Epigenetic Variation: Amount, Causes, and Consequences (Genetics)

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Epigenetic variation: amount, causes,

and consequences (Genetics)
1. Introduction
The diversity of human phenotypes that we observe is the result of genetic and
epigenetic variation and the interaction of these biological variables with
environmental factors. Both large-scale and small-scale genome sequencing projects, as
well as more recent eorts to dene structural variation (copy number variation and
subkaryotypic insertions, deletions and rearrangements), have resulted in an important
initial description of the amount and type of genetic variation in the human genome. On
the other hand, the scale of epigenetic variation in the human population is only
beginning to be investigated.
Epigenetic variation may arise by diverse mechanisms but, at the molecular level, it
reects dierences in the spatial conguration of chromatin and its interactions and
function. Multiple biochemical processes (DNA methylation, histone methylation,
acetylation, phosphorylation, sumoylation, etc.) are associated with these dierences.
One important consequence of this variability is the resultant variation in gene
expression, although many other eects have also been described (see the following
text).
In the same way that somatic mutations can be transmitted through successive cell
divisions, epigenetic marks can change during the lifespan of an organism and also be
transmitted somatically through subsequent cell divisions. In fact, the normal phenotypic
diversity found between the dierent cell types of an organism is, with a few notable
exceptions in the immune system, epigenetically controlled.
Interestingly, traits that result from particular patterns of epigenetic modication can
also be transmitted between generations in some circumstances. The term epialleles
has been coined to describe such dierent epigenetic states (Article 36, Variable
expressivity and epigenetics, Volume 1). However, unlike DNA sequence changes,
epigenetic modications are often reversible at much higher frequencies than the
mutation rate. This is an important characteristic, because epigenetic marks can be reset
between generations and they can change in response to the environment. Because
epigenetic variation can also be genetically controlled, it constitutes a potentially
important link between environmental and genetic factors (Cui etal., 1998; Nakagawa
etal., 2001; Sandovici etal., 2003). Such a response to the environment could be mediated
by metabolic changes that result in epigenetic modications (Paldi, 2003; Waterland and
Jirtle, 2004; Wol et al., 1998). Consequently, epigenetic variability is not only a source of
phenotypic plasticity in response to the environment, but these epigenetic alterations can
also, potentially, be transmitted between generations, with very important implications in
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evolution (Rutherford and Heniko, 2003; Sollars et al., 2003).

To better understand the relevance of epigenetic variation, we will discuss the extent
(how much?), the origin (what are the causes?), and the implications (what are the
consequences?) of this important source of phenotypic variation.
2. Epigenetic variation: how much?

2.1. Epigenetic variation arises from multiple mechanisms
It is dicult to estimate the precise extent of epigenetic variation because it
occurs at multiple levels and as a result of multiple processes. The epigenetic variation
resulting from inactivation of X chromosome provides a classic example of how multiple
and distinct processes can give rise to very large uctuation in phenotype among
genetically similar or identical (Fraga et al., 2005) individuals. In human females (as in
other female mammals), one of the two X chromosomes is inactivated by epigenetic
means. Once one of the two X chromosomes is chosen for inactivation early in
development, and the same X chromosome remains inactive in all descendants of that cell
(Article 41, Initiation of X-chromosome inacti-vation, Volume 1). The inactive X
chromosome becomes a cytologically visible heterochromatic body. This cytological
manifestation of femaleness (the Barr body) is to a large extent (but not completely
(Disteche, 1995)) transcriptionally inert. This means that each single cell expresses only
one allele of most (approximately 85%) (Carrel and Willard, 2005) X-linked genes. If both
X chromosomes have the same probability of being inactivated, the average women will
have the paternal X chromosome inactive in 50% of her cells and the maternal X inactive
in the remaining 50% of her cells. However, because the process of choosing the X
chromosome for inactivation has a large stochastic component (Article 41, Initiation of
X-chromosome inactivation, Volume 1), individual women will have dierent patterns of
X-inactivation (Figure 1a). In fact, there is a minor fraction of females in whom >90% of
the cells have the same X chromosome inactivated (Figure 1a). These females will have
highly preferential expression of either maternal or paternal alleles of all X-linked genes
aected by the inactivation process.
