Amanda Klimczuk

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The Battle of the Sexes:
How Intragenomic Conflict Explains Oddities of Mammalian Imprinting

I. The Double Paradox of Genetic Imprinting
Natural selection is the process by which a trait that confers a relative reproductive advantage
upon its bearers is disproportionately represented in subsequent generations, provided that the
trait is heritable. The most obvious ways for an organism to succeed according to these criteria
is to develop the ability to create identical copies of itselfcopies that will in turn maintain the
reproductive ability and propensity of the parentwith as little variation as possible. This simple
strategy of asexual reproduction is so obviously efficient that it is hard to conceive how an
alternative could evolve at all. But several organisms, including all mammals (Haig and Westoby
1989), utilize the much more cumbersome strategy of finding a compatible mate with whom to
jointly create a completely unique individual. Sexual reproduction is essentially gambling with
genes, and the circumstances that favored its evolution are puzzling (Ridley 2003), but one clear
benefit of diploidy is its ability to mask the phenotypic expression of deleterious recessive alleles
that would otherwise rapidly accumulate in the population, with catastrophic consequences
(Muller 1932).
It is therefore profoundly confusing (Fundele, Surani, and Allen; Hurst) that one of the
two copies of certain mammalian genes are reliably and systematically deactivated. This
phenomenon, called imprinting, is an expression of epigenetic regulationcreating
functional differences between genetically identical code (Li). The process of imprinting occurs
due to the silencing of specific genes in parental germlines that are subsequently inherited by the
offspring (Chaillet). Early research estimated that 100 genes are imprinted (Hurst), but
subsequent studies have identified more than 1,000 candidates (Kelsey 2011). The process is
carefully regulated in that some genes are expressed only when paternally-derived, others only
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when maternally-derived, and imprinted cell lineages are found only in specific tissues
(including the brain, liver, and placenta (Hurst)). Mechanistically, allelic silencing is largely
effected by selective methylation (i.e., the addition of a methyl group to the adenine or cytosine
of a stretch of DNA), which prevents gene transcription (Li).
The fact of genetic imprinting is part of a troubling double-paradox. Why would
organisms evolve sexual reproduction, which itself seems unbeneficial, only to partially erase
some of the protective benefits of being biallelic? How can we explain a robust phenomenon that
seems to fly in the face of natural selection? One probable answer, which defines imprinting as
the result of intragenomic conflict, is bizarre almost beyond imagination. However, it is difficult
to describe the conflict model out of context; it requires some background explanation, discussed
below.
II. Conflicts With Kin
Let us leave aside the difficult question of how sexual reproduction might have evolved and
simply accept that, for whatever reason, it did. Having sex has consequences even at the genetic
level.
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Barring mutation, the offspring of an asexual parent is identical to that parent because it
inherits an unaltered copy of her hereditary material. Thus from the perspective of selection, the
fitness of the offspring is indistinguishable from the fitness of the parent. Put another way: from
the parents perspective the offsprings success is as good as its own; genetically speaking, that
mother might as well be her offspring. This is not the case with sexual reproduction because each
offspring is only half-identical to each parent. The genetic interests of the parent and progeny are
related, but not identical, which leads to a divergence between the optimal amount of parental

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Under standard Darwinian theory, the individual organismnot the geneis the unit on which natural selection
acts. We need not abandon this idea to exploit the usefulness of referring to genes as self-interested entities
competing for representation in the next generation, provided that we do not interpret the metaphor too literally (see
Reassessing Dawkins Replicators in The Harvard Brain (2009)).
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investment in any given offspring since the parents do best by devoting energy to many babies,
but each baby does best by monopolizing parental resources. The evolutionary logic of parent-
offspring conflict, which occurs commonly in nature (Arnqvist and Rowe 2005), has been
recognized and formalized by Robert Trivers (1974) through his model of kinship analysis. Put
simply, an offspring will value continued parental support so long as the fitness benefits it
receives (B) are greater than the costs incurred by family members (C) whose interests are
weighted according to the degree of relatedness (r) (i.e., B > rC).
III. Conflicts Within
This, however, is only part of the story, because sexual reproduction also creates another
unavoidable consequence: conflict between males and females. When progeny are the product of
two parents, it is likely that they will bear unequal shares of the energetic burden of provisioning
the offspring until maturity (except in rare cases where both parents together could raise more
successful offspring than each could alone (e.g., monogamy)). Natural selection has thus favored
the specialization of sexually-reproducing creatures into two types that generally pursue
distinct reproductive strategies. One sextypically the femaleinvests more energy into raising
and rearing children not only through gestation and/or after birth, but even before conception by
producing fewer, larger gametes than the male (anisogamy). Because the energetic and
temporal costs of reproduction are far higher for females than for males, females do well to
carefully choose an appropriate mate with whom to reproduce, whereas males do well to
inseminate as many mates as possible. The sexes are perpetually in conflict except, again, in
cases of monogamy which restrict the males interests such that they entirely overlap with his
one and only partner (Arnqvist and Rowe 2005).
