Download The role of sex chromosomes in sexual dimorphism

doi: 10.1111/jeb.12345
The role of sex chromosomes in sexual dimorphism: discordance
between molecular and phenotypic data
R. DEAN & J. E. MANK
Department of Genetics, Evolution and Environment, University College London, London, UK
Keywords:
Abstract
feminization;
gene expression;
masculinization;
sex chromosomes;
sexual dimorphism;
sexual selection.
In addition to initial sex determination, genes on the sex chromosomes are
theorized to play a particularly important role in phenotypic differences
between males and females. Sex chromosomes in many species display
molecular signatures consistent with these theoretical predictions, particularly through sex-specific gene expression. However, the phenotypic implications of this molecular signature are unresolved, and the role of the sex
chromosomes in quantitative genetic studies of phenotypic sex differences is
largely equivocal. In this article, we examine molecular and phenotypic data
in the light of theoretical predictions about masculinization and feminization of the sex chromosomes. Additionally, we discuss the role of genetic
and regulatory complexities in the genome–phenotype relationship, and
ultimately how these affect the overall role of the sex chromosomes in sex
differences.
Are sex chromosomes important in
sexual dimorphism?
In addition to the differences associated with sex determination, development of the gonad and gamete delivery, males and females in many organisms exhibit an
array of somatic dimorphisms, including morphology,
anatomy, life history and behaviour, among many others (Fairbairn, 2013). Sexually dimorphic phenotypes
often have complex genetic architectures and questions
related to how separate female and male phenotypes
are encoded within a genome that is largely shared
have long been at the heart of evolutionary biology
(Lande, 1980, 1987; Reeve & Fairbairn, 2001; Badyaev,
2002).
The shared genome places a constraint on the evolution of male- and female-specific phenotypes (e.g. Delph et al., 2004; Poissant et al., 2010), and this means
that differences between male- and female-specific
fitness optima can lead to sexual conflict. Concerns
about this constraint have led many to look to the sex
chromosomes, the only regions of the genome that
Correspondence: Judith E. Mank, Department of Genetics, Evolution and
Environment, University College London, The Darwin Building, Gower
Street, London WC1E 6BT, UK. Tel.: +44 (203) 108 4228;
e-mail: [email protected]
differ between the sexes, as potential hot spots for the
genes underlying sexual dimorphism and potential foci
of sexual conflict. Theoretical models have long predicted that the sex chromosomes should play a disproportionately large role in sexual antagonism (e.g. Rice,
1984; but see Fry, 2010). This theory can be extended
to sexual dimorphism if the resolution of sexual antagonism via modifiers of sexually antagonistic loci is also
X-linked (Rice, 1984). However, the predictions of this
latter two locus model, requiring both a sex-linked sexually antagonist coding locus and a sex-linked sex-specific regulatory element, have been questioned
(Connallon & Clark, 2010). Regardless of this debate,
there is an expansive and compelling body of evolutionary theory about the role of the sex chromosomes
in sexual conflict and for different models of sexual
selection (Rice, 1984; Kirkpatrick & Hall, 2004; Albert
& Otto, 2005; Van Doorn & Kirkpatrick, 2007, among
many others).
There are two primary types of sex chromosome systems, male (XX XY) and female (ZW ZZ) heterogamety,
which between them have four types (X,Y,Z and W) of
sex chromosomes. In male heterogametic systems,
females have two X chromosomes and males one X
chromosome and one Y chromosome. In female
heterogamety, females have one Z chromosome and one
W chromosome, and males two Z chromosomes. There-
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fore, Y and W chromosomes are limited to males and
females, respectively, whereas X and Z chromosomes are
shared by both sexes but are more often present in
females (X chromosome) or males (Z chromosome). In
theory, both coding and regulatory loci on each of the
sex chromosome types should be sexualized in unique
and specific ways (Table 1). Even though the sex-limited
Y and W chromosomes often contain relatively few
genes, those that remain are thought to play a crucial
role in male (for the Y chromosome) and female (for the
W chromosome) traits, as strong sex-specific selection is
needed to maintain genes on these chromosomes once
recombination is suppressed (Bachtrog, 2013). X and Z
chromosomes are thought to be masculinized (having
accumulated a greater degree of male-benefit alleles
than the autosomes) and feminized (accumulating
greater female-benefit alleles than the autosomes) in different ways depending on the dominance of alleles. In
male heterogamety, the hemizygosity experienced by
males may give the X chromosome a disproportionately
large role in traits encoded by recessive alleles that benefit males, as X-linked genes are always exposed to selection in males. Additionally, sexual selection models
Table 1 Predicted sexualization of sex chromosomes.
