Emerging Trends in The Social and Behavioral Sciences

Genetics and the Life Course

Item

Title

Genetics and the Life Course

Author

Charney, Evan

Research Area

Special Areas of Interdisciplinary Study

Topic

Genetics, the Individual and Society

Abstract

A life‐course perspective is committed to the proposition that from conception to death, all human outcomes are the result of a continual interaction between the individual and all of the environments that he or she inhabits at any given point in time. Early development is a critical period, a window of time during the life course when a given exposure can have a critical or permanent influence on later outcomes. But the impact of exposures upon outcomes does not end at any specific point in time, inasmuch as life is a continuing interactive and adaptive process. We now know that what applies to human beings also applies to their genomes. The “outcome” of any gene at any given point in time (whether or not it is used to transcribe a particular protein, what form of that protein, and how much) is a product of the interaction between the gene and the multiple environments of which it is a part, which include the epigenome, the cell, the biological human, and the assorted environments he or she occupies (e.g., geographical, socioeconomic, ethnic, etc.). Early life experiences can permanently “reprogram” the epigenome and gene transcription with life‐long behavioral consequences. At the same time, the epigenome as well as the genome continue to be environmentally responsive throughout the life course.

Related Essays

Telomeres (Psychology), Nancy Adler and Aoife O'Donovan

Social Epigenetics: Incorporating Epigenetic Effects as Social Cause and Consequence (Sociology), Douglas L. Anderton and Kathleen F. Arcaro

The Sexual Division of Labor (Anthropology), Rebecca Bliege Bird and Brian F. Codding

Sexual Behavior (Anthropology), Melissa Emery Thompson

Genetic and Environmental Approaches to Political Science (Political Science), Zoltán Fazekas and Peter K. Hatemi

Evolutionary Approaches to Understanding Children's Academic Achievement (Psychology), David C. Geary and Daniel B. Berch

Genetics and Social Behavior (Anthropology), Henry Harpending and Gregory Cochran

An Evolutionary Perspective on Developmental Plasticity (Psychology), Sarah Hartman and Jay Belsky

Genetic Foundations of Attitude Formation (Political Science), Christian Kandler et al.

Niche Construction: Implications for Human Sciences (Anthropology), Kevin N. Laland and Michael O'Brien

Evolutionary Perspectives on Animal and Human Personality (Anthropology), Joseph H. Manson and Lynn A. Fairbanks

Behavioral Heterochrony (Anthropology), Victoria Wobber and Brian Hare

Identifier

etrds0146

extracted text

Genetics and the Life Course
EVAN CHARNEY

Abstract
A life-course perspective is committed to the proposition that from conception to
death, all human outcomes are the result of a continual interaction between the individual and all of the environments that he or she inhabits at any given point in time.
Early development is a critical period, a window of time during the life course when
a given exposure can have a critical or permanent influence on later outcomes. But
the impact of exposures upon outcomes does not end at any specific point in time,
inasmuch as life is a continuing interactive and adaptive process. We now know that
what applies to human beings also applies to their genomes. The “outcome” of any
gene at any given point in time (whether or not it is used to transcribe a particular
protein, what form of that protein, and how much) is a product of the interaction
between the gene and the multiple environments of which it is a part, which include
the epigenome, the cell, the biological human, and the assorted environments he or
she occupies (e.g., geographical, socioeconomic, ethnic, etc.). Early life experiences
can permanently “reprogram” the epigenome and gene transcription with life-long
behavioral consequences. At the same time, the epigenome as well as the genome
continue to be environmentally responsive throughout the life course.

INTRODUCTION
In the most general sense, a life-course perspective is committed to two
propositions: First, that from conception to death, all human “outcomes”
or phenotypes (health, disease, psychology, behavior) are the result of a
continual interaction between the individual and all the environments that
she inhabits at any given point in time. These environments are always
nested, multiple, and interactive. An embryo occupies the environment of
the mother’s womb, which occupies the environment of the mother’s body;
the mother occupies an environment at once familial, socioeconomic, ethnic,
cultural, and geographic. To understand human outcomes we must take into
account the potential impact of all of these interconnected environments.
Thus characterized, a life-course perspective encompasses a developmental approach. Second, human life is an ongoing interactive process and
change—environmental and biological—continues from conception to death
Emerging Trends in the Social and Behavioral Sciences. Edited by Robert Scott and Stephen Kosslyn.
© 2015 John Wiley & Sons, Inc. ISBN 978-1-118-90077-2.

1

2

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

and the trajectory of any given stage of development will be influenced by
the preceding stages. Hence, the need to look at the life course as opposed to
a snapshot view of the individual at any given point in time.
How does genetics fit into a life-course perspective? As we shall see, to
understand the relationship between genetics and outcomes (or phenotypes)
we must adopt the same stance toward the gene that we do toward the person: In sickness and in health, in normal and abnormal development, the
“behavior” of genes or genomes cannot be understood apart from the nested
environments in which they are located. Hence, by necessity, any consideration of genetics from a life-course perspective encompasses much more
than the physical presence and structure of a gene, whether one gene or one
thousand. As in the case of the biological person, the genome itself (or rather
genomes, because persons possess more than one) changes throughout the
life course. Hence, the need to consider the “life course” of the genome itself.
It is important to note that what is here characterized as “genetics and the life
course” is based on cutting-edge research in molecular genetics and recent
discoveries that are overturning many traditional dogmas.
A gene is a segment of DNA that contains information that can be used,
by the cell, to construct amino acids, the building blocks of proteins. In the
process known as gene transcription, a segment of DNA is copied to produce
messenger RNA, which serves as a template for the synthesis of protein. In
structures called ribosomes, the messenger RNA template is used to form a
particular protein in a process known as translation. Persons inherit at least
two copies of a gene, one from each parent. Each copy of a gene is called
an allele, and alleles from both parents may be identical or they may differ
slightly. These structural differences between alleles can be found in many
different configurations or versions. When two or more versions of an allele
for a gene occur in >1% of a given population, it is referred to as a polymorphism. A version of an allele that occurs in <1% of the population is called
a mutation. A genotype refers to the specific alleles one possesses, and all of
one’s inherited alleles are her genome. It is common to speak of a (single)
genome, but as we shall see, all persons possess multiple genomes.
INHERITANCE
The life course of the genome begins before conception in the gametes: the
egg cell or oocyte supplied from the mother and the sperm cell from the
father. Each gamete supplies half of our full complement of chromosomes
and half of our alleles. Genes, however, are by no means the only biological
agent of inheritance. From our mothers we also inherit, via the oocyte,
assorted nutrients, abundant messenger RNAs, noncoding RNAs (RNA
molecules not involved in translation) and a variety of organelles, structures

Genetics and the Life Course

3

within a cell that perform essential cellular functions. From sperm, we
inherit, in addition to half our DNA, messenger RNAs and noncoding
RNAs, as well as an organelle known as a centrosome, which facilitates
cellular division and plays a key role in human fertility and the ability
of embryos to undergo normal development (Chatzimeletiou, Morrison,
Prapas, Prapas, & Handyside, 2008).
Among the organelles we inherit are mitochondria, which perform
essential cellular functions including the generation of cellular energy.
mtDNA (mitochondrial deoxyribonucleic acid) is inherited solely from
the mother inasmuch as mitochondria from sperm are destroyed shortly
after fertilization. Mitochondria contain multiple copies of their own DNA
molecules—mtDNA—that are distinct from the more familiar nuclear DNA
contained in the nuclei of all of our cells. Oocytes from the same mother may
contain anywhere from 11,000 to 903,000 mtDNA molecules per oocyte, and
mitochondrial number, distribution, and structure play essential roles in
fertilization and normal embryonic development. Studies indicate that the
mean number of copies of mtDNA in human fertilized oocytes is ∼250,000,
while for unfertilized oocytes, the mean is 164,000, and it has been suggested
that a mitochondrial complement of at least ∼100,000 copies of mtDNA is
required for normal embryonic development (Shoubridge & Wai, 2007).
A number of different factors have been shown to influence both the number of mitochondria (and hence the amount of mtDNA) and the manner
in which mitochondria function post-fertilization. Maternal fertility declines
rapidly from a peak conception rate at age 22. In addition to having fewer
eggs ovulating, the “quality” of a woman’s eggs declines; and one of the
contributing factors is a loss of mitochondria due to the accumulation of
age-dependent mutations of mtDNA (Jones & Lopez, 2013). With age, there
is also an increase in mutations in the oocyte’s nuclear DNA and by age 40,
half of a woman’s eggs are chromosomally abnormal (the nuclear DNA is
contained in the chromosomes), and 2 years later this figure rises to 90%
(Jones & Lopez, 2013). One common chromosomal abnormality is trisomy,
three copies of a particular chromosome, and depending on the chromosome
affected, the result can be a number of different “trisomic” disorders in offspring.
After ovulation, the oocyte enters a state of arrest during which DNA
transcription stops and after fertilization transcription does not begin until
after the embryo reaches the two-cell stage, when transcription commences
via a process known as embryonic genome activation (EGA). How can an
embryo develop during this period with a nonfunctioning genome? The
answer is that while transcription is stopped during this period, translation,
the synthesis of proteins from messenger RNA, is not. The oocyte contains
a vast array of messenger RNAs that are translated into proteins in the

4

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

ribosomes (which are also inherited with the oocyte). Messenger RNAs are
also present in smaller amounts in sperm and their translation pre-EGA is
almost certainly critical for normal development. In addition to messenger
RNA, both egg and sperm contain numerous kinds of noncoding RNAs
that function as a vast regulatory system, controlling the extent to which
messenger RNAs can be translated into proteins. Before EGA, development
is controlled largely via the translation of messenger RNAs and the activity
of noncoding RNAs inherited via the egg and sperm.
EPIGENETICS: EMBRYOGENESIS AND BEYOND
How, precisely, is transcription of DNA stopped before EGA and how is
it restarted? The answer is the epigenome. There are many epigenetic processes, but the two most studied are histone modification and DNA methylation. Within chromosomes, DNA is combined with proteins called histones
to form chromatin, a highly coiled and compact structure. Modifications to
histones can change the structure of the chromatin causing it to wind more or
less tightly, making the DNA more or less accessible to special proteins called
transcription factors. Without being accessible to transcription factors, DNA
transcription cannot occur. DNA methylation is the addition of a chemical
compound to specific sites on the DNA molecule and acts as a physical barrier to transcription factors. In other words, both histone modification and
DNA methylation, by regulating the extent to which regions of DNA (i.e.,
“genes”) are accessible to transcription factors, can effectively turn genes on
and off. It is hard to underestimate the significance of the epigenome. In fact,
embryogenesis itself is an epigenetic process.
After fertilization the early embryo, the zygote, is in a state of totipotency,
that is, the small number of cells of which it is initially composed can develop
into any cell in the body (e.g., a heart cell, a neuron, a skin cell). Development is, in part, the differentiation of totipotent cells into specialized types
of cells. In later development, these differentiated cells of the body (e.g., a
heart cell, a neuron, a skin cell) are radically different in appearance and function despite the fact that they contain the same nuclear DNA. The epigenome
is responsible for both totipotency and subsequent cellular differentiation.
What differentiates a skin cell from a neuron is not differences in nuclear
DNA (although, as we shall see, their nuclear DNA may in fact differ), but
rather differences in their epigenomes. This means that in a skin cell and neuron different genes are turned on and off and hence, only certain genes can
be transcribed in each type of cell. It is this difference in epigenetic “switches” or “markings” that leads to the radically different form and function of
different types of cells.