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In light of these facts, evolutionary biologist David Haig realized that calculations of
kinship theory, which assume that a given gene is equally likely to be found in a creatures
siblings, is unfounded except in strictly monogamous systems (2002). In polygamy, the cost-
benefit ratios calculated by an offsprings genes differ based on whether they were inherited
from the male or female germline. More concretely, offspring share on average 50% of egg-
derived genes with their siblings, but far fewer sperm-derived genes because those genes may
come from an unrelated father. Because of this discrepancy, siblings are supposed to have less
genetic interests in each otherand thus less concern for the costs they inflict on their
mothers future reproductionthan would be predicted by typical kinship analysis, as shown in
the table below. (Proportion alleles shared with siblings can be thought of as a proxy for r, the
coefficient of relatedness, in Trivers equation).
Sibling Relatedness
Same Father Different Father
Proportion alleles shared via maternal line (average) .5 .5
Proportion alleles shared via paternal line (average) .5 As small as 0
Proportion alleles shared with siblings (average) .5 As small as .25

In Haigs words, an offsprings paternally-derived genes have different interests from the
offsprings maternally-derived genes because they are less likely to be present in a mothers
other offspring. Thereforepaternally-derived genes have less to lose from costs to the mothers
future reproduction (Haig 2002). A fetal offsprings paternal genes would do very well by
knowing that they came from a male lineage, because in doing so they could extract more
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resources from the motherat a cost to her and her future mates offspring, but to their own
benefit (Haig and Westoby 1989).
Haigs ingenious proposal is that genomic imprinting results from the conflicting
interests of maternal and paternal genes. Intragenomic conflict is an established phenomenon that
takes many different forms (Burt and Trivers 2006), but this theory is exciting in that it meshes
epigenetics with sexual conflict. It is able to explain why methylation would be different in the
male and female germlines and why it would need to be reset in each subsequent generation
(genes are passed from male to female bodies and vice versa) (Bartolomei). It also predicts that
imprinting arising from sexual conflict should only occur in a small subset of genesthose that
influence the amount of resources obtained by an offspring at the expense of its future half-
siblings (Haig 2002)and only in certain lineages, e.g., those in which the female gives birth to
live young (viviparous lineages). The next section illustrates some peculiar examples of
imprinting that provide support for the sexual conflict model.
IV. Genes at War: Experimental Evidence
A. Embryonic Growth
Parent-specific gene expression is known to be vital for mammalian development in part because
of studies of embryonic development in mice. The most revealing experiments come from
artificially creating uniparental disomiesembryos that contain the full diploid complement of
chromosomes from only male (androgenetic) or only female (gynogenetic) germ cells. In theory,
these should develop as well as normal lab-created embryos unless the double dose of male or
female sex-specific imprinting has a deleterious effect. This is, in fact, exactly what is found.
Both male-derived and female-derived fetuses die in utero (Fundele, Surani and Allen).
However, Barton et al. noted that only androgenetic embryos have enlarged trophoblasts
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(embryonic cells that draw nutrients from maternal tissues) compared to controls (Haig and
Westoby 1989). Alternatively, scientists can create chimeric mice with an admixture of wildtype
and androgenetic or gynogenetic cellsi.e., mice whose cells are relatively more paternally-
imprinted relatively more maternally-imprinted. In this case, androgenetic chimeras are larger
than average fetuses and gynogenetic chimeras are smaller and fare poorly after birth, perhaps
due to a failure to nourish themselves by suckling their mothers (Fundele, Surani and Allen).
These findings parallel imprinting studies in flowering plants, which are nourished by the
endosperman organ much like the mammalian placentathat is functional only when
comprised of a 2:1 ratio of female- to male-imprinted chromosomes, probably to prevent male-
driven hypertrophy of the tissue (Haig and Westoby 1989).