Sex
Chromosome
Type
Sex-specific effects
Male heterogamety
X chromosome
Dominant
Accumulation of femalebenefit alleles and/or
female-biased genes
(feminization)
Fewer than expected
male-benefit alleles
and/or male-biased
genes
(demasculinization)
Y chromosome
Accumulation of malebenefit alleles, only
expressed in males
(masculinization)
Female heterogamety
Z chromosome
Dominant
Accumulation of malebenefit alleles and/or
male-biased genes
(masculinization)
Fewer than expected
female-benefit alleles
and/or female-biased
genes (defeminization)
W chromosome
Accumulation of femalebenefit alleles, only
expressed in females
(feminization)
Recessive
Accumulation of malebenefit alleles and/or
male-biased genes
(masculinization)
Fewer than expected
female-benefit alleles
and/or female-biased
genes (defeminization)
Recessive
Accumulation of femalebenefit alleles and/or
female-biased genes
(feminization)
Fewer than expected
male-benefit alleles
and/or male-biased
genes (demasculinization)
suggest that X chromosomes should accumulate genes
that act as honest signals of male quality (Kirkpatrick &
Hall, 2004). Alternatively, the fact that the X chromosome is more often present in females may give it a larger role in traits encoded by dominant alleles that
benefit females because the X chromosome is twice as
often present in females than males (Rice, 1984).
These predictions in converse are expected of Z chromosomes (i.e. a feminization for Z-linked recessive variation, and masculinization of dominant alleles).
Additionally, the inheritance pattern of Z chromosomes,
which are the only sex chromosome that can be passed
from a male to both his sons and his daughters, is
thought to foster the spread of sexually selected traits
that are the product of female preference (Reeve &
Pfennig, 2003; Kirkpatrick & Hall, 2004). And these are
just some of the models suggesting that sex chromosomes are likely to play a large role in sexually dimorphic and sexually selected traits, with many other
variations pervading the literature (e.g. Albert & Otto,
2005; Van Doorn & Kirkpatrick, 2007).
Predictions and assumptions about the role of the sex
chromosomes in sex differences are often so pervasive
that it is sometimes assumed that all sex differences
ultimately derive from sex-linked genes or have
hijacked the sex-determination pathway (Williams &
Carroll, 2009; Matson & Zarkower, 2012). The latter
view implies that sex determination is always based on
sex chromosome complement; however, most animals,
many of which have clear sexual dimorphism, lack sex
chromosomes. It is therefore clear that sex chromosomes are not required for sexual dimorphism. Consequently, it follows that not all sexually selected or
sexually dimorphic traits need necessarily be sex-linked
in species with sex chromosomes. Accepting this reality
leads to some important questions: How important are
the sex chromosomes in phenotypic sex differences?
When the sex chromosomes are responsible for phenotypic dimorphisms, what is the underlying genetic
mechanism? In species without sex chromosomes, how
are sexually dimorphic phenotypes encoded?
Testing and quantifying the role of the sex chromosomes in phenotypic sex differences has been a major
endeavour in many laboratories for quite some time,
and the results have been somewhat mixed. Although
some sexually dimorphic phenotypes have been linked
to sex chromosomes (Cowley et al., 1986; Chase et al.,
2005; Kitano et al., 2009, although see Saetre et al.,
2003; Roberts et al., 2009; Natri et al., 2013), many others have not (e.g. Knief et al., 2012; Poissant et al.,
2012; Schielzeth et al., 2012). Anecdotal, species-specific reports are heavily influenced by a reporting bias,
and few meta-analyses recover a disproportionately
large role for the sex chromosomes in sexually dimorphic phenotypes or sex-specific fitness. For example,
a survey of putatively sexually selected genes in
Drosophila melanogaster (Fitzpatrick, 2004) did not detect
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significant over-representation of sex linkage. Additionally, a meta-analysis of genetic variance in several sexually dimorphic traits in birds did not detect
significantly more sex linkage than the size of the sex
chromosome would predict (Husby et al. 2013). Similarly, there was no significant association between sex
chromosome type and sexually selected traits in fish
(Mank et al., 2006).