Genetics and the Life Course

5

Egg and sperm are both distinct types of cells. When their DNAs are joined
in the zygote, their epigenetic markings are erased (with one important
exception to be considered subsequently). This leads to totipotency, the
ability of the cells of the early embryo to become any cells of the body. As
development progresses, cells lose their totipotency as different epigenetic
marks are established and become differentiated as specialized types of cells
(e.g., a neuron or a skin cell). Differentiated cells will only give rise, through
cellular division or mitosis, to cells of their own kind; for example, skin cells
will only give rise to skin cells and heart cells to heart cells. This is a form
of cellular inheritance. Hence, one definition of epigenetics is the study of
heritable changes in gene transcribability and phenotype that occur without
changes in DNA sequence.
While epigenetic modifications of the genome can be stable throughout
the life course, such as the epigenetic modifications that contribute to cellular differentiation during embryogenesis, they can also be environmentally
responsive, changing the transcribability of the genome in response to environmental inputs. The term environmental epigenomics reflects the constant
interplay between the environment, which includes both endogenous (e.g.,
hormone levels or immune status) and exogenous (e.g., the perinatal environment) factors, and the epigenome. Consider several examples.
One exception to the initial erasure of epigenetic marks during embryogenesis concerns imprinted genes. Imprinting is an epigenetic phenomenon
in which specific alleles are expressed in a parent of origin manner. In
paternally imprinted genes, the paternal allele is epigenetically modified,
preventing its transcription and leading to transcription solely from the
maternal allele; in maternally imprinted genes, the maternal allele is epigenetically modified, preventing its transcription and leading to transcription
solely from the paternal allele. The epigenetic marks of imprinted genes are
maintained throughout embryogenesis. Abnormalities of imprinting can
result in imprinting disorders.
One striking finding to emerge from the global rise of in vitro fertilization
(IVF)—fertilization of an egg in a petri dish and implantation in the womb
up to 6 days post fertilization—as a method of artificial reproduction is the
rise of rare imprinting disorders among IVF-conceived children. Current
estimates are that IVF children are approximately 514 times more likely to
develop Beckwith–Wiedeman syndrome (BWS), a rare imprinting disorder,
than non-IVF children, although the total numbers remain small owing to
the rarity of the disorder (Hiura et al., 2012). Findings of an increased rate
of analogous imprinting disorders in IVF animal models appear to rule out
the possibility that this could be associated with subfertility. The reason for
this increase in imprinting disorders is not known, but it could be due to
any aspect of the IVF environment—the manipulation of egg and sperm,

6

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

the cultivation of the zygote in the suboptimal environment of a petri dish
before implantation in the womb—disrupting the maintenance of epigenetic
marks on imprinted genes.
It is well established that the prenatal environment can have a profound
impact on developmental outcomes. The developmental origins of health
and disease (DOHAD) is now an established area of medical research.
Research in this field has demonstrated that factors such as maternal underor overnutrition, or maternal levels of stress—factors often associated with
the mother’s socioeconomic status—can increase the risk of, for example,
diabetes and obesity in children and diabetes, obesity, and cardiovascular
disease in adults (Gluckman & Hanson, 2006). There is growing evidence
that one of the mechanisms by which these environmental factors influence
developmental outcomes is via environmentally induced changes to the
epigenome (Lillycrop & Burdge, 2011). For example, there is evidence that
maternal stress during pregnancy can reprogram the stress response of
offspring with lifelong behavioral consequences (Mueller & Bale, 2008).
It is not only the prenatal environment that can reprogram the epigenome
with significant developmental consequences. Mother rats that exhibit
high-quality mothering (as measured by the amount of time they spend
licking and grooming their pups) rear pups that, as adults, exhibit lower
levels of stress as measured both physiologically and behaviorally, while
pups raised by low-quality mothers exhibit, as adults, high levels of stress.
Furthermore, female pups raised by high-quality mothers become, as adults,
high-quality mothers themselves, while the females raised by low-quality
mothers become low-quality mothers. Low-quality mothers also begin
reproducing earlier and more frequently. Cross-fostering studies, in which
pups are separated at birth from their biological mothers and raised by foster
mothers, have consistently indicted that adult offspring are more likely
to resemble their foster as opposed to biological mothers in stress-related
responses and rearing behavior. These differences in rearing behavior have
been associated with epigenetic changes in offspring in regions of the brain
involved in both the stress response and maternal behavior (Weaver et al.,
2004).
Such environmentally induced epigenetic changes in gene transcribability
and phenotype can serve an important adaptive function by enabling
phenotypic plasticity. Phenotypic plasticity can be defined broadly as the
ability of an organism to change phenotype in response to its environment. Modern evolutionary biology reflects the idea that adaptation is
not limited to the process of natural selection (i.e., adaptation at the level
of the species), but includes adaptation of the individual organism to its
ecological niche. Adversity during perinatal development can forecast an
increased level of demand in the environment the offspring will occupy.

Genetics and the Life Course

7

Under such conditions, the animal’s best interest is to enhance its behavioral
(e.g., vigilance, fearfulness) and endocrine responsiveness to stress. These
responses promote detection of potential threat, avoidance learning, and
metabolic/cardiovascular responses that are essential under the increased
demands of the stressor. Under high-risk conditions, when the probability
of extended periods of growth and survival are low, the optimal strategy is
to maximize the number of offspring through accelerated mating, increasing
the chances that at least some offspring will survive to reproductive maturity.
Such conditions favor a shift in reproductive investment toward quantity,
while more favorable environmental conditions favor greater investment
in individual offspring at the cost of mating, as offspring quality predicts
successful competition for available resources and reproductive fitness.
Finally, there is a growing body of evidence that it is not only the epigenetic
markings on imprinted genes that are not erased during embryogenesis.
Specifically, there is evidence that environmentally induced changes to the
epigenome can escape embryonic erasure and be transmitted intergenerationally. For example, studies have demonstrated that when a male rodent
embryo is exposed in the womb to the endocrine disruptor vinclozolin (a
common fungicide), it develops a phenotype characterized by defects in
sperm production and subfertility. This defect has been associated with
epigenetic changes at specific imprinted genes known to be involved in
spermatogenesis. In the absence of any further exposure to vinclozolin, the
phenotype can be transmitted from the exposed male to male offspring for
up to three generations. In other words, an environmentally induced change
to the epigenome and gene expression, and the resulting phenotype, can be
transmitted intergenerationally without any change to the DNA sequence
(Stouder & Paoloni-Giacobino, 2010). Decreases in human spermatogenesis
are associated with imprinting defects on a number of the same genes that
have shown abnormal epigenetic patterns in vinclozolin studies (Stouder &
Paoloni-Giacobino, 2010). This is particularly suggestive given that in the
past century a significant decline in sperm count has been documented in
young, healthy males in industrialized countries, a finding that may in part
explain a parallel decline in birthrates (Joffe, 2010). The rapidity of these
changes strongly suggests that environmental factors play a role. Endocrine
disruptors are a plausible contributing factor given their ubiquitousness
in the environment in the form of herbicides, insecticides, and fungicides,
resulting in daily exposure for many human populations.
ANEUPLOIDY
Epigenetic changes are changes that occur to DNA expression without any
change to DNA content and sequence. Development, however, involves

8

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

changes to both. It is commonly assumed that each cell in the body contains two alleles (with a few exceptions) because each cell contains two
chromosomes. Any departure from two chromosomes per cell (diploidy)
is called aneuploidy. Errors of chromosomal replication are a normal part
of embryogenesis, leading to a surprisingly high number of cells that
exhibit one or another form of aneuploidy. Despite the association between
aneuploidy and illness, there is a surprisingly high amount of chromosomal
aneuploidy in the healthy adult brain. Recent conservative estimates place
the overall percentage of aneuploid neural cells in the adult brain at an
astonishing 10%, involving monosomy (1 chromosome), trisomy (3 chromosomes), tetrasomy (4 chromosomes), polyploidy (>4 chromosomes), and
uniparental disomy (two copies of a chromosome from the same parent)
(Rehen, 2005). Given an estimated 86 billion neurons in the adult brain,
this yields a rough (conservative) estimate of 8.6 billion aneuploid neurons.
Various lines of evidence indicate that brain tissues may be more prone to
aneuploidy than other tissues. Mature aneuploid neurons are functionally
active and integrated into brain circuitry. One likely result of this is neuronal
signaling differences caused by altered gene transcription, as documented in
mammalian neural cells. Thus, a network composed of intermixed diploid
and aneuploid neurons might produce unique signaling properties.
RETROTRANSPOSONS
One striking finding to emerge from the completion of the human
genome-sequencing project is that approximately 48% of the genome
is composed of transposable elements or “jumping genes” (Gibbs, 2003).
Retrotransposons are a class of transposable DNA elements that move
about the genome by a “copy and paste” mechanism known as retrotransposition. Retrotransposons first copy themselves to RNA, while the
original DNA copy is maintained at the same location. The RNA copy is
then “reverse-transcribed” into DNA and the DNA is inserted into the
genome at a new location. Hence, these elements expand in number as they
retrotranspose, leading to an increase in genomic DNA content and a change
in DNA sequence and structure at the region of insertion. In so doing, they
alter both the DNA sequence at the region of insertion and the total amount
of DNA in the genomes in which they insert themselves. Because of their
potential to disrupt genomic functioning by copying and pasting themselves
throughout the genome in an uncontrolled manner, most transposable
elements and retrotransposons are “turned off” by the epigenome. However,
for a period during early embryogenesis retrotransposons are released
from their epigenetic silencing. Why this occurs is not known, although the
prevalence of retrotransposition in the brain has led to speculation that the

Genetics and the Life Course

9

genetic diversity they create may in some way be related to the diversity
of neurons (there are up to 10,000 different kinds of neurons in the normal
adult brain) (Sciamanna, Vitullo, Curatolo, & Spadafora, 2009).
In addition to being activated during embryogenesis, retrotransposons are
also active in those parts of the brain (the hippocampus and subventricular
zone) that produce new neurons throughout life (Baillie et al., 2011). The
level of production of new neurons in the adult brain is positively and negatively modulated by environmental conditions, including environmental
enrichment, stress, and aging. Exercise is known to have a significant impact
upon hippocampal neurogenesis: it significantly increases the amount of
brain-derived neurotropic factor (BDNF) in the hippocampus, a protein that
supports the survival of existing neurons and encourages the growth and
differentiation of new neurons and synapses (Gomez-Pinilla, Zhuang, Feng,
Ying, & Fan, 2011). In mice, voluntary wheel running has been shown both
to significantly increase neurogenesis in the brain and to double the amount
of hippocampal retrotransposition (Muotri, Marchetto, Zhao, & Gage, 2009).
What this entails is that the structure of the genome itself can change in
response to environmental conditions. In humans, depending on its impact
upon the brain, retrotransposon-induced DNA variability might induce
behavioral changes that could help the individual adapt better to changing environments or, alternatively, increase the risk of neuropsychiatric
disorders.
TELOMERES AND mtDNA
Telomeres are repeating DNA sequences bound by special protein complexes
located at both ends of each of the (presumed) 46 chromosomes in the cells
of the human body. They protect the base pairs at the ends of the chromosomes from deterioration and prevent them from fusing with neighboring
chromosomes. Each time chromosomes are replicated in the process of cellular division, some of the telomere is lost (25–200 base pairs per division).
When the telomere becomes too short, the chromosome reaches a critical
length and can no longer replicate; this results in cell death. In highly proliferating cells such as germ and stem cells, telomere length is maintained by
the enzyme telomerase, but in most cells of the body the activity of telomerase is low, and telomere length provides a marker for cellular aging. In
recent years, shorter telomere length has been associated with a broad range
of aging-related diseases, including many forms of cancer, stroke, vascular
dementia, cardiovascular disease, obesity, osteoporosis, and diabetes. Telomeres of obese women have been found to be 240 base pairs shorter than those
of lean women, and the telomeres of smokers are 18% shorter than nonsmokers (Valdes et al., 2005). Shortened telomere length has also been associated