In addition to this partly stochastic, partly genetic variability in the fraction of
cells in which a particular X chromosome remains active (see next section), there is also
population-level and intraindividual variability in the extent of X-inactivation. It has been
documented that a fraction of X-linked genes have escaped inactivation (reviewed in
Disteche, 1995). Interestingly, some genes are inactivated in some human samples, but
escape inactivation in others (Carrel and Willard, 2005). In addition, the level of
expression of such escapees also diers between samples (Carrel and Willard, 2005).
Therefore, even genetically identical women (monozygotic twins) can dier in their
mosaic pattern of X-inactivation, the number of genes that escape X-inactivation, and the
levels of expression of some X-linked genes. In addition, some genes that have been
inactivated may become reactivated as a function of age (Wareham et al., 1987) or other
environmental factors, although not all X-linked genes appear equally susceptible to
reactivation (Migeon et al., 1988; Pagani et al., 1990).
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Figure 1 Origin of X-inactivation variation. (a) Much of the variation in the

human results from the stochastic component of the X-inactivation choice
process. Y-axis represents the fraction of women with the indicated percent of
cells with the same X chromosome active (Naumova et al., 1996 and our
unpublished data). Approximately one-third of women have either X
chromosomes inactivated in one-half of their of cells (purple bar) and
approximately 60% of women (purple bar plus green bar) have X-inactivation
ratios between 50:50 and 70:30. However, approximately 7% of women have
highly skewed patterns of X-inactivation, that is, greater than 90:10 (blue bar) in
favor of the inactivation of a particular X chromosome. (b) Moving average of
change in X-inactivation score in individual females (over nearly two decades;
see Sandovici et al., 2004) as a function of age. Females who were greater than
60 years of age when the rst sample was taken show signicantly more
variation over time than younger females. (c) Heritable eects on X-chromosome
inactivation variation. Distribution of X-inactivation ratios in heterozygous Xcea
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/Xcec mouse females each circle represents an individual female mouse (de la
Casa-Esperon et al., 2002). The X-controlling element locus aects the
probability that an X chromosome will become inactive, so that X chromosomes
carrying the Xcea allele have a higher probability of being inactivated than X
chromosomes carrying the Xcec allele. The observed mean X-inactivation ratio of
this population of females is 25% of cells with an active Xcea -carrying X
chromosome
A similar variability in a long-term inactivation phenomenon has been observed
for another class of monoallelically expressed genes located in the autosomes, the
imprinted genes. Imprinted genes are expected to be expressed exclusively, or nearly
exclusively, from the paternal or the maternal copy (Article 37, Evolution of genomic
imprinting in mammals, Volume 1). Several studies have shown that some imprinted
genes (e.g., IGF2, HTR2A genes) are expressed from both alleles in a small fraction of
normal individuals (Bunzel etal., 1998; Sakatani et al., 2001), while others (IGF2R)
exhibit the reciprocal characteristic of being imprinted in only a small fraction of
individuals (Xu et al., 1993).
Expression levels between alleles have been found to be variable for several
imprinted genes in human tissues (Dao etal., 1998; McMinn etal., 2006), and have also
been observed at nonimprinted autosomal genes. In fact, large-scale transcription
proling studies in humans have shown dierential expression of alleles at a large
proportion of loci (up to 54%, depending on the cuto level of dierential expression
selected (Lo etal., 2003)) and, interestingly, the degree of dierence in expression
between particular alleles varies between individuals (Lin etal., 2005; Lo etal., 2003; Pant
etal., 2006; Pastinen etal., 2004). Moreover, skewing of allelic expression is not
necessarily in the same direction: in some individuals who are heterozygous for the same
alleles, the allele that is preferentially expressed diers (Lo etal., 2003; Pastinen etal.,
2004). This observation suggests that trans-modiers and epigenetic variation are
involved in the control of allelic dierences in expression, in addition to polymorphisms in
cis-regulatory sequences. Such extensive variation in allelic expression must have a large
impact in generating phenotypic diversity.