More recently, molecular work has used gene expression and other regulatory differences between females
and males to test theoretical predictions about sexualization of the sex chromosomes. Under the assumption
that male-biased genes are beneficial to males and
female-biased genes are beneficial to females (e.g. Connallon & Clark, 2011; Pointer et al., 2013; Table 1), gene
expression data can be used to test for significant masculinization (more male-biased genes than expected) or
feminization (more female-biased genes than expected)
of sex chromosome gene expression. Molecular data
interpreted within this framework are far more concordant than phenotypic studies, with a consistent pattern
of masculinization and/or feminization of X, Y, Z and W
chromosomes across different species and in accordance
with theoretical predictions. The pattern is often so clear
that it is difficult at times to understand why sex chromosomes are not always the major players in phenotypic studies of sexual dimorphism.
Our goal here is to address the discordance between
phenotypic and molecular studies. To do this, we
attempt to synthesize phenotypic and molecular studies
related to the sexualization of the sex chromosomes.
We examine the theory and empirical data on this topic
and speculate wildly as to why molecular genetic and
phenotypic data might not show concordant patterns.
The role of the sex chromosomes in
phenotypic sexual dimorphism and sexspecific fitness
There are empirical data to support an important role
for the sex-limited chromosomes, the male-limited Y
chromosome in XX-XY species and the female-limited
W in ZZ-ZW species, in sex-specific traits. For example,
many male colour polymorphisms have been mapped
to the guppy Y chromosome (Winge, 1922), the Y
chromosome is important for male fitness in Drosophila
(Chippindale & Rice, 2001; Lemos et al., 2008), the
human Y chromosome is crucial to male fertility (Lange
et al., 2009), and the Y chromosome in Silene latifolia
has been shown to control many dimorphic floral traits
(Scotti & Delph, 2006; Delph et al., 2010). Similarly,
W chromosomes have been shown to harbour female
coloration genes in cichlids (Roberts et al. 2009; Parnell
& Streelman, 2013) and play a key role in female fertility in chickens (Moghadam et al., 2012).
There are also examples of the homogametic sex
chromosomes, the X and the Z, playing important roles
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in sex-specific phenotypes. For example, the X chromosome influences sexually antagonistic fitness variation
(Gibson et al., 2002; Foerster et al., 2007; Innocenti &
Morrow, 2010), sexually selected behavioural and morphological traits (Reinhold, 1998), sexual dimorphism
in stalked-eyed fly eye span (Wolfenbarger & Wilkinson, 2001), dimorphism in body size in dogs (Chase
et al., 2005), dimorphic expression of Drosophila cuticular hydrocarbons (Chenoweth & Blows, 2003; Chenoweth et al., 2008) and a suite of dimorphic Drosophila
morphometrics (Cowley et al., 1986; Cowley & Atchley,
1988). Similarly, in female heterogametic systems,
female mating preference genes in a moth were identified on the Z chromosome (Iyengar et al., 2002), and
female mate preference and male plumage traits have
been linked to the flycatcher Z chromosome (Saetre
et al., 2003; Saether et al., 2007).
The examples above do not represent an exhaustive
list, but they do illustrate the power of species-specific
reports on particular phenotypes. Reading through these
examples, it may seem as although the sex chromosomes
play a huge role in sexual dimorphism. However, there
are three things to consider:
First, some of the above cases do not make clear
how often sexually dimorphic traits have been shown
to be under autosomal control, for instance dimorphism over beak coloration and size in finches (Knief
et al., 2012; Schielzeth et al., 2012), male dimorphism
in turkeys (Pointer et al., 2013), horn traits in big horn
sheep (Poissant et al., 2012) and, for sex-specific
phenotypes, mate preferences in Heliconius butterflies
(Merrill et al., 2011). Meta-analyses synthesizing multiple studies, species or traits can create a less-biased estimate of the role of sex linkage in sexual dimorphism.
Although they are of course dependent upon the
underlying literature and can be influenced by reporting and publication biases, they are still in many ways
fairer and less likely to be influenced by reporting and
journal preferences. Some meta-analyses do report a
disproportionately large role of the sex chromosomes
(e.g. Reinhold, 1998; Lindholm & Breden, 2002); however, more often they do not recover a larger role than
would be expected based on the relative size of the sex
chromosomes in sex-specific traits (Fitzpatrick, 2004;
Fairbairn & Roff, 2006; Mank et al., 2006; Husby et al.,
2013).