10

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

with an array of environmental stressors including chronic psychological
stress (Chae et al., 2014), and even with socioeconomic status in children aged
7–12 (Needham, Fernandez, Lin, Epel, & Blackburn, 2012).
Aging has been associated with a wide spectrum of alterations in mitochondria and mtDNA, including increased disorganization of mitochondrial
structure, a decline in energy production, and accumulation of mtDNA mutations. The mitochondrial theory of aging proposes that progressive accumulation of mutations in mtDNA during a lifetime leads to an inevitable decline
in mitochondrial function. The precise role of mtDNA mutation in aging
remains uncertain, but their increase as part of the aging process is beyond
doubt (Chistiakov, Sobenin, Revin, Orekhov, & Bobryshev, 2014).
CONCLUSION
Much of the effort to explicate the relationship between genotype and phenotype to date has been devoted to trying to find “predisposing” polymorphisms, gene variants that are risk factors for, or allow one to predict, complex phenotypes associated with both sickness [e.g., type 1 diabetes (T1D) or
schizophrenia] and health (longevity, intelligence). While a few such polymorphisms have been identified (e.g., the BRCA1 and 2 genes are associated
with an increased risk of genetic breast and uterine cancer), their identification has been largely unsuccessful. For disorders, such as T1D, which have
been associated with many different polymorphisms—in the case of T1D,
60 and counting, only a small number of genetically susceptible individuals
progress to clinical disease, and heritability estimates for T1D are relatively
low (Knip et al., 2012). In other words, the polymorphisms lack predictive
value, indicating that the disease is the result of some form of complex biological predisposition interacting in complex ways with as yet unknown environmental triggers. Adding to the complexity is the fact that more than one
protein can be transcribed from the same gene.
Given that there are estimated to be more than 100,000 proteins in the
human body—and the number may be significantly higher—yet approximately 20,000 genes in the human genome, necessitates a rethinking of the
assumption that each gene contains the ‘instructions’ for making just one
protein. AS (alternative splicing) allows a single gene to produce multiple
transcripts. AS occurs when newly transcribed RNA (known as pre-mRNA)
is rearranged by processes in the cellular environment. This results in
different mRNAs and different proteins, called isoforms (Nilsen & Graveley,
2010). AS is estimated to occur in 95% of human genes, and can result in
numerous proteins being synthesised from the same gene (e.g., the neurexin
proteins are encoded by three genes, but it is estimated that more than 1000

Genetics and the Life Course

11

neurexin isoforms are produced by extensive AS). Isoforms of the same gene
can exert radically different and even opposed physiological effects.
From a life-course perspective on the genotype–phenotype relationship,
the failure to find predisposing genes for most complex human traits is not
at all surprising: Genes are not the sole biological agent of inheritance; as
a result of chance errors in replication and the activity of retrotransposons
during the developmental process, persons do not have one genome, but
different genomes in different cells in their bodies; the epigenome, which is
a key to the entire process of development from conception on, can be highly
environmentally responsive and can reprogram gene expressivity in enduring ways in response to environmental inputs; the environment changes not
only gene expressivity, but the genome (or genomes) itself, through processes such as retrotransposition, the shortening of telomeres, and mutations
in mtDNA. These changes are associated with the life course—telomere
shortening and mutation accumulation in mtDNA are part of the aging
process—and are influenced by the environments the individual occupies
throughout her life: Telomere length has been associated in children and
adults with stressful environments (such as environments characterized by
low socioeconomic status); retrotransposition continues throughout life in
certain brain regions and is associated, via increased neurogenesis, with
environmental inputs such as environmental stimulation and exercise.
The problem with the search for genes “for,” or genes “predisposing for”
complex phenotypes is that first, it unscientifically privileges genes as the
sole biological agent of inheritance, ignoring all of the other inherited biological elements in the absence of which genes would have no effect whatsoever. It is well to keep in mind, particularly regarding the search for genes
involved in, for example, intelligence, that humans possess fewer protein-coding
genes than corn. One of the surprising findings of the Genome Project was
that the human genome contains an estimated 20,000 protein-coding genes,
less than maize (i.e., corn), which contains over 32,000 protein-coding genes,
and close in number to the nematode, with approximately 19,000. And many
genes appear to be preserved across species. Surely, the distinctive properties of the human brain and human behavior are the result of something
other than what we have less of than corn. Second, this search is based on
a static conception of the genome, ignoring the manifold transformations
it undergoes as part of its, and our, life course. And third, it presupposes
the anachronistic dichotomy between “nature” and “nurture,” “genes,” and
“environment.” Is chromatin, for example, in which the DNA is wrapped
and which allows genes to be transcribed by changing its configuration in
response to environmental inputs, “genes” or “environment”? When the configuration of genes changes in response to environmental inputs, does the
environment “become” genes? The life-course approach shows us that such

12

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

simplistic dichotomies belie the complexity, fluidity, and temporality of the
biological world.
REFERENCES
Baillie, J. K, Barnett, M. W, Upton, K. R, Gerhardt, D. J, Richmond, T. A, De Sapio, F.,
… Faulkner, G. J. (2011). Somatic retrotransposition alters the genetic landscape
of the human brain. Nature 479(7374): 534–537.
Chae, D. H., Nuru-Jeter, A. M., Adler, N. E., Brody, G. H., Lin, J., Blackburn,
E. H., & Epel, E. S. (2014). Discrimination, racial bias, and telomere length in
African-American men. American Journal of Preventive Medicine, 46(2), 103–111.
Chatzimeletiou, K., Morrison, E. E., Prapas, N., Prapas, Y., & Handyside, A. H.
(2008). The centrosome and early embryogenesis: Clinical insights. Reproductive
Biomedicine Online, 16(4), 485–491.
Chistiakov, D. A., Sobenin, I. A., Revin, V. V., Orekhov, A. N., & Bobryshev, Y. V.
(2014). Mitochondrial aging and age-related dysfunction of mitochondria. BioMed
Research International, 2014, 238463.
Gibbs, R. A. (2003). The international HapMap project. Nature, 426(6968), 789–796.
Gluckman, P. D., & Hanson, M. A. (2006). Developmental origins of health and disease.
Cambridge, England: Cambridge University Press.
Gomez-Pinilla, F., Zhuang, Y., Feng, J., Ying, Z., & Fan, G. (2011). Exercise impacts
brain-derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation. The European Journal of Neuroscience, 33(3), 383–390.
Hiura, H., Okae, H., Miyauchi, N., Sato, F., Sato, A, Van De Pette, M., … Arima, T.
(2012). Characterization of DNA methylation errors in patients with imprinting
disorders conceived by assisted reproduction technologies. Human Reproduction,
27(8): 2541–2548.
Joffe, M. (2010). What has happened to human fertility? Human Reproduction, 25(2),
295–307.
Jones, R. E., & Lopez, K. H. (2013). Human reproductive biology. Waltham, MA: Elsevier.
Knip, M., Veijola, R., Virtanen, S. M., Hyoty, H., Vaarala, O., & Akerblom, H. K. (2012).
Environmental triggers and determinants of type 1 diabetes. Diabetes, 54(Suppl 2),
S125–S136.
Lillycrop, K. A., & Burdge, G. C. (2011). Epigenetic changes in early life and future
risk of obesity. International Journal of Obesity, 35(1), 72–83.
Mueller, B. R., & Bale, T. L. (2008). Sex-specific programming of offspring emotionality after stress early in pregnancy. The Journal of Neuroscience, 28(36), 9055–9065.
Muotri, A. R., Marchetto, M. C. N., Zhao, C., & Gage, F. H. (2009). Environmental
influence on L1 retrotransposons in the adult hippocampus. Hippocampus, 19(10),
1002–1007.
Needham, B. L., Fernandez, J. R., Lin, J., Epel, E. S., & Blackburn, E. H. (2012).
Socioeconomic status and cell aging in children. Social Science & Medicine, 74(12),
1948–1951.
Nilsen, T. W., & Graveley, B. R. (2010). Expansion of the eukaryotic proteome by
alternative splicing. Nature, 463, 457–463.

Genetics and the Life Course

13

Rehen, S. K. (2005). Constitutional aneuploidy in the normal human brain. Journal of
Neuroscience, 25, 2176–2180.
Sciamanna, I., Vitullo, P., Curatolo, A., & Spadafora, C. (2009). Retrotransposons,
reverse transcriptase and the genesis of new genetic information. Gene, 448(2),
180–186.
Shoubridge, E., & Wai, T. (2007). Mitochondrial DNA and the mammalian
oocyte. Current Topics in Developmental Biology, 77(06), 87–111. doi:10.1016/S00702153(06)77004-1
Stouder, C., & Paoloni-Giacobino, A. (2010). Transgenerational effects of the
endocrine disruptor vinclozolin on the methylation pattern of imprinted genes
in the mouse sperm. Reproduction, 139(2), 373–379.
Valdes, A. M., Andrew, T., Gardner, J. P., Kimura, M., Oelsner, E., Cherkas, L. F., …
Spector, T. D. (2005). Obesity, cigarette smoking, and telomere length in women.
Lancet, 366(9486): 662–664.
Weaver, I. C., Cervoni, N., Champagne, F. A., D’Alessio, A. C., Sharma, S., & Seckl, J.
R. (2004). Epigenetic programming by maternal behavior. Nature Neuroscience, 7,
847–854.

EVAN CHARNEY SHORT BIOGRAPHY
Evan Charney is Associate Professor of Public Policy, Duke University, Faculty Fellow, Duke Institute for Brain Sciences, and Researcher, Duke Institute
for Genome Sciences and Policy.
RELATED ESSAYS
Telomeres (Psychology), Nancy Adler and Aoife O’Donovan
Social Epigenetics: Incorporating Epigenetic Effects as Social Cause and Consequence (Sociology), Douglas L. Anderton and Kathleen F. Arcaro
The Sexual Division of Labor (Anthropology), Rebecca Bliege Bird and Brian
F. Codding
Sexual Behavior (Anthropology), Melissa Emery Thompson
Genetic and Environmental Approaches to Political Science (Political Science),
Zoltán Fazekas and Peter K. Hatemi
Evolutionary Approaches to Understanding Children’s Academic Achievement (Psychology), David C. Geary and Daniel B. Berch
Genetics and Social Behavior (Anthropology), Henry Harpending and Gregory Cochran
An Evolutionary Perspective on Developmental Plasticity (Psychology), Sarah
Hartman and Jay Belsky
Genetic Foundations of Attitude Formation (Political Science), Christian Kandler et al.

14

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

Niche Construction: Implications for Human Sciences (Anthropology), Kevin
N. Laland and Michael O’Brien
Evolutionary Perspectives on Animal and Human Personality (Anthropology), Joseph H. Manson and Lynn A. Fairbanks
Behavioral Heterochrony (Anthropology), Victoria Wobber and Brian Hare



Genetics and the Life Course
EVAN CHARNEY

Abstract
A life-course perspective is committed to the proposition that from conception to
death, all human outcomes are the result of a continual interaction between the individual and all of the environments that he or she inhabits at any given point in time.
Early development is a critical period, a window of time during the life course when
a given exposure can have a critical or permanent influence on later outcomes. But
the impact of exposures upon outcomes does not end at any specific point in time,
inasmuch as life is a continuing interactive and adaptive process. We now know that
what applies to human beings also applies to their genomes. The “outcome” of any
gene at any given point in time (whether or not it is used to transcribe a particular
protein, what form of that protein, and how much) is a product of the interaction
between the gene and the multiple environments of which it is a part, which include
the epigenome, the cell, the biological human, and the assorted environments he or
she occupies (e.g., geographical, socioeconomic, ethnic, etc.). Early life experiences
can permanently “reprogram” the epigenome and gene transcription with life-long
behavioral consequences. At the same time, the epigenome as well as the genome
continue to be environmentally responsive throughout the life course.

INTRODUCTION
In the most general sense, a life-course perspective is committed to two
propositions: First, that from conception to death, all human “outcomes”
or phenotypes (health, disease, psychology, behavior) are the result of a
continual interaction between the individual and all the environments that
she inhabits at any given point in time. These environments are always
nested, multiple, and interactive. An embryo occupies the environment of
the mother’s womb, which occupies the environment of the mother’s body;
the mother occupies an environment at once familial, socioeconomic, ethnic,
cultural, and geographic. To understand human outcomes we must take into
account the potential impact of all of these interconnected environments.
Thus characterized, a life-course perspective encompasses a developmental approach. Second, human life is an ongoing interactive process and
change—environmental and biological—continues from conception to death
Emerging Trends in the Social and Behavioral Sciences. Edited by Robert Scott and Stephen Kosslyn.
© 2015 John Wiley & Sons, Inc. ISBN 978-1-118-90077-2.

