SES, suggesting that a persistentepigenetic 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. Freelet al. (2008) investigated an interesting intersection between HPA axis activity, corticosteroidphenotype, and blood pressure by assaying genetic variants in CYP11B1 and CYP11B2, genes thatencode the enzymes that help regulate cortisol and aldosterol production; the authors speculatethat 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 AfricanAmericans (Nguyen et al. 2013), although all African populations exhibit higher levels of geneticvariation, which reflects the deep time depth of humans in Africa.

Very few studies have tested theories to explain the multiple health disparities that plagueAfrican 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 (Boulteret 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 treatmentto others acted in conjunction with other genetic variants to reveal a new class of genes involvedin 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 thenecessity 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 discriminationare 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 paceof epigenetic investigations into the impact of stress on health and disease risk. However, it isimportant to note that the field of social and behavioral epigenetics is not sufficiently matureto rely solely on hypothesis-testing perspectives; instead, we need broad, unbiased collection ofsamples and data to develop the appropriate questions and hypotheses. For instance, although wehave known for decades that increased DNA methylation at gene promoters is generally associatedwith reduced gene expression, there is no consensus on how DNA methylation is measured orinterpreted 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 isnecessary? Palma-Gudiel et al. (2015b) argue that particular sites (at NR3C1) should be analyzedrather than mean methylation measures; they found that NR3C1 CpG site 36 strongly associateswith 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 fromalmost two dozen studies, which do not currently exist for any gene except NR3C1. Furthermore,


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there is always the chance that different CpG sites might be important in a different populationwith a different psychosocial stressor; thus the field will benefit from the collection of methylationdata across many CpG sites.

Additional foundational questions abound. For example, most scholars believe there is a criticalwindow of time in which stressful experiences are most impactful on biology and presumably onthe genome, but the limits and characteristics of the critical window are not known. When does thecritical time period start and end? Does the critical period differ for different stressors? Does theimpact of a stressor slowly diminish during this time period? Do some stressors have more impactthan others and, if so, how does this increased impact manifest?

Investigators are also concerned about the samples and types of epigenetic variation that areassayed. Most studies use samples from peripheral tissues, such as blood and saliva, even thoughwe 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 bywhich cells with the same genome sequence become different types of cells. Therefore, epigeneticdifferences 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 sensitiveto psychosocial stressors: Is that variation similarly reflected in the nervous system and peripheraltissues?

The vast majority of DNA methylation studies thus far have focused on the presence of amethyl group at the fifth position of a cytosine base (5-mC) when the cytosine is followedby a guanine base (a CpG site). However, there are additional products that are derived from5-mC, e.g., 5-hydroxymethylcytosine (5-hmC) and 5-formylcytosine (5-fC), as well as cytosinemethylation at non-CpG sites. Some of these additional methylation products, such as 5-hmC, arepresent at high frequencies in the brain and primordial germ cells (Pastor et al. 2013), but they areless frequently studied because they are generally more difficult to assay and occur in samples thatare difficult to collect. Furthermore, other classes of epigenetic modifications do exist, includingmultiple types of histone modifications, chromatin modifiers, and noncoding RNAs. Ultimately,all types of epigenetic modifications must be assayed to determine their significance with respectto epigenetically determined responses to psychosocial stressors. Some progress has been made indetermining 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 thanare promoters (Johansson et al. 2013, Reynolds et al. 2014); thus, Illumina’s (San Diego, Califor-nia) new methylation assay platform (Infinium MethylationEPIC BeadChip) includes ∼350,000CpG sites in enhancer regions.

Finally, we know that DNA methylation is erased and new DNA methylation profiles aregenerated twice during gamete formation and development of the new embryo (i.e., germ linereprogramming), 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., DNAmethylation is <10% in mouse sperm and egg germ cells (Popp et al. 2010), which is entirelyconsistent 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 somesites genetically determined and methylation at other sites environmentally determined? Can onesite 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 forgenerations? Does it depend on the stressor and the strength of the stressor? Anthropology, withits multidisciplinary approach that integrates social and biological perspectives, is well positionedto address these questions.