Second, there is a strong reporting bias. Because of
the clear theoretical expectations, researchers recovering sex linkage for sexually dimorphic traits often
emphasize the role of sex chromosomes in the given
trait in the resulting manuscript. Those studies that fail
to recover the predicted relationship are less likely to
discuss the predictions or lack of observed sex linkage.
And, because of the theoretical expectations, studies
that do recover sex linkage may be more likely to be
published in higher impact multidisciplinary journals,
whereas those that do not, often receive less notice.
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Third, for polygenic traits spanning multiple loci, it is
important to consider the relative size of the sex chromosomes compared with the autosomal portion of the
genome when determining whether they play a disproportionately large role. For example, the Drosophila
melanogaster X chromosome constitutes around 20% of
the genome and carries >15% of the coding genes. Given
this large size, many traits, sexually dimorphic or not,
will map to the sex chromosomes, and it is important to
account for the relative size of the sex chromosomes in
such studies. An over-representation can only be
assessed with an appropriate null expectation. For
example, Wolfenbarger and Wilkinson (2001) showed
that the X chromosome in stalk-eyed flies accounted for
25% variation in eye span, even though the chromosome harbours 12% of the male genome. This suggests
that the X is over-represented in this sexually selected
trait. However, there are other considerations, such
as dosage compensation (below) that should be considered.
Molecular signatures of sex chromosome
sexualization
The theoretical models that predict that the sex chromosomes should accumulate genes with sex-specific fitness effects, and by extension genes underlying sexual
dimorphism (e.g. Rice, 1984), have recently been
extended to molecular data under two assumptions:
first, sex-biased genes represent genes with different
expression optima for females and males (Connallon &
Clark, 2011; Pointer et al., 2013), and second, sexbiased genes represent at least partially resolved sexual
conflict (Connallon & Knowles, 2005; Connallon &
Clark, 2010). In this framework, genes expressed at
higher levels in females (female-biased genes) confer
female benefits and contribute to female-specific phenotypes, and genes expressed at higher levels in males
(male-biased genes) confer benefits to males and encode
male-specific phenotypes. Regions of the genome, particularly the sex chromosomes, have been shown to be sexualized in specific ways. Regions that contain more
female-biased or male-biased genes than would be
expected due to chance are often referred to as feminized
or masculinized, respectively. Similarly, regions can also
be defeminized, with a deficit of female-biased genes or
demasculinized with a deficit of male-biased genes. The
models are really not applicable to the sex-limited nonrecombining regions of Y and W chromosomes, which by
definition can only be expressed in males and females,
respectively. The theory predicts an expected feminization of X chromosomes for dominant alleles, which
would be observable at the molecular level through an
excess of female-biased genes, possibly concurrent with
demasculinization, or a deficit of male-biased genes,
when compared to the autosomes. Similarly, we would
expect, based on theoretical predictions, a masculiniza-
tion of Z chromosomes through an excess of malebiased dominant alleles, possibly in concert with a
decrease in female-biased genes (defeminization).
Hemizygosity would lead to a masculinization of X
chromosomes for recessive alleles and feminization of
Z chromosomes.
Sexualization of X and Z chromosomes has been documented in nearly every species thus far assessed
(Table 2). For example, the X chromosome has been
both feminized (it has an over-abundance of femalebiased genes) and demasculinized (it is depauperate in
male-biased loci) in Drosophila (Parisi et al., 2003; Ranz
et al. 2003; Sturgill et al., 2007; Meisel et al., 2012). The
mammalian X chromosome also shows evidence of
feminization (Khil et al., 2004), although young malebiased genes are enriched on the mammalian X (Zhang
et al., 2010). Additionally, both the X chromosomes of
C. elegans (Reinke et al., 2004) and the flour beetle
(Prince et al., 2010) are also feminized, although the
latter effect may be due, at least in part, to the peculiar
pattern of dosage compensation in this species. The
avian Z chromosome is masculinized (Wright et al.,
2012) and defeminized (Mank & Ellegren, 2009). The Z
chromosome in silk worm also shows patterns of masculinization (Arunkumar et al., 2009), as does the pea
aphid X chromosome, potentially due to its unusual
transmission pattern resulting from periodic parthenogenesis (Jaquiery et al., 2013). Finally, the mosquito X
chromosome shows evidence of demasculinization
(Magnusson et al., 2012).