1

2

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

and the trajectory of any given stage of development will be influenced by
the preceding stages. Hence, the need to look at the life course as opposed to
a snapshot view of the individual at any given point in time.
How does genetics fit into a life-course perspective? As we shall see, to
understand the relationship between genetics and outcomes (or phenotypes)
we must adopt the same stance toward the gene that we do toward the person: In sickness and in health, in normal and abnormal development, the
“behavior” of genes or genomes cannot be understood apart from the nested
environments in which they are located. Hence, by necessity, any consideration of genetics from a life-course perspective encompasses much more
than the physical presence and structure of a gene, whether one gene or one
thousand. As in the case of the biological person, the genome itself (or rather
genomes, because persons possess more than one) changes throughout the
life course. Hence, the need to consider the “life course” of the genome itself.
It is important to note that what is here characterized as “genetics and the life
course” is based on cutting-edge research in molecular genetics and recent
discoveries that are overturning many traditional dogmas.
A gene is a segment of DNA that contains information that can be used,
by the cell, to construct amino acids, the building blocks of proteins. In the
process known as gene transcription, a segment of DNA is copied to produce
messenger RNA, which serves as a template for the synthesis of protein. In
structures called ribosomes, the messenger RNA template is used to form a
particular protein in a process known as translation. Persons inherit at least
two copies of a gene, one from each parent. Each copy of a gene is called
an allele, and alleles from both parents may be identical or they may differ
slightly. These structural differences between alleles can be found in many
different configurations or versions. When two or more versions of an allele
for a gene occur in >1% of a given population, it is referred to as a polymorphism. A version of an allele that occurs in <1% of the population is called
a mutation. A genotype refers to the specific alleles one possesses, and all of
one’s inherited alleles are her genome. It is common to speak of a (single)
genome, but as we shall see, all persons possess multiple genomes.
INHERITANCE
The life course of the genome begins before conception in the gametes: the
egg cell or oocyte supplied from the mother and the sperm cell from the
father. Each gamete supplies half of our full complement of chromosomes
and half of our alleles. Genes, however, are by no means the only biological
agent of inheritance. From our mothers we also inherit, via the oocyte,
assorted nutrients, abundant messenger RNAs, noncoding RNAs (RNA
molecules not involved in translation) and a variety of organelles, structures

Genetics and the Life Course

3

within a cell that perform essential cellular functions. From sperm, we
inherit, in addition to half our DNA, messenger RNAs and noncoding
RNAs, as well as an organelle known as a centrosome, which facilitates
cellular division and plays a key role in human fertility and the ability
of embryos to undergo normal development (Chatzimeletiou, Morrison,
Prapas, Prapas, & Handyside, 2008).
Among the organelles we inherit are mitochondria, which perform
essential cellular functions including the generation of cellular energy.
mtDNA (mitochondrial deoxyribonucleic acid) is inherited solely from
the mother inasmuch as mitochondria from sperm are destroyed shortly
after fertilization. Mitochondria contain multiple copies of their own DNA
molecules—mtDNA—that are distinct from the more familiar nuclear DNA
contained in the nuclei of all of our cells. Oocytes from the same mother may
contain anywhere from 11,000 to 903,000 mtDNA molecules per oocyte, and
mitochondrial number, distribution, and structure play essential roles in
fertilization and normal embryonic development. Studies indicate that the
mean number of copies of mtDNA in human fertilized oocytes is ∼250,000,
while for unfertilized oocytes, the mean is 164,000, and it has been suggested
that a mitochondrial complement of at least ∼100,000 copies of mtDNA is
required for normal embryonic development (Shoubridge & Wai, 2007).
A number of different factors have been shown to influence both the number of mitochondria (and hence the amount of mtDNA) and the manner
in which mitochondria function post-fertilization. Maternal fertility declines
rapidly from a peak conception rate at age 22. In addition to having fewer
eggs ovulating, the “quality” of a woman’s eggs declines; and one of the
contributing factors is a loss of mitochondria due to the accumulation of
age-dependent mutations of mtDNA (Jones & Lopez, 2013). With age, there
is also an increase in mutations in the oocyte’s nuclear DNA and by age 40,
half of a woman’s eggs are chromosomally abnormal (the nuclear DNA is
contained in the chromosomes), and 2 years later this figure rises to 90%
(Jones & Lopez, 2013). One common chromosomal abnormality is trisomy,
three copies of a particular chromosome, and depending on the chromosome
affected, the result can be a number of different “trisomic” disorders in offspring.
After ovulation, the oocyte enters a state of arrest during which DNA
transcription stops and after fertilization transcription does not begin until
after the embryo reaches the two-cell stage, when transcription commences
via a process known as embryonic genome activation (EGA). How can an
embryo develop during this period with a nonfunctioning genome? The
answer is that while transcription is stopped during this period, translation,
the synthesis of proteins from messenger RNA, is not. The oocyte contains
a vast array of messenger RNAs that are translated into proteins in the

4

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

ribosomes (which are also inherited with the oocyte). Messenger RNAs are
also present in smaller amounts in sperm and their translation pre-EGA is
almost certainly critical for normal development. In addition to messenger
RNA, both egg and sperm contain numerous kinds of noncoding RNAs
that function as a vast regulatory system, controlling the extent to which
messenger RNAs can be translated into proteins. Before EGA, development
is controlled largely via the translation of messenger RNAs and the activity
of noncoding RNAs inherited via the egg and sperm.
EPIGENETICS: EMBRYOGENESIS AND BEYOND
How, precisely, is transcription of DNA stopped before EGA and how is
it restarted? The answer is the epigenome. There are many epigenetic processes, but the two most studied are histone modification and DNA methylation. Within chromosomes, DNA is combined with proteins called histones
to form chromatin, a highly coiled and compact structure. Modifications to
histones can change the structure of the chromatin causing it to wind more or
less tightly, making the DNA more or less accessible to special proteins called
transcription factors. Without being accessible to transcription factors, DNA
transcription cannot occur. DNA methylation is the addition of a chemical
compound to specific sites on the DNA molecule and acts as a physical barrier to transcription factors. In other words, both histone modification and
DNA methylation, by regulating the extent to which regions of DNA (i.e.,
“genes”) are accessible to transcription factors, can effectively turn genes on
and off. It is hard to underestimate the significance of the epigenome. In fact,
embryogenesis itself is an epigenetic process.
After fertilization the early embryo, the zygote, is in a state of totipotency,
that is, the small number of cells of which it is initially composed can develop
into any cell in the body (e.g., a heart cell, a neuron, a skin cell). Development is, in part, the differentiation of totipotent cells into specialized types
of cells. In later development, these differentiated cells of the body (e.g., a
heart cell, a neuron, a skin cell) are radically different in appearance and function despite the fact that they contain the same nuclear DNA. The epigenome
is responsible for both totipotency and subsequent cellular differentiation.
What differentiates a skin cell from a neuron is not differences in nuclear
DNA (although, as we shall see, their nuclear DNA may in fact differ), but
rather differences in their epigenomes. This means that in a skin cell and neuron different genes are turned on and off and hence, only certain genes can
be transcribed in each type of cell. It is this difference in epigenetic “switches” or “markings” that leads to the radically different form and function of
different types of cells.

Genetics and the Life Course

5

Egg and sperm are both distinct types of cells. When their DNAs are joined
in the zygote, their epigenetic markings are erased (with one important
exception to be considered subsequently). This leads to totipotency, the
ability of the cells of the early embryo to become any cells of the body. As
development progresses, cells lose their totipotency as different epigenetic
marks are established and become differentiated as specialized types of cells
(e.g., a neuron or a skin cell). Differentiated cells will only give rise, through
cellular division or mitosis, to cells of their own kind; for example, skin cells
will only give rise to skin cells and heart cells to heart cells. This is a form
of cellular inheritance. Hence, one definition of epigenetics is the study of
heritable changes in gene transcribability and phenotype that occur without
changes in DNA sequence.
While epigenetic modifications of the genome can be stable throughout
the life course, such as the epigenetic modifications that contribute to cellular differentiation during embryogenesis, they can also be environmentally
responsive, changing the transcribability of the genome in response to environmental inputs. The term environmental epigenomics reflects the constant
interplay between the environment, which includes both endogenous (e.g.,
hormone levels or immune status) and exogenous (e.g., the perinatal environment) factors, and the epigenome. Consider several examples.
One exception to the initial erasure of epigenetic marks during embryogenesis concerns imprinted genes. Imprinting is an epigenetic phenomenon
in which specific alleles are expressed in a parent of origin manner. In
paternally imprinted genes, the paternal allele is epigenetically modified,
preventing its transcription and leading to transcription solely from the
maternal allele; in maternally imprinted genes, the maternal allele is epigenetically modified, preventing its transcription and leading to transcription
solely from the paternal allele. The epigenetic marks of imprinted genes are
maintained throughout embryogenesis. Abnormalities of imprinting can
result in imprinting disorders.
One striking finding to emerge from the global rise of in vitro fertilization
(IVF)—fertilization of an egg in a petri dish and implantation in the womb
up to 6 days post fertilization—as a method of artificial reproduction is the
rise of rare imprinting disorders among IVF-conceived children. Current
estimates are that IVF children are approximately 514 times more likely to
develop Beckwith–Wiedeman syndrome (BWS), a rare imprinting disorder,
than non-IVF children, although the total numbers remain small owing to
the rarity of the disorder (Hiura et al., 2012). Findings of an increased rate
of analogous imprinting disorders in IVF animal models appear to rule out
the possibility that this could be associated with subfertility. The reason for
this increase in imprinting disorders is not known, but it could be due to
any aspect of the IVF environment—the manipulation of egg and sperm,

6

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

the cultivation of the zygote in the suboptimal environment of a petri dish
before implantation in the womb—disrupting the maintenance of epigenetic
marks on imprinted genes.
It is well established that the prenatal environment can have a profound
impact on developmental outcomes. The developmental origins of health
and disease (DOHAD) is now an established area of medical research.
Research in this field has demonstrated that factors such as maternal underor overnutrition, or maternal levels of stress—factors often associated with
the mother’s socioeconomic status—can increase the risk of, for example,
diabetes and obesity in children and diabetes, obesity, and cardiovascular
disease in adults (Gluckman & Hanson, 2006). There is growing evidence
that one of the mechanisms by which these environmental factors influence
developmental outcomes is via environmentally induced changes to the
epigenome (Lillycrop & Burdge, 2011). For example, there is evidence that
maternal stress during pregnancy can reprogram the stress response of
offspring with lifelong behavioral consequences (Mueller & Bale, 2008).
It is not only the prenatal environment that can reprogram the epigenome
with significant developmental consequences. Mother rats that exhibit
high-quality mothering (as measured by the amount of time they spend
licking and grooming their pups) rear pups that, as adults, exhibit lower
levels of stress as measured both physiologically and behaviorally, while
pups raised by low-quality mothers exhibit, as adults, high levels of stress.
Furthermore, female pups raised by high-quality mothers become, as adults,
high-quality mothers themselves, while the females raised by low-quality
mothers become low-quality mothers. Low-quality mothers also begin
reproducing earlier and more frequently. Cross-fostering studies, in which
pups are separated at birth from their biological mothers and raised by foster
mothers, have consistently indicted that adult offspring are more likely
to resemble their foster as opposed to biological mothers in stress-related
responses and rearing behavior. These differences in rearing behavior have
been associated with epigenetic changes in offspring in regions of the brain
involved in both the stress response and maternal behavior (Weaver et al.,
2004).
Such environmentally induced epigenetic changes in gene transcribability
and phenotype can serve an important adaptive function by enabling
phenotypic plasticity. Phenotypic plasticity can be defined broadly as the
ability of an organism to change phenotype in response to its environment. Modern evolutionary biology reflects the idea that adaptation is
not limited to the process of natural selection (i.e., adaptation at the level
of the species), but includes adaptation of the individual organism to its
ecological niche. Adversity during perinatal development can forecast an
increased level of demand in the environment the offspring will occupy.