2.2. Variability in the biochemical marks associated with epigenetic

variation
The types of epigenetic marks that result in allelic variation in gene expression can be
of diverse nature. The best known and most extensively investigated are covalent
modications of DNA and core histones. DNA methylation at CpG sites shows a degree of
variability between dierent individuals at multiple loci. This is the case for imprinted
genes like IGF2/H19 and IGF2R, for which interindividual variation in methylation
patterns has been observed in the dierentially methylated regions associated with their
expression (Sandovici etal., 2003). Interestingly, alterations in normal methylation
patterns of these regions have been associated with loss of imprinting (LOI), a common
observation in several types of cancer (Cui et al., 1998; Nakagawa et al., 2001). Another
interesting example of interindividual variation at an imprinted gene is PEG1: this gene
codes two isoform, one imprinted (isoform 1) and one expressed biallelically in multiple
tissues (isoform 2). However, in a large subset of human placentae, isoform 2 allelic
expression dierences are observed, as well as interindividual variation in methylation of
an associated CpG island (McMinn et al., 2006).
Interindividual variability in methylation patterns has been also described
outside of imprinted genes or even protein coding regions: this is the case of
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methylation dierences between humans that is observed in specic Alu repeated

sequences (Sandovici et al., 2005). These observations reect the fact that DNA
methylation may have roles in addition to transcriptional control (de la Casa-Esperon and
Sapienza, 2003; Pardo-Manuel de Villena etal., 2000; Sandovici etal., 2005).
Studies in other organisms also support the idea that variation in DNA methylation
could be a widespread phenomenon. For instance, variation in cytosine methylation has
been described in rRNA genes of natural accessions of the owering plant Arabidopsis
thaliana (Riddle and Richards, 2002), as well as in retrotransposons (Rangwala et al.,
2006). Also, dierentially methylated P1 pigment gene alleles have been observed in
maize (Das and Messing, 1994). Importantly, studies in Arabidopsis have also shown that
both natural and induced methylation changes can be transmitted to the ospring and
result in developmental abnormalities in some instances (Kakutani et al., 1999; Rangwala
et al., 2006; Riddle and Richards, 2005).
3. Epigenetic variation: what are the causes?

Epigenetic variation is the result of three types of processes: stochastic,
environmental, and heritable. Variation in X-inactivation illustrates all three of these
processes: during embryogenesis, one of the two X chromosomes is inactivated in each
cell and clonally transmitted through successive mitotic divisions. Because this choice
has a stochastic component (although some deterministic models are also capable of
explaining the observations (Williams and Wu, 2004)), the X-inactivation patterns of a
population of females approximates a normal distribution. The average female has about
half of her cells with the maternal X chromosome inactive and half with the paternal X
chromosome inactive. However, a small proportion of females show skewed patterns with
a particular X chromosome being inactive in most cells (Figure 1a). Therefore, females
are a mosaic for the expression of X-linked genes, and not even genetically identical
females need show the same mosaic pattern.
The so-called skewing of X-inactivation is not always the rare consequence of the
stochastic nature of the choice process. In some instances, skewing is the result of
selection against X chromosomes carrying deleterious mutations, and the cell
type-specicity of this skewing, as in X-linked agammaglobulinemia (skewing for
inactivation of the mutant XLA/BTK allele in B-lymphocytes but not in T-lymphocytes),
highlights the role of functional cellular selection (Fearon et al., 1987; reviewed in
Belmont, 1996). In addition, skewing appears more common in older women, which
suggests the contribution of environmental factors throughout their lifespan (Busque et
al., 1996; Gale et al., 1997; Sharp et al., 2000). In this regard, X-inactivation seems to
remain quite stable over many years during earlier ages (Sandovici et al., 2004) (Figure
1b). Many older females, however, exhibit substantial changes over the timescales at
which younger females do not exhibit changes (Sandovici et al., 2004). In this regard, we
have speculated (Sandovici et al., 2004) that acquired skewing of X-inactivation in older
females may result from discontinuous or catastrophic processes that result in decreased
numbers of stem cells or an age-related tendency toward bone marrow clonality or
myelodysplasia.