However, it is important to note that there are several complicating factors when assessing the relative
proportion of sex-biased genes on the sex chromosomes. First, different animals have different mechanisms, with different efficacies, of dosage compensation
on the X or Z chromosome (Mank, 2013). The heterogametic sex has only one copy of X- or Z-linked genes
compared with the homogametic sex. Because gene
dose often correlates with expression level, this means
that many genes are expressed less in the heterogametic sex due to halved copy number (Guo et al., 1996;
Malone et al., 2012). In some organisms, sex chromosome dosage compensation has evolved to correct for
this imbalance. In other organisms, only a small subset
of genes are compensated, and the majority of the
chromosome shows expression differences between the
sexes (reviewed in Mank, 2013). In male heterogametic
species with incomplete dosage compensation, the X
chromosome will appear to be very strongly femalebiased. Similarly, incomplete dosage compensation in
female heterogametic species would appear to lead to
the appearance of a very strong masculinization of gene
expression. When incomplete dosage compensation is
not recognized and corrected for, it can lead to a false
perception of an excess of sex-biased genes on sex
chromosomes as a function of sexual conflict, rather
than dose effects.
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Table 2 Empirical sexualization of gene expression on the sex chromosomes of various animals.
Masculinization
Feminization
Demasculinization
X chromosome
Mammals, for young
male-biased genes
(Zhang et al., 2010)
Pea aphid (Jaquiery et al., 2013)
Flour beetle (Prince et al., 2010)
C. elegans
(Magnusson et al., 2012)
Fruit fly (Meisel et al., 2012)
Mouse (Khil et al., 2004)
Mosquito (Magnusson et al., 2012)
Fruit fly (Parisi et al., 2003;
Sturgill et al., 2007;
Bachtrog et al., 2010)
Z chromosome
Chicken (Wright et al., 2012)
Silk worm (Arunkumar et al., 2009)
Second, some animals exhibit meiotic sex chromosome inactivation (MSCI) in the heterogametic sex.
Although evidence is conflicting, it is thought that
MSCI occurs in placental mammals (Turner et al., 2005;
Cocquet et al., 2009), where transcription from the X
chromosome is nearly entirely shut off in the meiotic
cells of males, but might be absent in Drosophila (Meiklejohn et al., 2011; but see Hense et al., 2007; Vibranovski et al., 2012) and birds (Guioli et al., 2012; but
see Shoenmakers et al., 2009). In those species where it
does occur, if uncorrected for in gonad tissue, MSCI
can create a false pattern of female bias on X chromosomes. Even though MSCI has not yet been definitely
shown for a Z chromosome and may not occur in any
female heterogametic species, it would theoretically
exacerbate male-biased expression observed in gonad
tissue.
Some of the earlier discordant results over relative
sexualization of X and Z chromosomes were due to the
fact that the presence, absence or efficacy of dosage
compensation and MSCI were unknown. However,
there are several species where the status of MSCI and
dosage compensation is known and accounted for.
Even accounting for dosage compensation and MSCI,
the X chromosome in both mouse and Drosophila has
been feminized for expression (Khil et al., 2004; Meisel
et al., 2012, respectively), and the Z chromosome has
been masculinized in birds (Wright et al., 2012). The
Drosophila X chromosome shows weaker and less consistent evidence of demasculinization (Meisel et al.,
2012), although this may be due to the mechanism of
dosage compensation in this clade (Vicoso & Charlesworth, 2009), explained in more detail below.
Random-X inactivation in female mammals does not
in itself present a confounding factor, as it equilibrates
gene dose between males and females. However, some
genes escape inactivation and are female-biased, which
can present a source of bias in the data. Correcting for
these species-specific regulatory peculiarities, there is
some enrichment of testis-expressed genes on the X
(Khil et al., 2004; Meisel et al., 2012). The confounding
effects of incomplete dosage compensation in birds
make it difficult to assess defeminization, although
there is some circumstantial evidence for it (Mank &
Ellegren, 2009).