Genetics and the Life Course

7

Under such conditions, the animal’s best interest is to enhance its behavioral
(e.g., vigilance, fearfulness) and endocrine responsiveness to stress. These
responses promote detection of potential threat, avoidance learning, and
metabolic/cardiovascular responses that are essential under the increased
demands of the stressor. Under high-risk conditions, when the probability
of extended periods of growth and survival are low, the optimal strategy is
to maximize the number of offspring through accelerated mating, increasing
the chances that at least some offspring will survive to reproductive maturity.
Such conditions favor a shift in reproductive investment toward quantity,
while more favorable environmental conditions favor greater investment
in individual offspring at the cost of mating, as offspring quality predicts
successful competition for available resources and reproductive fitness.
Finally, there is a growing body of evidence that it is not only the epigenetic
markings on imprinted genes that are not erased during embryogenesis.
Specifically, there is evidence that environmentally induced changes to the
epigenome can escape embryonic erasure and be transmitted intergenerationally. For example, studies have demonstrated that when a male rodent
embryo is exposed in the womb to the endocrine disruptor vinclozolin (a
common fungicide), it develops a phenotype characterized by defects in
sperm production and subfertility. This defect has been associated with
epigenetic changes at specific imprinted genes known to be involved in
spermatogenesis. In the absence of any further exposure to vinclozolin, the
phenotype can be transmitted from the exposed male to male offspring for
up to three generations. In other words, an environmentally induced change
to the epigenome and gene expression, and the resulting phenotype, can be
transmitted intergenerationally without any change to the DNA sequence
(Stouder & Paoloni-Giacobino, 2010). Decreases in human spermatogenesis
are associated with imprinting defects on a number of the same genes that
have shown abnormal epigenetic patterns in vinclozolin studies (Stouder &
Paoloni-Giacobino, 2010). This is particularly suggestive given that in the
past century a significant decline in sperm count has been documented in
young, healthy males in industrialized countries, a finding that may in part
explain a parallel decline in birthrates (Joffe, 2010). The rapidity of these
changes strongly suggests that environmental factors play a role. Endocrine
disruptors are a plausible contributing factor given their ubiquitousness
in the environment in the form of herbicides, insecticides, and fungicides,
resulting in daily exposure for many human populations.
ANEUPLOIDY
Epigenetic changes are changes that occur to DNA expression without any
change to DNA content and sequence. Development, however, involves

8

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

changes to both. It is commonly assumed that each cell in the body contains two alleles (with a few exceptions) because each cell contains two
chromosomes. Any departure from two chromosomes per cell (diploidy)
is called aneuploidy. Errors of chromosomal replication are a normal part
of embryogenesis, leading to a surprisingly high number of cells that
exhibit one or another form of aneuploidy. Despite the association between
aneuploidy and illness, there is a surprisingly high amount of chromosomal
aneuploidy in the healthy adult brain. Recent conservative estimates place
the overall percentage of aneuploid neural cells in the adult brain at an
astonishing 10%, involving monosomy (1 chromosome), trisomy (3 chromosomes), tetrasomy (4 chromosomes), polyploidy (>4 chromosomes), and
uniparental disomy (two copies of a chromosome from the same parent)
(Rehen, 2005). Given an estimated 86 billion neurons in the adult brain,
this yields a rough (conservative) estimate of 8.6 billion aneuploid neurons.
Various lines of evidence indicate that brain tissues may be more prone to
aneuploidy than other tissues. Mature aneuploid neurons are functionally
active and integrated into brain circuitry. One likely result of this is neuronal
signaling differences caused by altered gene transcription, as documented in
mammalian neural cells. Thus, a network composed of intermixed diploid
and aneuploid neurons might produce unique signaling properties.
RETROTRANSPOSONS
One striking finding to emerge from the completion of the human
genome-sequencing project is that approximately 48% of the genome
is composed of transposable elements or “jumping genes” (Gibbs, 2003).
Retrotransposons are a class of transposable DNA elements that move
about the genome by a “copy and paste” mechanism known as retrotransposition. Retrotransposons first copy themselves to RNA, while the
original DNA copy is maintained at the same location. The RNA copy is
then “reverse-transcribed” into DNA and the DNA is inserted into the
genome at a new location. Hence, these elements expand in number as they
retrotranspose, leading to an increase in genomic DNA content and a change
in DNA sequence and structure at the region of insertion. In so doing, they
alter both the DNA sequence at the region of insertion and the total amount
of DNA in the genomes in which they insert themselves. Because of their
potential to disrupt genomic functioning by copying and pasting themselves
throughout the genome in an uncontrolled manner, most transposable
elements and retrotransposons are “turned off” by the epigenome. However,
for a period during early embryogenesis retrotransposons are released
from their epigenetic silencing. Why this occurs is not known, although the
prevalence of retrotransposition in the brain has led to speculation that the

Genetics and the Life Course

9

genetic diversity they create may in some way be related to the diversity
of neurons (there are up to 10,000 different kinds of neurons in the normal
adult brain) (Sciamanna, Vitullo, Curatolo, & Spadafora, 2009).
In addition to being activated during embryogenesis, retrotransposons are
also active in those parts of the brain (the hippocampus and subventricular
zone) that produce new neurons throughout life (Baillie et al., 2011). The
level of production of new neurons in the adult brain is positively and negatively modulated by environmental conditions, including environmental
enrichment, stress, and aging. Exercise is known to have a significant impact
upon hippocampal neurogenesis: it significantly increases the amount of
brain-derived neurotropic factor (BDNF) in the hippocampus, a protein that
supports the survival of existing neurons and encourages the growth and
differentiation of new neurons and synapses (Gomez-Pinilla, Zhuang, Feng,
Ying, & Fan, 2011). In mice, voluntary wheel running has been shown both
to significantly increase neurogenesis in the brain and to double the amount
of hippocampal retrotransposition (Muotri, Marchetto, Zhao, & Gage, 2009).
What this entails is that the structure of the genome itself can change in
response to environmental conditions. In humans, depending on its impact
upon the brain, retrotransposon-induced DNA variability might induce
behavioral changes that could help the individual adapt better to changing environments or, alternatively, increase the risk of neuropsychiatric
disorders.
TELOMERES AND mtDNA
Telomeres are repeating DNA sequences bound by special protein complexes
located at both ends of each of the (presumed) 46 chromosomes in the cells
of the human body. They protect the base pairs at the ends of the chromosomes from deterioration and prevent them from fusing with neighboring
chromosomes. Each time chromosomes are replicated in the process of cellular division, some of the telomere is lost (25–200 base pairs per division).
When the telomere becomes too short, the chromosome reaches a critical
length and can no longer replicate; this results in cell death. In highly proliferating cells such as germ and stem cells, telomere length is maintained by
the enzyme telomerase, but in most cells of the body the activity of telomerase is low, and telomere length provides a marker for cellular aging. In
recent years, shorter telomere length has been associated with a broad range
of aging-related diseases, including many forms of cancer, stroke, vascular
dementia, cardiovascular disease, obesity, osteoporosis, and diabetes. Telomeres of obese women have been found to be 240 base pairs shorter than those
of lean women, and the telomeres of smokers are 18% shorter than nonsmokers (Valdes et al., 2005). Shortened telomere length has also been associated

10

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

with an array of environmental stressors including chronic psychological
stress (Chae et al., 2014), and even with socioeconomic status in children aged
7–12 (Needham, Fernandez, Lin, Epel, & Blackburn, 2012).
Aging has been associated with a wide spectrum of alterations in mitochondria and mtDNA, including increased disorganization of mitochondrial
structure, a decline in energy production, and accumulation of mtDNA mutations. The mitochondrial theory of aging proposes that progressive accumulation of mutations in mtDNA during a lifetime leads to an inevitable decline
in mitochondrial function. The precise role of mtDNA mutation in aging
remains uncertain, but their increase as part of the aging process is beyond
doubt (Chistiakov, Sobenin, Revin, Orekhov, & Bobryshev, 2014).
CONCLUSION
Much of the effort to explicate the relationship between genotype and phenotype to date has been devoted to trying to find “predisposing” polymorphisms, gene variants that are risk factors for, or allow one to predict, complex phenotypes associated with both sickness [e.g., type 1 diabetes (T1D) or
schizophrenia] and health (longevity, intelligence). While a few such polymorphisms have been identified (e.g., the BRCA1 and 2 genes are associated
with an increased risk of genetic breast and uterine cancer), their identification has been largely unsuccessful. For disorders, such as T1D, which have
been associated with many different polymorphisms—in the case of T1D,
60 and counting, only a small number of genetically susceptible individuals
progress to clinical disease, and heritability estimates for T1D are relatively
low (Knip et al., 2012). In other words, the polymorphisms lack predictive
value, indicating that the disease is the result of some form of complex biological predisposition interacting in complex ways with as yet unknown environmental triggers. Adding to the complexity is the fact that more than one
protein can be transcribed from the same gene.
Given that there are estimated to be more than 100,000 proteins in the
human body—and the number may be significantly higher—yet approximately 20,000 genes in the human genome, necessitates a rethinking of the
assumption that each gene contains the ‘instructions’ for making just one
protein. AS (alternative splicing) allows a single gene to produce multiple
transcripts. AS occurs when newly transcribed RNA (known as pre-mRNA)
is rearranged by processes in the cellular environment. This results in
different mRNAs and different proteins, called isoforms (Nilsen & Graveley,
2010). AS is estimated to occur in 95% of human genes, and can result in
numerous proteins being synthesised from the same gene (e.g., the neurexin
proteins are encoded by three genes, but it is estimated that more than 1000

Genetics and the Life Course

11

neurexin isoforms are produced by extensive AS). Isoforms of the same gene
can exert radically different and even opposed physiological effects.
From a life-course perspective on the genotype–phenotype relationship,
the failure to find predisposing genes for most complex human traits is not
at all surprising: Genes are not the sole biological agent of inheritance; as
a result of chance errors in replication and the activity of retrotransposons
during the developmental process, persons do not have one genome, but
different genomes in different cells in their bodies; the epigenome, which is
a key to the entire process of development from conception on, can be highly
environmentally responsive and can reprogram gene expressivity in enduring ways in response to environmental inputs; the environment changes not
only gene expressivity, but the genome (or genomes) itself, through processes such as retrotransposition, the shortening of telomeres, and mutations
in mtDNA. These changes are associated with the life course—telomere
shortening and mutation accumulation in mtDNA are part of the aging
process—and are influenced by the environments the individual occupies
throughout her life: Telomere length has been associated in children and
adults with stressful environments (such as environments characterized by
low socioeconomic status); retrotransposition continues throughout life in
certain brain regions and is associated, via increased neurogenesis, with
environmental inputs such as environmental stimulation and exercise.
The problem with the search for genes “for,” or genes “predisposing for”
complex phenotypes is that first, it unscientifically privileges genes as the
sole biological agent of inheritance, ignoring all of the other inherited biological elements in the absence of which genes would have no effect whatsoever. It is well to keep in mind, particularly regarding the search for genes
involved in, for example, intelligence, that humans possess fewer protein-coding
genes than corn. One of the surprising findings of the Genome Project was
that the human genome contains an estimated 20,000 protein-coding genes,
less than maize (i.e., corn), which contains over 32,000 protein-coding genes,
and close in number to the nematode, with approximately 19,000. And many
genes appear to be preserved across species. Surely, the distinctive properties of the human brain and human behavior are the result of something
other than what we have less of than corn. Second, this search is based on
a static conception of the genome, ignoring the manifold transformations
it undergoes as part of its, and our, life course. And third, it presupposes
the anachronistic dichotomy between “nature” and “nurture,” “genes,” and
“environment.” Is chromatin, for example, in which the DNA is wrapped
and which allows genes to be transcribed by changing its configuration in
response to environmental inputs, “genes” or “environment”? When the configuration of genes changes in response to environmental inputs, does the
environment “become” genes? The life-course approach shows us that such