Additionally, preference for the inactivation of a particular X chromosome can have a
completely dierent origin compared to the selection for particular clonal cell
populations or against disadvantageous mutations. Several studies in human and mice
have shown that preference for X-inactivation can be heritable and genetically controlled
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(Cattanach and Isaacson, 1967; Naumova etal., 1996, 1998; Plenge et al., 1997) In the
mouse, the X-controlling element (Xce) is well known for its participation in the
X-inactivation choice, so chromosomes carrying dierent alleles of Xce have dierent
probabilities of being inactivated (Cattanach and Isaacson, 1967) (Figure 1c). Additional
autosomal loci also participate in the genetic control of the choice of the X chromosome
to be inactivated in mice (Chadwick and Willard, 2005; Percec et al., 2002, 2003).
Moreover, parent-of-origin eects have also been observed in both mice (Takagi and
Sasaki, 1975) and humans (Chadwick and Willard, 2005).
Stochastic, environmental, and genetic factors result in variability in X-chromosome inactivation and, consequently, generate a gamut of phenotypes for each of
the X-linked genes, with multiple implications. The relative abundance of transcripts of
each allele of any gene subject to X-inactivation reects the fraction of cells with each of
the two chromosomes active, as well as any allelic dierences in expression that are
intrinsic to specic alleles. Variations in such relative expression result in the spectrum
of phenotypes observed in the population. For instance, a correlation between
X-inactivation patterns and meiotic recombination levels (genomewide) has been
described in female mice (de la Casa-Esperon etal., 2002). The biological importance of
this trait (recombination levels) in the human population cannot be overestimated as it is
a major determinant of female fecundity and reproductive lifespan. If recombination
levels are controlled by gene/s in the X chromosome, then levels of recombination can
change accordingly with the relative expression of dierent alleles of such gene/s.
Because this is only one of the numerous genes in the X chromosome, the phenotypic
diversity generated by similar phenomena related to X-inactivation processes is expected
to be large in female mammals.
Similarly, epigenetic variability between individuals at multiple autosomal loci can be
the result of multiple processes. Since erasure and establishment of epigenetic marks is a
dynamic process that occurs during the lifespan of organisms, especially during
gametogenesis and embryogenesis (reviewed in Latham, 1999; Mann and Bartolomei,
2002; Article 33, Epigenetic reprogramming in germ cells and preimplantation embryos,
Volume 1), there is ample room for stochastic factors to contribute to the diversity of
patterns observed. Environmental eects have also been described. Nutritional factors
can induce epigenetic modications such as changes in the expression of imprinted
genes; moreover, maternal diet can aect the methylation status of transposable
elements and the expression of nearby genes in mice (reviewed in Waterland and Jirtle,
2004). Examples of environmental eects have also been reported in rats, in which
variations in maternal care behavior result in epigenetic changes in the ospring at the
level of histone acetylation and DNA methylation of the consensus sequence for the
NGFI-A transcription factor of the glucocorticoid receptor gene. Consequently,
expression of this gene in the hippocampus can be modied by maternal care, which
might be the basis for the changes in stress response observed in this gene in the
ospring (reviewed in Fish etal., 2004). Environmental eects could be also the basis for
the changes observed in epigenetic marks over time. DNA methylation patterns change
with aging in a complex fashion, although overall hypomethylation has been observed in
most vertebrate tissues (Mays-Hoopes etal., 1986; Richardson, 2003). For instance,
changes in the methylation prole of the c-myc proto-oncogene have been described
during the aging process of mice. Because this is a gene involved in many tumor
processes, similar temporal alterations of epigenetic marks might be part of the basis of
the increasing incidence of cancer with age (Ono et al., 1986, 1989).