Defeminization
Chicken (Mank &
Ellegren, 2009)
Possible causes of discordance
The concordance of the molecular sexualization of the
sex chromosomes is in stark contrast to the equivocal
phenotypic results of the relative role of the sex chromosomes in sexual dimorphism and sex-specific fitness.
Gene expression and QTL studies measure different
components and require different assumptions, and
this, along with several other factors, may explain some
of the discordance between these two approaches.
Phenotypic studies may underestimate the role of
the sex chromosomes
QTL studies rely on intrasexual polymorphism and variation, whereas molecular approaches do not. This fact
alone may account for a great deal of the discordance.
Moreover, molecular studies of gene expression sexualization often ignore any intrasexual variation and simply average over all the individuals of each sex. In
addition to being based on different underlying data
types, QTL studies can only identify traits for which
polymorphisms exist, and this may be particularly problematic for the sex chromosomes, which often have
reduced effective population size (Charlesworth et al.,
1987). Furthermore, QTL studies sometimes ignore the
Y or W chromosome, which of course makes it impossible to determine the role of the sex-limited chromosomes in sexually dimorphic traits. Additionally,
quantitative genetic approaches to complex phenotypes,
particularly in natural populations with smaller sample
numbers, can miscalculate the effect size of specific loci
and potentially fail to identify some contributing loci
due to the Beavis effect, which leads to a stronger perceived association to fewer QTL in situations with fewer
samples (Slate, 2013). For traits with many contributing
loci, only a few will be detected, and this could make it
difficult to obtain a fair estimate of the contribution of
sex-linked genes. Recent work on the transcriptional
differences among males with different levels of sexual
dimorphism in the wild turkey suggests that some sexspecific traits may have many contributing loci (Pointer
et al., 2013). A recent genome-wide association study
(GWAS) of sexually dimorphic traits in 270 000
humans also revealed a complex genetic architecture
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with many contributing loci (Randall et al., 2013). If
this is generally true, then this may limit the ability of
QTL approaches, particularly in natural populations, to
accurately reconstruct the genetic architecture and
therefore the supporting role of the sex chromosomes.
Phenotypic studies may underestimate the role of the
sex chromosomes through the type of phenotype studied. First, predictions for sex chromosome linkage are
strongest for sex-limited or strongly sexually dimorphic
phenotypes, and weaker for less dimorphic phenotypes
(Fairbairn & Roff, 2006). Second, genomic studies find
X chromosomes to be feminized through the accumulation of female-biased genes, and yet most examples of
phenotypic sexual dimorphism are sexual display traits
which are usually exaggerated in males (Andersson,
1994). Although theory predicts male-biased recessive
alleles to accumulate on the X (Rice, 1984), based on
the molecular signature of feminization, we might
expect X chromosome linkage at the phenotypic level
for sexually dimorphic traits that are exaggerated in
females. The strongest, and therefore possibly easier to
detect, associations between X chromosomes and sexual
dimorphism would be expected for highly dimorphic
traits exaggerated in females, such as body size in some
insects (e.g. Cowley & Atchley, 1988).
Additionally, most genes have pleiotropic effects
(Wright, 1968) which impose constraints on their evolutionary pathway, and this may complicate the role of
the sex chromosomes in sexual dimorphism. A pleiotropic gene subject to sex-specific selection is not free to
evolve in response to that selection alone. Its chromosomal location may reflect a mix of sex-specific and
nonsex-specific selection (Fitzpatrick, 2004). This mixture may limit the role of the sex chromosomes in sexually dimorphic phenotypes that are controlled by
strongly pleiotropic genes, particularly because such
genes are not expected on the nonrecombining regions
of the sex-limited Y and W chromosomes. Importantly,
pleiotropic genes involved in sexually dimorphic traits
may contribute to trait variability. However, the degree
of pleiotropy differs greatly among loci, and we might
expect that the general predictions are fairly accurate
for less pleiotropic genes. That said, although the term
pleiotropy is usually defined broadly as the multiple
functions of a single locus, pleiotropy is actually measured in a variety of different ways. For example, measures of pleiotropy encompass such disparate metrics as
tissue-specificity (e.g. expression breadth, Mank et al.,
2008; Meisel, 2011), connectivity of genetic networks
(Ayroles et al., 2009) or even expression at different life
stages (e.g. antagonistic pleiotropy, Williams, 1957).
Integrating these various measures into a cohesive test
of the role of pleiotropy in sex chromosomes and
dimorphism is an important area for future work.