12

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

simplistic dichotomies belie the complexity, fluidity, and temporality of the
biological world.
REFERENCES
Baillie, J. K, Barnett, M. W, Upton, K. R, Gerhardt, D. J, Richmond, T. A, De Sapio, F.,
… Faulkner, G. J. (2011). Somatic retrotransposition alters the genetic landscape
of the human brain. Nature 479(7374): 534–537.
Chae, D. H., Nuru-Jeter, A. M., Adler, N. E., Brody, G. H., Lin, J., Blackburn,
E. H., & Epel, E. S. (2014). Discrimination, racial bias, and telomere length in
African-American men. American Journal of Preventive Medicine, 46(2), 103–111.
Chatzimeletiou, K., Morrison, E. E., Prapas, N., Prapas, Y., & Handyside, A. H.
(2008). The centrosome and early embryogenesis: Clinical insights. Reproductive
Biomedicine Online, 16(4), 485–491.
Chistiakov, D. A., Sobenin, I. A., Revin, V. V., Orekhov, A. N., & Bobryshev, Y. V.
(2014). Mitochondrial aging and age-related dysfunction of mitochondria. BioMed
Research International, 2014, 238463.
Gibbs, R. A. (2003). The international HapMap project. Nature, 426(6968), 789–796.
Gluckman, P. D., & Hanson, M. A. (2006). Developmental origins of health and disease.
Cambridge, England: Cambridge University Press.
Gomez-Pinilla, F., Zhuang, Y., Feng, J., Ying, Z., & Fan, G. (2011). Exercise impacts
brain-derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation. The European Journal of Neuroscience, 33(3), 383–390.
Hiura, H., Okae, H., Miyauchi, N., Sato, F., Sato, A, Van De Pette, M., … Arima, T.
(2012). Characterization of DNA methylation errors in patients with imprinting
disorders conceived by assisted reproduction technologies. Human Reproduction,
27(8): 2541–2548.
Joffe, M. (2010). What has happened to human fertility? Human Reproduction, 25(2),
295–307.
Jones, R. E., & Lopez, K. H. (2013). Human reproductive biology. Waltham, MA: Elsevier.
Knip, M., Veijola, R., Virtanen, S. M., Hyoty, H., Vaarala, O., & Akerblom, H. K. (2012).
Environmental triggers and determinants of type 1 diabetes. Diabetes, 54(Suppl 2),
S125–S136.
Lillycrop, K. A., & Burdge, G. C. (2011). Epigenetic changes in early life and future
risk of obesity. International Journal of Obesity, 35(1), 72–83.
Mueller, B. R., & Bale, T. L. (2008). Sex-specific programming of offspring emotionality after stress early in pregnancy. The Journal of Neuroscience, 28(36), 9055–9065.
Muotri, A. R., Marchetto, M. C. N., Zhao, C., & Gage, F. H. (2009). Environmental
influence on L1 retrotransposons in the adult hippocampus. Hippocampus, 19(10),
1002–1007.
Needham, B. L., Fernandez, J. R., Lin, J., Epel, E. S., & Blackburn, E. H. (2012).
Socioeconomic status and cell aging in children. Social Science & Medicine, 74(12),
1948–1951.
Nilsen, T. W., & Graveley, B. R. (2010). Expansion of the eukaryotic proteome by
alternative splicing. Nature, 463, 457–463.

Genetics and the Life Course

13

Rehen, S. K. (2005). Constitutional aneuploidy in the normal human brain. Journal of
Neuroscience, 25, 2176–2180.
Sciamanna, I., Vitullo, P., Curatolo, A., & Spadafora, C. (2009). Retrotransposons,
reverse transcriptase and the genesis of new genetic information. Gene, 448(2),
180–186.
Shoubridge, E., & Wai, T. (2007). Mitochondrial DNA and the mammalian
oocyte. Current Topics in Developmental Biology, 77(06), 87–111. doi:10.1016/S00702153(06)77004-1
Stouder, C., & Paoloni-Giacobino, A. (2010). Transgenerational effects of the
endocrine disruptor vinclozolin on the methylation pattern of imprinted genes
in the mouse sperm. Reproduction, 139(2), 373–379.
Valdes, A. M., Andrew, T., Gardner, J. P., Kimura, M., Oelsner, E., Cherkas, L. F., …
Spector, T. D. (2005). Obesity, cigarette smoking, and telomere length in women.
Lancet, 366(9486): 662–664.
Weaver, I. C., Cervoni, N., Champagne, F. A., D’Alessio, A. C., Sharma, S., & Seckl, J.
R. (2004). Epigenetic programming by maternal behavior. Nature Neuroscience, 7,
847–854.

EVAN CHARNEY SHORT BIOGRAPHY
Evan Charney is Associate Professor of Public Policy, Duke University, Faculty Fellow, Duke Institute for Brain Sciences, and Researcher, Duke Institute
for Genome Sciences and Policy.
RELATED ESSAYS
Telomeres (Psychology), Nancy Adler and Aoife O’Donovan
Social Epigenetics: Incorporating Epigenetic Effects as Social Cause and Consequence (Sociology), Douglas L. Anderton and Kathleen F. Arcaro
The Sexual Division of Labor (Anthropology), Rebecca Bliege Bird and Brian
F. Codding
Sexual Behavior (Anthropology), Melissa Emery Thompson
Genetic and Environmental Approaches to Political Science (Political Science),
Zoltán Fazekas and Peter K. Hatemi
Evolutionary Approaches to Understanding Children’s Academic Achievement (Psychology), David C. Geary and Daniel B. Berch
Genetics and Social Behavior (Anthropology), Henry Harpending and Gregory Cochran
An Evolutionary Perspective on Developmental Plasticity (Psychology), Sarah
Hartman and Jay Belsky
Genetic Foundations of Attitude Formation (Political Science), Christian Kandler et al.

14

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

Niche Construction: Implications for Human Sciences (Anthropology), Kevin
N. Laland and Michael O’Brien
Evolutionary Perspectives on Animal and Human Personality (Anthropology), Joseph H. Manson and Lynn A. Fairbanks
Behavioral Heterochrony (Anthropology), Victoria Wobber and Brian Hare


Genetics and the Life Course
EVAN CHARNEY

Abstract
A life-course perspective is committed to the proposition that from conception to
death, all human outcomes are the result of a continual interaction between the individual and all of the environments that he or she inhabits at any given point in time.
Early development is a critical period, a window of time during the life course when
a given exposure can have a critical or permanent influence on later outcomes. But
the impact of exposures upon outcomes does not end at any specific point in time,
inasmuch as life is a continuing interactive and adaptive process. We now know that
what applies to human beings also applies to their genomes. The “outcome” of any
gene at any given point in time (whether or not it is used to transcribe a particular
protein, what form of that protein, and how much) is a product of the interaction
between the gene and the multiple environments of which it is a part, which include
the epigenome, the cell, the biological human, and the assorted environments he or
she occupies (e.g., geographical, socioeconomic, ethnic, etc.). Early life experiences
can permanently “reprogram” the epigenome and gene transcription with life-long
behavioral consequences. At the same time, the epigenome as well as the genome
continue to be environmentally responsive throughout the life course.

INTRODUCTION
In the most general sense, a life-course perspective is committed to two
propositions: First, that from conception to death, all human “outcomes”
or phenotypes (health, disease, psychology, behavior) are the result of a
continual interaction between the individual and all the environments that
she inhabits at any given point in time. These environments are always
nested, multiple, and interactive. An embryo occupies the environment of
the mother’s womb, which occupies the environment of the mother’s body;
the mother occupies an environment at once familial, socioeconomic, ethnic,
cultural, and geographic. To understand human outcomes we must take into
account the potential impact of all of these interconnected environments.
Thus characterized, a life-course perspective encompasses a developmental approach. Second, human life is an ongoing interactive process and
change—environmental and biological—continues from conception to death
Emerging Trends in the Social and Behavioral Sciences. Edited by Robert Scott and Stephen Kosslyn.
© 2015 John Wiley & Sons, Inc. ISBN 978-1-118-90077-2.

1

2

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

and the trajectory of any given stage of development will be influenced by
the preceding stages. Hence, the need to look at the life course as opposed to
a snapshot view of the individual at any given point in time.
How does genetics fit into a life-course perspective? As we shall see, to
understand the relationship between genetics and outcomes (or phenotypes)
we must adopt the same stance toward the gene that we do toward the person: In sickness and in health, in normal and abnormal development, the
“behavior” of genes or genomes cannot be understood apart from the nested
environments in which they are located. Hence, by necessity, any consideration of genetics from a life-course perspective encompasses much more
than the physical presence and structure of a gene, whether one gene or one
thousand. As in the case of the biological person, the genome itself (or rather
genomes, because persons possess more than one) changes throughout the
life course. Hence, the need to consider the “life course” of the genome itself.
It is important to note that what is here characterized as “genetics and the life
course” is based on cutting-edge research in molecular genetics and recent
discoveries that are overturning many traditional dogmas.
A gene is a segment of DNA that contains information that can be used,
by the cell, to construct amino acids, the building blocks of proteins. In the
process known as gene transcription, a segment of DNA is copied to produce
messenger RNA, which serves as a template for the synthesis of protein. In
structures called ribosomes, the messenger RNA template is used to form a
particular protein in a process known as translation. Persons inherit at least
two copies of a gene, one from each parent. Each copy of a gene is called
an allele, and alleles from both parents may be identical or they may differ
slightly. These structural differences between alleles can be found in many
different configurations or versions. When two or more versions of an allele
for a gene occur in >1% of a given population, it is referred to as a polymorphism. A version of an allele that occurs in <1% of the population is called
a mutation. A genotype refers to the specific alleles one possesses, and all of
one’s inherited alleles are her genome. It is common to speak of a (single)
genome, but as we shall see, all persons possess multiple genomes.
INHERITANCE
The life course of the genome begins before conception in the gametes: the
egg cell or oocyte supplied from the mother and the sperm cell from the
father. Each gamete supplies half of our full complement of chromosomes
and half of our alleles. Genes, however, are by no means the only biological
agent of inheritance. From our mothers we also inherit, via the oocyte,
assorted nutrients, abundant messenger RNAs, noncoding RNAs (RNA
molecules not involved in translation) and a variety of organelles, structures

Genetics and the Life Course

3

within a cell that perform essential cellular functions. From sperm, we
inherit, in addition to half our DNA, messenger RNAs and noncoding
RNAs, as well as an organelle known as a centrosome, which facilitates
cellular division and plays a key role in human fertility and the ability
of embryos to undergo normal development (Chatzimeletiou, Morrison,
Prapas, Prapas, & Handyside, 2008).
Among the organelles we inherit are mitochondria, which perform
essential cellular functions including the generation of cellular energy.
mtDNA (mitochondrial deoxyribonucleic acid) is inherited solely from
the mother inasmuch as mitochondria from sperm are destroyed shortly
after fertilization. Mitochondria contain multiple copies of their own DNA
molecules—mtDNA—that are distinct from the more familiar nuclear DNA
contained in the nuclei of all of our cells. Oocytes from the same mother may
contain anywhere from 11,000 to 903,000 mtDNA molecules per oocyte, and
mitochondrial number, distribution, and structure play essential roles in
fertilization and normal embryonic development. Studies indicate that the
mean number of copies of mtDNA in human fertilized oocytes is ∼250,000,
while for unfertilized oocytes, the mean is 164,000, and it has been suggested
that a mitochondrial complement of at least ∼100,000 copies of mtDNA is
required for normal embryonic development (Shoubridge & Wai, 2007).
A number of different factors have been shown to influence both the number of mitochondria (and hence the amount of mtDNA) and the manner
in which mitochondria function post-fertilization. Maternal fertility declines
rapidly from a peak conception rate at age 22. In addition to having fewer
eggs ovulating, the “quality” of a woman’s eggs declines; and one of the
contributing factors is a loss of mitochondria due to the accumulation of
age-dependent mutations of mtDNA (Jones & Lopez, 2013). With age, there
is also an increase in mutations in the oocyte’s nuclear DNA and by age 40,
half of a woman’s eggs are chromosomally abnormal (the nuclear DNA is
contained in the chromosomes), and 2 years later this figure rises to 90%
(Jones & Lopez, 2013). One common chromosomal abnormality is trisomy,
three copies of a particular chromosome, and depending on the chromosome
affected, the result can be a number of different “trisomic” disorders in offspring.
After ovulation, the oocyte enters a state of arrest during which DNA
transcription stops and after fertilization transcription does not begin until
after the embryo reaches the two-cell stage, when transcription commences
via a process known as embryonic genome activation (EGA). How can an
embryo develop during this period with a nonfunctioning genome? The
answer is that while transcription is stopped during this period, translation,
the synthesis of proteins from messenger RNA, is not. The oocyte contains
a vast array of messenger RNAs that are translated into proteins in the

4

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

ribosomes (which are also inherited with the oocyte). Messenger RNAs are
also present in smaller amounts in sperm and their translation pre-EGA is
almost certainly critical for normal development. In addition to messenger
RNA, both egg and sperm contain numerous kinds of noncoding RNAs
that function as a vast regulatory system, controlling the extent to which
messenger RNAs can be translated into proteins. Before EGA, development
is controlled largely via the translation of messenger RNAs and the activity
of noncoding RNAs inherited via the egg and sperm.
EPIGENETICS: EMBRYOGENESIS AND BEYOND
How, precisely, is transcription of DNA stopped before EGA and how is
it restarted? The answer is the epigenome. There are many epigenetic processes, but the two most studied are histone modification and DNA methylation. Within chromosomes, DNA is combined with proteins called histones
to form chromatin, a highly coiled and compact structure. Modifications to
histones can change the structure of the chromatin causing it to wind more or
less tightly, making the DNA more or less accessible to special proteins called
transcription factors. Without being accessible to transcription factors, DNA
transcription cannot occur. DNA methylation is the addition of a chemical
compound to specific sites on the DNA molecule and acts as a physical barrier to transcription factors. In other words, both histone modification and
DNA methylation, by regulating the extent to which regions of DNA (i.e.,
“genes”) are accessible to transcription factors, can effectively turn genes on
and off. It is hard to underestimate the significance of the epigenome. In fact,
embryogenesis itself is an epigenetic process.
After fertilization the early embryo, the zygote, is in a state of totipotency,
that is, the small number of cells of which it is initially composed can develop
into any cell in the body (e.g., a heart cell, a neuron, a skin cell). Development is, in part, the differentiation of totipotent cells into specialized types
of cells. In later development, these differentiated cells of the body (e.g., a
heart cell, a neuron, a skin cell) are radically different in appearance and function despite the fact that they contain the same nuclear DNA. The epigenome
is responsible for both totipotency and subsequent cellular differentiation.
What differentiates a skin cell from a neuron is not differences in nuclear
DNA (although, as we shall see, their nuclear DNA may in fact differ), but
rather differences in their epigenomes. This means that in a skin cell and neuron different genes are turned on and off and hence, only certain genes can
be transcribed in each type of cell. It is this difference in epigenetic “switches” or “markings” that leads to the radically different form and function of
different types of cells.