Finally, epigenetic diversity can be the result of heritable variants that aect the
formation or stability of epigenetic marks. It has been observed that allelic dierences in
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the expression of several genes are transmitted in families, although the patterns of
transmission are variable (Pastinen et al., 2004; Yan et al., 2002). In some instances, the
transmission of allelic imbalance is compatible with Mendelian inheritance, and even
associated with transmission of particular polymorphisms (haplotypes), suggesting the
participation of cis-acting elements in the regulation of allelic expression (Yan et al.,
2002), whether they are of genetic or epigenetic origin. In fact, studies showing
transmission of de novo induced methylation changes indicate that chromatin
modications, per se, are heritable (Kakutani et al., 1999; Stokes et al., 2002). Moreover,
abnormal methylation patterns at the dierentially methylated regions of the IGF2/H19
and IGF2R imprinted genes have been found to cluster in families (Sandovici et al.,
2003). Also, methylation levels at particular Alu repeated sequences show interindividual
dierences when the insertions were paternally versus maternally transmitted (Sandovici
et al., 2005). In the case of imprinting defects, epimutations in an imprinting control
region of human chromosome 15 have been associated with a substantial percentage of
cases of the neurodevelopmental disorders Angelman and Prader-Willi syndromes (see
Article 29, Imprinting in Prader-Willi and Angelman syndromes, Volume 1). Recent
studies have shown that both cis- and trans-acting factors seem to increase the risk of
conceiving a child with Angelman syndrome (AS) (Zogel et al., 2006). Trans-acting
genetic elements have also been involved in changes in the imprinting status of the Dlk1
gene in mouse brain (Croteau et al., 2005). In this case, reactivation of the normally
silent maternal allele correlates with the methylation status of a dierentially methylated
region. Therefore, epigenetic information constitutes a code superimposed on the genetic
information, thereby increasing phenotypic diversity. Much future research will no doubt
focus on determining whether epigenetic variation makes a signicant contribution to
common complex genetic disorders, such as diabetes, hypertension, schizophrenia,
Alzheimers disease and the like, in humans.
4. Epigenetic variation: what are the consequences?

Phenotypic diversity is the direct consequence of much epigenetic variation. As
we mentioned before, epigenetic modications can result in allelic expression imbalance
within (dierential expression levels) or between cells (monoallelic and mosaic
expression). This, in turn, can result in phenotypic dierences between cells, tissues,
and/or individuals. The most obvious example is that of monozygotic twins: although
genetically identical, numerous phenotypic dierences appear during their life span. The
same is true at the epigenetic level: recent studies have shown that dierences in DNA
methylation and histone acetylation between twins are present throughout the genome
(Fraga et al., 2005). Therefore, epigenetic dierences could be the basis of many
phenotypic discordances observed between twins, including their susceptibility to
complex diseases (Wong et al., 2005).
4.1. Epigenetic variation and disease

Epigenetic variation is particularly important for genes involved in diseases. For
instance, the fragile-X syndrome of mental retardation is associated with an expansion in
the number of CGG repeats in the promoter and 5 untranslated region of the FMR1 gene
on chromosome X. This expansion results in hypermethylation of the region and silencing
of the FMR1 gene (Hansen et al., 1992). Short expansions (premutations) do not have
apparent phenotypic eects, while long expansions are observed in aected individuals.
Notably, the severity of the disease ranges from severe mental retardation to only mild
learning disabilities. It is possible that the observed gamut of symptoms depends, at least
in part, on epigenetic dierences, because variability in methylation in this region has
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been observed between and within individuals (Genc etal., 2000; Stoger etal., 1997) and
changes in the CGG repeat length might also result in additional chromatin and
transcriptional modications.