These findings are exactly what would be predicted by the sexual conflict hypothesis,
which proposes that imprinting has evolved in mammals and flowering plants because their
offspring are nourished directly from maternal tissues (Moore and Haig 1991) and that
paternally-expressed genes [are]parasites on the maternal supply of resources (Hurst). It
seems likely that imprinted genes evolved in lockstep, with paternal genes evolving to exploit
females and maternal genes evolving defensively in response (Hurst). Runaway selection would
allow both paternal and maternal imprints to increase in potency, but always deadlocked
(because both parents share the need to producing viable offspring) (Moore and Haig 1991).
Gene expression of both parents is therefore necessary for survival, or the fetus is destroyed by
maternal excess or paternal excess (Moore and Haig 1991).
B. IGF2 and IGF2R
Insulin-like growth factor 2 (IGF2) promotes tissue growth in mice and humans. In mice, this
gene is expressed only via the paternal allele in mice after embryonic implantation. Igf2r (the
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IGF2-receptor), in contrast, is expressed only via the maternal allele. This structure binds IGF2
and other proteins and transfers them to lysosomes for degradation; it slows growth and may thus
be involved in tumor suppression. This is another potential example of sexual conflict, with the
father striving to promote embryonic growth at the mothers expense and the mother working to
avoid this injury (Feil, Moore et al.).
C. Angelmans Syndrome and Prader-Willi Syndrome: Complementary Parent-of-Origin
Disorders in Humans
The deletion of a particular region (11-13) on the long arm of chromosome 15 has developmental
consequences in humans that have complementary effects depending on whether the deleted
region was of maternal or paternal origin. Symptoms seem to reflect the paternal and maternal
excesses in the direction predicted by the intragenomic conflict hypothesis. Individuals with only
a maternal imprint (Prader-Willi Syndrome) initially fail to thrive (as do chimeric gynogenetic
mice) but develop extreme hyperphagia (intense appetite) at the time of weaning, indicating a
strong preference for non-maternal sources of nutrition. In contrast, children with only a paternal
imprint (Angelmans Syndrome) are hyperactive and prone to nighttime awakenings, which pose
burdens to new mothers (Haig 2002).
V. What Remains Unexplained
The theory that genetic imprinting is an expression of an intragenomic arms race accords with
many discoveries, including but not limited to those discussed above, that would seem
inexplicably arbitrary if the phenomenon were merely an evolutionary byproduct. However, it
is unable to account for all of the known facts about imprinted genes. First, it offers no
explanation as to why imprinted genes should tend to cluster together. More seriously, there is at
least one gene that acts in a manner completely contradictory to the hypothesis (i.e., paternal
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gene expression actually conserves the mothers resources at the expense of the offsprings, and
vice versa). Imprinted genes (for example, igf2) also appear to be highly conserved and slowly-
evolving, which is not what we would expect in cases of antagonistic genetic interactions (Hurst;
but see Burt and Trivers 2006).
More than a dozen alternative explanations of imprinting exist; some are more plausible
than others. One such hypothesis posits that imprinting exists to signal a mother if her fetus is
chromosomally abnormal so that she quickly aborts the fetus without wasting time or energy on
it. This might even help explain why Down Syndrome (trisomy 21) is more common in older
women; the stringent threshold for offspring acceptability is lowered as childbearing years
come to an end. Another hypothesis proposes that imprinting is not an expression of conflict, but
of cooperation, that benefits offspring: developing fetuses are highly-related, so they benefit
from a mechanism that promotes cooperate and sharing of maternal resources. Few to none of
these hypotheses have the power to explain the specifics of maternal and paternal imprinting,
including tissue-specific expression and direction effects. However, it is not only possible but
probable that imprinting has more than one function; there need not be a solitary explanation of
its significance.
VI. Stepping Back & Looking Forward
As the body of literature on imprinting and intragenomic conflict continues to grow there open
many new avenues for exploration, particularly in humans. For example, the dense collection of
imprinted genes in the brain, particularly in the hypothalamus, suggest that imprinting may play
a role in postnatal behaviors (Burt and Trivers 2006; Swaney 2011), including the attraction to or
avoidance of incest based on the asymmetric costs and benefits of an incestuous relationship
(Haig 1999). One study has already found differences in the autistic and schizotypal traits of
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those with Klinefelter Syndrome (XXY karyotype) dependent on whether the extra X
chromosome was of maternal or paternal origin (Bruining, van Rijn et al. 2010). Imprinting is
exciting because it suggests an alternative way for genes to transmit information from generation
to generation. Our understanding of and appreciation for genetic complexity has burgeoned from
Mendelian inheritance, to complex traits, to epigenetic regulation, to genetic conflict, and now to
smart conflict between genetic elements that seem to follow context-dependent strategies.
Genes are, in a sense, cleverer than we expected.
References
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