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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 futurehealth and disease risk.

2. An evolutionary perspective combines fetal development plasticity and transgenerationalinheritance to propose an epigenetic mechanism that allows short-term adaptation toenvironmental changes in contrast with long-term adaptation based on genetic change.

3. Epigenetic modifications, specifically DNA methylation, may mediate the translation ofearly-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 thesocial and behavioral environment that alter gene expression and phenotype.

6. Multiple studies have found associations between DNA methylation (at genes such asNR3C1, BDNF, and other HPA axis genes as well as genome-wide) and a wide range ofpsychosocial stressors (including prenatal exposure to maternal depression, anxiety, warstress, or intimate partner violence; childhood presence of sexual and physical abuse, lowsocioeconomic 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 ofpsychosocial 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 mightbe 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 whommy 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. Fundingwas provided by National Science Foundation grants BCS 1231264 and 0820687 and grants fromthe University of Florida (UF) Clinical and Translational Science Institute, UF College of LiberalArts and Science, and a UF Research Opportunity Seed Fund award.

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AN45-FrontMatter ARI 28 September 2016 9:1

Annual Review ofAnthropology

Volume 45, 2016 Contents

Perspective

A Life in Evolutionary AnthropologyClifford J. Jolly � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

Archaeology

Archaeological Evidence of Epidemics Can Inform Future EpidemicsSharon N. DeWitte � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �63

Collaborative Archaeologies and Descendant CommunitiesChip Colwell � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 113

Reaching the Point of No Return: The Computational Revolutionin ArchaeologyLeore Grosman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 129

Archaeologies of OntologyBenjamin Alberti � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 163

Archaeology and Contemporary WarfareSusan Pollock � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 215

The Archaeology of Pastoral NomadismWilliam Honeychurch and Cheryl A. Makarewicz � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 341

Urbanism and Anthropogenic LandscapesArlen F. Chase and Diane Z. Chase � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 361

Decolonizing Archaeological Thought in South AmericaAlejandro Haber � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 469

Biological Anthropology

Out of Asia: Anthropoid Origins and the Colonization of AfricaK. Christopher Beard � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 199

Early Environments, Stress, and the Epigenetics of Human HealthConnie J. Mulligan � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 233

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Native American Genomics and Population HistoriesDeborah A. Bolnick, Jennifer A. Raff, Lauren C. Springs, Austin W. Reynolds,

and Aida T. Miro-Herrans � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 319

Disease and Human/Animal InteractionsMichael P. Muehlenbein � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 395

Anthropology of Language and Communicative Practices

Intellectual Property, Piracy, and CounterfeitingAlexander S. Dent � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �17

Science Talk and Scientific ReferenceMatthew Wolfgram � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �33

Language, Translation, TraumaAlex Pillen � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �95

(Dis)fluencyJurgen Jaspers � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 147

Some Recent Trends in the Linguistic Anthropology of NativeNorth AmericaPaul V. Kroskrity � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 267

Sociocultural Anthropology

Urban Space and Exclusion in AsiaErik Harms � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �45

Historicity and AnthropologyCharles Stewart � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �79

Anthropological STS in AsiaMichael M. J. Fischer � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 181

CancerJuliet McMullin � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 251

Affect Theory and the EmpiricalDanilyn Rutherford � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 285

Where Have All the Peasants Gone?Susana Narotzky � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 301

Scripting the Folk: History, Folklore, and the Imagination of Placein BengalRoma Chatterji � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 377

Reproductive Tourism: Through the Anthropological “Reproscope”Michal Rachel Nahman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 417

Contents vii

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Design and AnthropologyKeith M. Murphy � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 433

Unfree LaborFilipe Calvao � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 451

Time as TechniqueLaura Bear � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 487

Indexes

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

Cumulative Index of Article Titles, Volumes 36–45 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 507

Errata

An online log of corrections to Annual Review of Anthropology articles may be found athttp://www.annualreviews.org/errata/anthro

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