Another interesting example of mosaicism has been observed in a small group of
AS patients, in whom an imprinting defect silences the maternal copy of the UBE3A
gene. However, some of these patients show mosaic maternal expression and methylation
of this gene, which, again, suggests the possibility of an epigenetic eect on the observed
variability in the severity of clinical symptoms (Nazlican et al., 2004).
Cancer has also been associated with epigenetic alterations, such as losses and
gains of methylation and LOI (Feinberg et al., 1988, 2002; Cui et al., 2003; Jones and
Baylin, 2002; Nakagawa et al., 2001). Interestingly, some of these alterations are also
observed in normal tissues of the same individuals, as highlighted by the gain of DNA
methylation in the imprinting control region upstream of H19 in human Wilms tumors
and in the non-neoplastic kidney parenchyma adjacent to these tumors (Cui et al., 1998,
2003; Moulton et al., 1994). Hence, epigenetic variation between individuals is probably
involved in susceptibility to develop cancer as well as other genetic diseases. Moreover,
since heritable epigenetic variation has been observed in many instances, it can actually
play an important role in quantitative trait variation, and selection acting on such
epialleles might result in rapid phenotypic changes, making it a formidable force in
evolution (Rutherford and Heniko, 2003; Sollars et al., 2003).
4.2. Epigenetic variation and development

Epigenetic variation also has important consequences in development and
dierentiation. A potentially important example of epigenetic changes as a result of
environmental eects is the eects of culture conditions on the expression of imprinted
genes in mouse embryos. It has been shown that some culture media perturbs gene
expression and results in aberrant methylation and expression of imprinted genes
(Doherty et al., 2000; Mann et al., 2004; Rinaudo and Schultz, 2004). Although some of
these abnormalities can be restored in the embryo proper (Mann et al., 2004), many
persist in the extraembryonic tissues and can potentially aect the development of the
embryo. In fact, several epidemiological studies suggest that assisted reproductive
technologies (ART) might result in an increased frequency of diseases caused by
imprinting defects, such as AS and Beckwith-Wiedemann syndrome (BWS) (Article 30,
Beckwith-Wiedemann syndrome, Volume 1).
Despite the many reassuring reports on the safety of ART, there have been a small
number of recent reports suggesting that ART children may be at increased risk for rare
congenital malformation syndromes that are related to defects in genome imprinting (Cox
et al., 2002; DeBaun et al., 2003; Halliday et al., 2004; Horsthemke et al., 2003; Niemitz
et al., 2004; Olivennes et al., 2001; Orstavik et al., 2003). At least three children
conceived by intracytoplasmic sperm injection (ICSI) have been diagnosed with AS
(Horsthemke et al., 2003; Orstavik et al., 2003) and at least 28 ART children (both in
vitro fertilization (IVF) and ICSI cases) have been diagnosed with BWS (Boerrigter et al.,
2002; Bonduelle et al., 2002; DeBaun et al., 2003; Gicquel et al., 2003; Halliday et al.,
2004; Koudstaal etal., 2000; Maher et al., 2003; Olivennes et al., 2001; Sutclie et al.,
1995). Because both AS and BWS are rare disorders (each aects approximately 1 in 15
000 children (Nicholls et al., 1998)), the appearance of even small numbers of cases is
unexpected except among a large sample of births. Therefore, the current data strongly
suggests that there is an association between increased risk for AS and BWS and ART.
With respect to BWS, the number of aected individuals observed is estimated to be up
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to nine times the expected incidence (Halliday et al., 2004).