Genetics and the Life Course

5

Egg and sperm are both distinct types of cells. When their DNAs are joined
in the zygote, their epigenetic markings are erased (with one important
exception to be considered subsequently). This leads to totipotency, the
ability of the cells of the early embryo to become any cells of the body. As
development progresses, cells lose their totipotency as different epigenetic
marks are established and become differentiated as specialized types of cells
(e.g., a neuron or a skin cell). Differentiated cells will only give rise, through
cellular division or mitosis, to cells of their own kind; for example, skin cells
will only give rise to skin cells and heart cells to heart cells. This is a form
of cellular inheritance. Hence, one definition of epigenetics is the study of
heritable changes in gene transcribability and phenotype that occur without
changes in DNA sequence.
While epigenetic modifications of the genome can be stable throughout
the life course, such as the epigenetic modifications that contribute to cellular differentiation during embryogenesis, they can also be environmentally
responsive, changing the transcribability of the genome in response to environmental inputs. The term environmental epigenomics reflects the constant
interplay between the environment, which includes both endogenous (e.g.,
hormone levels or immune status) and exogenous (e.g., the perinatal environment) factors, and the epigenome. Consider several examples.
One exception to the initial erasure of epigenetic marks during embryogenesis concerns imprinted genes. Imprinting is an epigenetic phenomenon
in which specific alleles are expressed in a parent of origin manner. In
paternally imprinted genes, the paternal allele is epigenetically modified,
preventing its transcription and leading to transcription solely from the
maternal allele; in maternally imprinted genes, the maternal allele is epigenetically modified, preventing its transcription and leading to transcription
solely from the paternal allele. The epigenetic marks of imprinted genes are
maintained throughout embryogenesis. Abnormalities of imprinting can
result in imprinting disorders.
One striking finding to emerge from the global rise of in vitro fertilization
(IVF)—fertilization of an egg in a petri dish and implantation in the womb
up to 6 days post fertilization—as a method of artificial reproduction is the
rise of rare imprinting disorders among IVF-conceived children. Current
estimates are that IVF children are approximately 514 times more likely to
develop Beckwith–Wiedeman syndrome (BWS), a rare imprinting disorder,
than non-IVF children, although the total numbers remain small owing to
the rarity of the disorder (Hiura et al., 2012). Findings of an increased rate
of analogous imprinting disorders in IVF animal models appear to rule out
the possibility that this could be associated with subfertility. The reason for
this increase in imprinting disorders is not known, but it could be due to
any aspect of the IVF environment—the manipulation of egg and sperm,

6

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

the cultivation of the zygote in the suboptimal environment of a petri dish
before implantation in the womb—disrupting the maintenance of epigenetic
marks on imprinted genes.
It is well established that the prenatal environment can have a profound
impact on developmental outcomes. The developmental origins of health
and disease (DOHAD) is now an established area of medical research.
Research in this field has demonstrated that factors such as maternal underor overnutrition, or maternal levels of stress—factors often associated with
the mother’s socioeconomic status—can increase the risk of, for example,
diabetes and obesity in children and diabetes, obesity, and cardiovascular
disease in adults (Gluckman & Hanson, 2006). There is growing evidence
that one of the mechanisms by which these environmental factors influence
developmental outcomes is via environmentally induced changes to the
epigenome (Lillycrop & Burdge, 2011). For example, there is evidence that
maternal stress during pregnancy can reprogram the stress response of
offspring with lifelong behavioral consequences (Mueller & Bale, 2008).
It is not only the prenatal environment that can reprogram the epigenome
with significant developmental consequences. Mother rats that exhibit
high-quality mothering (as measured by the amount of time they spend
licking and grooming their pups) rear pups that, as adults, exhibit lower
levels of stress as measured both physiologically and behaviorally, while
pups raised by low-quality mothers exhibit, as adults, high levels of stress.
Furthermore, female pups raised by high-quality mothers become, as adults,
high-quality mothers themselves, while the females raised by low-quality
mothers become low-quality mothers. Low-quality mothers also begin
reproducing earlier and more frequently. Cross-fostering studies, in which
pups are separated at birth from their biological mothers and raised by foster
mothers, have consistently indicted that adult offspring are more likely
to resemble their foster as opposed to biological mothers in stress-related
responses and rearing behavior. These differences in rearing behavior have
been associated with epigenetic changes in offspring in regions of the brain
involved in both the stress response and maternal behavior (Weaver et al.,
2004).
Such environmentally induced epigenetic changes in gene transcribability
and phenotype can serve an important adaptive function by enabling
phenotypic plasticity. Phenotypic plasticity can be defined broadly as the
ability of an organism to change phenotype in response to its environment. Modern evolutionary biology reflects the idea that adaptation is
not limited to the process of natural selection (i.e., adaptation at the level
of the species), but includes adaptation of the individual organism to its
ecological niche. Adversity during perinatal development can forecast an
increased level of demand in the environment the offspring will occupy.

Genetics and the Life Course

7

Under such conditions, the animal’s best interest is to enhance its behavioral
(e.g., vigilance, fearfulness) and endocrine responsiveness to stress. These
responses promote detection of potential threat, avoidance learning, and
metabolic/cardiovascular responses that are essential under the increased
demands of the stressor. Under high-risk conditions, when the probability
of extended periods of growth and survival are low, the optimal strategy is
to maximize the number of offspring through accelerated mating, increasing
the chances that at least some offspring will survive to reproductive maturity.
Such conditions favor a shift in reproductive investment toward quantity,
while more favorable environmental conditions favor greater investment
in individual offspring at the cost of mating, as offspring quality predicts
successful competition for available resources and reproductive fitness.
Finally, there is a growing body of evidence that it is not only the epigenetic
markings on imprinted genes that are not erased during embryogenesis.
Specifically, there is evidence that environmentally induced changes to the
epigenome can escape embryonic erasure and be transmitted intergenerationally. For example, studies have demonstrated that when a male rodent
embryo is exposed in the womb to the endocrine disruptor vinclozolin (a
common fungicide), it develops a phenotype characterized by defects in
sperm production and subfertility. This defect has been associated with
epigenetic changes at specific imprinted genes known to be involved in
spermatogenesis. In the absence of any further exposure to vinclozolin, the
phenotype can be transmitted from the exposed male to male offspring for
up to three generations. In other words, an environmentally induced change
to the epigenome and gene expression, and the resulting phenotype, can be
transmitted intergenerationally without any change to the DNA sequence
(Stouder & Paoloni-Giacobino, 2010). Decreases in human spermatogenesis
are associated with imprinting defects on a number of the same genes that
have shown abnormal epigenetic patterns in vinclozolin studies (Stouder &
Paoloni-Giacobino, 2010). This is particularly suggestive given that in the
past century a significant decline in sperm count has been documented in
young, healthy males in industrialized countries, a finding that may in part
explain a parallel decline in birthrates (Joffe, 2010). The rapidity of these
changes strongly suggests that environmental factors play a role. Endocrine
disruptors are a plausible contributing factor given their ubiquitousness
in the environment in the form of herbicides, insecticides, and fungicides,
resulting in daily exposure for many human populations.
ANEUPLOIDY
Epigenetic changes are changes that occur to DNA expression without any
change to DNA content and sequence. Development, however, involves

8

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

changes to both. It is commonly assumed that each cell in the body contains two alleles (with a few exceptions) because each cell contains two
chromosomes. Any departure from two chromosomes per cell (diploidy)
is called aneuploidy. Errors of chromosomal replication are a normal part
of embryogenesis, leading to a surprisingly high number of cells that
exhibit one or another form of aneuploidy. Despite the association between
aneuploidy and illness, there is a surprisingly high amount of chromosomal
aneuploidy in the healthy adult brain. Recent conservative estimates place
the overall percentage of aneuploid neural cells in the adult brain at an
astonishing 10%, involving monosomy (1 chromosome), trisomy (3 chromosomes), tetrasomy (4 chromosomes), polyploidy (>4 chromosomes), and
uniparental disomy (two copies of a chromosome from the same parent)
(Rehen, 2005). Given an estimated 86 billion neurons in the adult brain,
this yields a rough (conservative) estimate of 8.6 billion aneuploid neurons.
Various lines of evidence indicate that brain tissues may be more prone to
aneuploidy than other tissues. Mature aneuploid neurons are functionally
active and integrated into brain circuitry. One likely result of this is neuronal
signaling differences caused by altered gene transcription, as documented in
mammalian neural cells. Thus, a network composed of intermixed diploid
and aneuploid neurons might produce unique signaling properties.
RETROTRANSPOSONS
One striking finding to emerge from the completion of the human
genome-sequencing project is that approximately 48% of the genome
is composed of transposable elements or “jumping genes” (Gibbs, 2003).
Retrotransposons are a class of transposable DNA elements that move
about the genome by a “copy and paste” mechanism known as retrotransposition. Retrotransposons first copy themselves to RNA, while the
original DNA copy is maintained at the same location. The RNA copy is
then “reverse-transcribed” into DNA and the DNA is inserted into the
genome at a new location. Hence, these elements expand in number as they
retrotranspose, leading to an increase in genomic DNA content and a change
in DNA sequence and structure at the region of insertion. In so doing, they
alter both the DNA sequence at the region of insertion and the total amount
of DNA in the genomes in which they insert themselves. Because of their
potential to disrupt genomic functioning by copying and pasting themselves
throughout the genome in an uncontrolled manner, most transposable
elements and retrotransposons are “turned off” by the epigenome. However,
for a period during early embryogenesis retrotransposons are released
from their epigenetic silencing. Why this occurs is not known, although the
prevalence of retrotransposition in the brain has led to speculation that the