The epidemiological assessment that ART may lead to an increase in the frequency of
defective genome imprints is also supported by biochemical characterization of alleles at
the relevant disease loci. All three cases of AS show allelic DNA methylation patterns
characteristic of a sporadic imprinting defect at the AS locus (i.e., complete or mosaic
absence of methylation on both maternal and paternal alleles (Horsthemke et al., 2003;
Orstavik et al., 2003)). None of the patients has a cytogenetically visible alteration of
chromosome 15 (which occurs in 70% of all AS cases (Nicholls et al., 1998)) and none has
a detectable microdeletion at the imprinting center, suggesting that all three cases are
due to sporadic, primary, epigenetic defects rather than genetic changes. Given that such
imprinting defects account for less than 5% of all AS cases (Buiting etal., 2001, 2003;
Nicholls et al., 1998), there is at least a suspicion that all three cases occurring in
patients following ICSI are of this type.
The case for the presence of primary epigenetic defects in the majority of the
BWS patients found among ART children is also supported by molecular analyses of
alleles at the BWS locus on chromosome 11. Nineteen of the 24 patients have been
analyzed for loss of imprinting (LOI; dened, in this context, as transcription of both
maternal and paternal alleles; or the specic changes in DNA methylation that track with
this phenomenon and provide a more robust marker in clinical samples) at one or more
imprinted genes within the BWS locus and 13 of the 19 cases showed LOI at either
KCNQ10T1 (DeBaun et al., 2003; Gicquel etal., 2003; Maher etal., 2003) or H19/IGF2
(DeBaun etal., 2003). With the addition of the BWS patients described by Halliday et al.,
2004, 16 out of a total of 22 cases examined showed LOI. Although imprinting defects are
more common in BWS than in AS, LOI still appears to be overrepresented among BWS
cases in ART children and ART is, in turn, overrepresented among BWS cases.
4.3. Epigenetic variation diversity

During the last several years, there has been a dramatic increase in the number of
studies attempting to elucidate the patterns and interrelationship between DNA
methylation, histone modications, noncoding RNAs, binding of nonhistone chromatin
proteins, nuclear positioning and interactions, and so on, which are part of the
epigenetic code (Article 27, The histone code and epigenetic inheritance, Volume 1).
Alterations of the chromatin conguration can aect interactions between DNA regions,
between chromosomes, and with other molecules. Most of the studies in epigenetic
variation have been focused on the dierent mechanisms and eects on gene expression
and its phenotypic consequences, including allelic dierences and disease, enhancers
and insulators, trans-sensing and paramutation, long-range interactions and nuclear
colocation, and so on. However, epigenetic changes have also been found to aect many
other chromosomal functions (see the following text). A classical example is the
centromere, in which multiple chromatin modications and proteins play a major role in
binding to the poles of the spindle and promoting chromosome segregation. Interestingly,
epigenetic changes can generate new domains with similar properties (neocentromeres)
that aect the segregation of chromosomes during mitosis and meiosis (Pardo-Manuel de
Villena and Sapienza, 2001; Rhoades and Dempsey, 1966; Warburton, 2004).
Consequently, changes in the segregation of chromosomes or chromatids can favor the
transmission of particular alleles to the next generations, with important consequences in
evolution and disease (Pardo-Manuel de Villena and Sapienza, 2001).
Another example of a biochemical process for which there is a strong epigenetic
eect is asynchronous DNA replication. Asynchronous replication is characteristic of
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regions containing monoallelically expressed genes (Mostoslavsky et al., 2001; Simon et

al., 1999) and, therefore, epigenetic dierences seem to be the basis for the dierential
replication between homologs at such regions. Consequently, these chromosomal regions
are interesting examples of how epigenetic modications of chromosomal regions have
not one but multiple eects (on replication and expression). In addition, a recent survey
of asynchronously replicated regions have found that they are located in close proximity
to areas of tandem gene duplication (Gimelbrant and Chess, 2006) although whether
such epigenetic marks play a role in chromosome stability in regions of duplications
remains to be determined.
Meiotic pairing and recombination constitute another example of a cellular
process in which epigenetic marking appears to play an important role. Functional and
epigenetic dierences between paternal and maternal chromosomes are a common
observation in sexually reproducing organisms (reviewed in de la Casa-Esperon and
Sapienza, 2003; Pardo-Manuel de Villena et al., 2000). However, only a few of such
dierences have been associated with imprinted gene expression. Consequently, it has
been postulated that parent-of-origin epigenetic dierences share a common origin and
function in all sexually reproducing organisms: to allow the recognition (and distinction)
between homologous chromosomes during the processes of recombination and repair (de
la Casa-Esperon and Sapienza, 2003; Pardo-Manuel de Villena et al., 2000). Indeed, a
recent study has shown that DNA methylation has a role in early meiotic stages: mice
decient in the DNA methyltransferase 3-like (Dnmt3L) gene are sterile and display
abnormal chromosome synapsis during meiosis (Bourchis and Bestor, 2004). Curiously,
normal expression of Dnmt3L occurs not in the meiotic cells, but in their precursors.
Hence, the epigenetic signals must be inherited through multiple cell divisions. Such
epigenetic signals are observed as DNA methylation of retrotransposons, which appear
demethylated in Dnmt3L knockout male germ cells. While methylation participates in the
normal silencing of mobile elements, retrotransposons are transcribed in the mutant
mice. Therefore, Dnmt3L mutant mice represent an example of how epigenetic changes
can not only aect transcription but can also reshape the genome by aecting synapsis
and allowing the mobilization of retrotransposons into new locations, with multiple
consequences. Consequently, studies of epigenetic variation cannot be restricted to
eects on gene expression, because it can also modulate many other chromosome
functions (de la Casa-Esperon and Sapienza, 2003; Pardo-Manuel de Villena etal., 2000;
Sandovici et al., 2005).
5. Conclusions
When discussing epigenetic variation, it is important to remember that we know little
about either the underlying mechanisms or the consequences. To mention a few recent
examples, studies on the viable yellow allele of the mouse agouti locus (Avy) have shown
that the expression of the agouti gene is correlated with the methylation status of
upstream sequences (Article 36, Variable expressivity and epigenetics, Volume 1).
Interestingly, epigenetic inheritance at this locus is not due to such methylation marks,
because they are erased during embryonic development (Blewitt etal., 2006). Therefore,
other epigenetic marks are responsible for the transmission of this epiallele to the
ospring. In this review, although we have mostly mentioned examples of variability in
methylation (because it has been the most frequently studied epigenetic mark in
mammals and is the rst subject of the Human Epigenome Project (Eckhardt et al.,
2004)), we hope that current and future studies will bring to light epigenetic variation at
many other levels. For instance, studies of the eects of histone tail modications at
multiple amino acid residues are an expanding eld, because the spectrum of
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modications and residues aected continues to grow (Article 27, The histone code and
epigenetic inheritance, Volume 1). In addition, new epigenetic marks and inheritance
modes are likely to be discovered. For instance, the role of small RNAs on epigenetic
changes has become prominent since the discovery of RNA interference in
Caenorhabditis elegans (Fire etal., 1998). Recent studies have revealed striking new
roles for RNA in non-Mendelian epigenetic inheritance, similar to paramutation in plants.
The homozygous wild-type progeny of mice that are heterozygous for a mutation in
the Kit gene (Rassoulzadegan et al., 2006) are found to exhibit the white spotting
phenotype that is characteristic of mice that carry a Kit mutation. Elaboration of this
phenotype is related to the zygotic inheritance of abnormally processed RNAs of the
normal allele.
A realistic description of the scale of epigenetic variation is hampered by the
diversity of causes and consequences and because the mechanism by which many
epigenetic marks are heritable remains obscure. An increasing number of studies are
aiming to integrate proles from dierent epigenetic marks and gene expression patterns
of particular chromosomal regions, in order to better understand the possibilities of
variations on the epigenetic code. The complexity and diversity of the epigenetic marks
and their implications poses a tremendous challenge, but understanding the nature of the
immense phenotypic diversity that surrounds us makes it worth the eort.
Next post: DNA methylation in epigenetics, development, and imprinting (Genetics)
Previous post: Developmental regulation of DNA methyltransferases (Genetics)
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