Genetics and the Life Course

9

genetic diversity they create may in some way be related to the diversity
of neurons (there are up to 10,000 different kinds of neurons in the normal
adult brain) (Sciamanna, Vitullo, Curatolo, & Spadafora, 2009).
In addition to being activated during embryogenesis, retrotransposons are
also active in those parts of the brain (the hippocampus and subventricular
zone) that produce new neurons throughout life (Baillie et al., 2011). The
level of production of new neurons in the adult brain is positively and negatively modulated by environmental conditions, including environmental
enrichment, stress, and aging. Exercise is known to have a significant impact
upon hippocampal neurogenesis: it significantly increases the amount of
brain-derived neurotropic factor (BDNF) in the hippocampus, a protein that
supports the survival of existing neurons and encourages the growth and
differentiation of new neurons and synapses (Gomez-Pinilla, Zhuang, Feng,
Ying, & Fan, 2011). In mice, voluntary wheel running has been shown both
to significantly increase neurogenesis in the brain and to double the amount
of hippocampal retrotransposition (Muotri, Marchetto, Zhao, & Gage, 2009).
What this entails is that the structure of the genome itself can change in
response to environmental conditions. In humans, depending on its impact
upon the brain, retrotransposon-induced DNA variability might induce
behavioral changes that could help the individual adapt better to changing environments or, alternatively, increase the risk of neuropsychiatric
disorders.
TELOMERES AND mtDNA
Telomeres are repeating DNA sequences bound by special protein complexes
located at both ends of each of the (presumed) 46 chromosomes in the cells
of the human body. They protect the base pairs at the ends of the chromosomes from deterioration and prevent them from fusing with neighboring
chromosomes. Each time chromosomes are replicated in the process of cellular division, some of the telomere is lost (25–200 base pairs per division).
When the telomere becomes too short, the chromosome reaches a critical
length and can no longer replicate; this results in cell death. In highly proliferating cells such as germ and stem cells, telomere length is maintained by
the enzyme telomerase, but in most cells of the body the activity of telomerase is low, and telomere length provides a marker for cellular aging. In
recent years, shorter telomere length has been associated with a broad range
of aging-related diseases, including many forms of cancer, stroke, vascular
dementia, cardiovascular disease, obesity, osteoporosis, and diabetes. Telomeres of obese women have been found to be 240 base pairs shorter than those
of lean women, and the telomeres of smokers are 18% shorter than nonsmokers (Valdes et al., 2005). Shortened telomere length has also been associated

10

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

with an array of environmental stressors including chronic psychological
stress (Chae et al., 2014), and even with socioeconomic status in children aged
7–12 (Needham, Fernandez, Lin, Epel, & Blackburn, 2012).
Aging has been associated with a wide spectrum of alterations in mitochondria and mtDNA, including increased disorganization of mitochondrial
structure, a decline in energy production, and accumulation of mtDNA mutations. The mitochondrial theory of aging proposes that progressive accumulation of mutations in mtDNA during a lifetime leads to an inevitable decline
in mitochondrial function. The precise role of mtDNA mutation in aging
remains uncertain, but their increase as part of the aging process is beyond
doubt (Chistiakov, Sobenin, Revin, Orekhov, & Bobryshev, 2014).
CONCLUSION
Much of the effort to explicate the relationship between genotype and phenotype to date has been devoted to trying to find “predisposing” polymorphisms, gene variants that are risk factors for, or allow one to predict, complex phenotypes associated with both sickness [e.g., type 1 diabetes (T1D) or
schizophrenia] and health (longevity, intelligence). While a few such polymorphisms have been identified (e.g., the BRCA1 and 2 genes are associated
with an increased risk of genetic breast and uterine cancer), their identification has been largely unsuccessful. For disorders, such as T1D, which have
been associated with many different polymorphisms—in the case of T1D,
60 and counting, only a small number of genetically susceptible individuals
progress to clinical disease, and heritability estimates for T1D are relatively
low (Knip et al., 2012). In other words, the polymorphisms lack predictive
value, indicating that the disease is the result of some form of complex biological predisposition interacting in complex ways with as yet unknown environmental triggers. Adding to the complexity is the fact that more than one
protein can be transcribed from the same gene.
Given that there are estimated to be more than 100,000 proteins in the
human body—and the number may be significantly higher—yet approximately 20,000 genes in the human genome, necessitates a rethinking of the
assumption that each gene contains the ‘instructions’ for making just one
protein. AS (alternative splicing) allows a single gene to produce multiple
transcripts. AS occurs when newly transcribed RNA (known as pre-mRNA)
is rearranged by processes in the cellular environment. This results in
different mRNAs and different proteins, called isoforms (Nilsen & Graveley,
2010). AS is estimated to occur in 95% of human genes, and can result in
numerous proteins being synthesised from the same gene (e.g., the neurexin
proteins are encoded by three genes, but it is estimated that more than 1000

Genetics and the Life Course

11

neurexin isoforms are produced by extensive AS). Isoforms of the same gene
can exert radically different and even opposed physiological effects.
From a life-course perspective on the genotype–phenotype relationship,
the failure to find predisposing genes for most complex human traits is not
at all surprising: Genes are not the sole biological agent of inheritance; as
a result of chance errors in replication and the activity of retrotransposons
during the developmental process, persons do not have one genome, but
different genomes in different cells in their bodies; the epigenome, which is
a key to the entire process of development from conception on, can be highly
environmentally responsive and can reprogram gene expressivity in enduring ways in response to environmental inputs; the environment changes not
only gene expressivity, but the genome (or genomes) itself, through processes such as retrotransposition, the shortening of telomeres, and mutations
in mtDNA. These changes are associated with the life course—telomere
shortening and mutation accumulation in mtDNA are part of the aging
process—and are influenced by the environments the individual occupies
throughout her life: Telomere length has been associated in children and
adults with stressful environments (such as environments characterized by
low socioeconomic status); retrotransposition continues throughout life in
certain brain regions and is associated, via increased neurogenesis, with
environmental inputs such as environmental stimulation and exercise.
The problem with the search for genes “for,” or genes “predisposing for”
complex phenotypes is that first, it unscientifically privileges genes as the
sole biological agent of inheritance, ignoring all of the other inherited biological elements in the absence of which genes would have no effect whatsoever. It is well to keep in mind, particularly regarding the search for genes
involved in, for example, intelligence, that humans possess fewer protein-coding
genes than corn. One of the surprising findings of the Genome Project was
that the human genome contains an estimated 20,000 protein-coding genes,
less than maize (i.e., corn), which contains over 32,000 protein-coding genes,
and close in number to the nematode, with approximately 19,000. And many
genes appear to be preserved across species. Surely, the distinctive properties of the human brain and human behavior are the result of something
other than what we have less of than corn. Second, this search is based on
a static conception of the genome, ignoring the manifold transformations
it undergoes as part of its, and our, life course. And third, it presupposes
the anachronistic dichotomy between “nature” and “nurture,” “genes,” and
“environment.” Is chromatin, for example, in which the DNA is wrapped
and which allows genes to be transcribed by changing its configuration in
response to environmental inputs, “genes” or “environment”? When the configuration of genes changes in response to environmental inputs, does the
environment “become” genes? The life-course approach shows us that such

12

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

simplistic dichotomies belie the complexity, fluidity, and temporality of the
biological world.
REFERENCES
Baillie, J. K, Barnett, M. W, Upton, K. R, Gerhardt, D. J, Richmond, T. A, De Sapio, F.,
… Faulkner, G. J. (2011). Somatic retrotransposition alters the genetic landscape
of the human brain. Nature 479(7374): 534–537.
Chae, D. H., Nuru-Jeter, A. M., Adler, N. E., Brody, G. H., Lin, J., Blackburn,
E. H., & Epel, E. S. (2014). Discrimination, racial bias, and telomere length in
African-American men. American Journal of Preventive Medicine, 46(2), 103–111.
Chatzimeletiou, K., Morrison, E. E., Prapas, N., Prapas, Y., & Handyside, A. H.
(2008). The centrosome and early embryogenesis: Clinical insights. Reproductive
Biomedicine Online, 16(4), 485–491.
Chistiakov, D. A., Sobenin, I. A., Revin, V. V., Orekhov, A. N., & Bobryshev, Y. V.
(2014). Mitochondrial aging and age-related dysfunction of mitochondria. BioMed
Research International, 2014, 238463.
Gibbs, R. A. (2003). The international HapMap project. Nature, 426(6968), 789–796.
Gluckman, P. D., & Hanson, M. A. (2006). Developmental origins of health and disease.
Cambridge, England: Cambridge University Press.
Gomez-Pinilla, F., Zhuang, Y., Feng, J., Ying, Z., & Fan, G. (2011). Exercise impacts
brain-derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation. The European Journal of Neuroscience, 33(3), 383–390.
Hiura, H., Okae, H., Miyauchi, N., Sato, F., Sato, A, Van De Pette, M., … Arima, T.
(2012). Characterization of DNA methylation errors in patients with imprinting
disorders conceived by assisted reproduction technologies. Human Reproduction,
27(8): 2541–2548.
Joffe, M. (2010). What has happened to human fertility? Human Reproduction, 25(2),
295–307.
Jones, R. E., & Lopez, K. H. (2013). Human reproductive biology. Waltham, MA: Elsevier.
Knip, M., Veijola, R., Virtanen, S. M., Hyoty, H., Vaarala, O., & Akerblom, H. K. (2012).
Environmental triggers and determinants of type 1 diabetes. Diabetes, 54(Suppl 2),
S125–S136.
Lillycrop, K. A., & Burdge, G. C. (2011). Epigenetic changes in early life and future
risk of obesity. International Journal of Obesity, 35(1), 72–83.
Mueller, B. R., & Bale, T. L. (2008). Sex-specific programming of offspring emotionality after stress early in pregnancy. The Journal of Neuroscience, 28(36), 9055–9065.
Muotri, A. R., Marchetto, M. C. N., Zhao, C., & Gage, F. H. (2009). Environmental
influence on L1 retrotransposons in the adult hippocampus. Hippocampus, 19(10),
1002–1007.
Needham, B. L., Fernandez, J. R., Lin, J., Epel, E. S., & Blackburn, E. H. (2012).
Socioeconomic status and cell aging in children. Social Science & Medicine, 74(12),
1948–1951.
Nilsen, T. W., & Graveley, B. R. (2010). Expansion of the eukaryotic proteome by
alternative splicing. Nature, 463, 457–463.

Genetics and the Life Course

13

Rehen, S. K. (2005). Constitutional aneuploidy in the normal human brain. Journal of
Neuroscience, 25, 2176–2180.
Sciamanna, I., Vitullo, P., Curatolo, A., & Spadafora, C. (2009). Retrotransposons,
reverse transcriptase and the genesis of new genetic information. Gene, 448(2),
180–186.
Shoubridge, E., & Wai, T. (2007). Mitochondrial DNA and the mammalian
oocyte. Current Topics in Developmental Biology, 77(06), 87–111. doi:10.1016/S00702153(06)77004-1
Stouder, C., & Paoloni-Giacobino, A. (2010). Transgenerational effects of the
endocrine disruptor vinclozolin on the methylation pattern of imprinted genes
in the mouse sperm. Reproduction, 139(2), 373–379.
Valdes, A. M., Andrew, T., Gardner, J. P., Kimura, M., Oelsner, E., Cherkas, L. F., …
Spector, T. D. (2005). Obesity, cigarette smoking, and telomere length in women.
Lancet, 366(9486): 662–664.
Weaver, I. C., Cervoni, N., Champagne, F. A., D’Alessio, A. C., Sharma, S., & Seckl, J.
R. (2004). Epigenetic programming by maternal behavior. Nature Neuroscience, 7,
847–854.

EVAN CHARNEY SHORT BIOGRAPHY
Evan Charney is Associate Professor of Public Policy, Duke University, Faculty Fellow, Duke Institute for Brain Sciences, and Researcher, Duke Institute
for Genome Sciences and Policy.
RELATED ESSAYS
Telomeres (Psychology), Nancy Adler and Aoife O’Donovan
Social Epigenetics: Incorporating Epigenetic Effects as Social Cause and Consequence (Sociology), Douglas L. Anderton and Kathleen F. Arcaro
The Sexual Division of Labor (Anthropology), Rebecca Bliege Bird and Brian
F. Codding
Sexual Behavior (Anthropology), Melissa Emery Thompson
Genetic and Environmental Approaches to Political Science (Political Science),
Zoltán Fazekas and Peter K. Hatemi
Evolutionary Approaches to Understanding Children’s Academic Achievement (Psychology), David C. Geary and Daniel B. Berch
Genetics and Social Behavior (Anthropology), Henry Harpending and Gregory Cochran
An Evolutionary Perspective on Developmental Plasticity (Psychology), Sarah
Hartman and Jay Belsky
Genetic Foundations of Attitude Formation (Political Science), Christian Kandler et al.

14

EMERGING TRENDS IN THE SOCIAL AND BEHAVIORAL SCIENCES

Niche Construction: Implications for Human Sciences (Anthropology), Kevin
N. Laland and Michael O’Brien
Evolutionary Perspectives on Animal and Human Personality (Anthropology), Joseph H. Manson and Lynn A. Fairbanks
Behavioral Heterochrony (Anthropology), Victoria Wobber and Brian Hare



Media

Genetics and the Life Course