In addition to the complications of pleiotropy, regulatory differences further confound our ability to predict
and detect the loci underlying sex differences. Most
evolutionary theory assumes, usually implicitly, cis-regulation of gene expression, where regulatory elements
are relatively close, and definitely on the same chromosome, as the gene they control. Studies across a broad
array of species have shown that only a small proportion of all gene regulation is purely in cis, and evidence
for an important role of trans-regulation (where more
distant elements control expression levels) spans Drosophila (Wayne et al., 2007), C. elegans (Li et al., 2006),
humans (Grundberg et al., 2012), mice (Van Nas et al.,
2010) and Arabidopsis (West et al., 2007) The location of
sexually dimorphic genes and their sex-specific regulation may be disparate, and this complicates matters
immensely. More nuanced theoretical predictions with
reasonable assumptions about cis- vs. trans-regulation
are very much needed.
Finally, discordance between molecular and phenotypic findings may simply be a power issue. The
restricted ability of genes to move around the genome
and the often relatively small size of the sex chromosomes might make detecting patterns of sex chromosome linkage particularly noisy due to stochasticity.
The fact that relatively few phenotypic traits have been
studied compared with thousands of genes assessed in
every transcriptomic analysis might mean we just do
not have sufficient power to detect an association. Furthermore, power to detect sex chromosome linkage
using the animal model approach is not simply a product of sample size, but also the type of pedigree information (specifically relationships outside the nuclear
family) available within the data set (Wolak & Keller,
2014). Even studies with large sample sizes might have
deceptively low power when it comes to measuring sex
chromosome linkage.
Molecular studies may overestimate the
sexualization of the sex chromosomes
Although there seems to be a clear pattern of sexualization of gene expression on the X and Z chromosomes,
it remains unclear how this translates to phenotypic
sex differences. The sexualization in many cases only
produces relatively small differences in expression
between males and females. Do small differences in
expression between the sexes translate to observable
phenotypic differences? How large does the magnitude
of sex bias need to be to have a meaningful phenotypic
effect? More work understanding the relationship
between sex-biased expression and sexually dimorphic
phenotypes is very much needed. Extending studies of
sex reversal via sex hormone treatment (such as Gordon et al., 2011) or experimental evolution to increase
phenotypic dimorphism (such as Delph et al., 2011) to
the transcriptome would be an excellent first start.
Additionally, the rate of sexualization of sex chromosome expression seems quite slow (Zhang et al., 2010;
Wright et al., 2012), and may be far slower than the
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evolution of the specific sexually dimorphic phenotypes
that we are most interested in, which often vary
between closely related species. If sexualization of sex
chromosomes is slow, how large a role can it play in
the evolution of sexually dimorphic phenotypes? Furthermore, what is the degree of sexualization of gene
expression for species with minimal levels of sexual
dimorphism? It is important to point out that these are
related questions and depend on the answers to the
questions posed in the preceding paragraph.
The confusing role of sex chromosome dosage
compensation, or lack thereof
Complete sex chromosome dosage compensation may
be confined to a small proportion of organisms with sex
chromosomes (Mank, 2013), and the presence, absence
or efficacy of sex chromosome dosage compensation
complicates the role of sex chromosomes in sexual
dimorphism considerably. For example, random female
X inactivation in mammals (although not strictly a dosage compensation mechanism, sensu Ohno, 1967) invalidates the assumption that the X chromosome is more
often selected in females for all types of dominant
genes. X inactivation in females is patchy, and tissues
are composed of groups of cells with either an active
maternal or paternal X chromosome (Carrel & Willard,
2005). For X-linked genes that are not secreted outside
the cell wall (cell-autonomous genes), only one copy is
expressed within any given patch of cells, and these
genes are effectively hemizygous within the cell patch
(Haig, 2006). This may suggest that the feminization of
the mammalian X chromosome (Khil et al., 2004)
applies predominately to secreted genes, which mix
throughout the body and remain effectively diploid in
females. We do not yet know how this might affect the
role of the X in sexually dimorphic phenotypes.
Drosophila counters the differences in gene dose of
the X chromosome by hyperexpression in males, yet
there are limits to how much a gene can be up-regulated. For genes expressed at relatively high levels,
males simply cannot hypertranscribe them sufficiently,
as the transcriptional machinery becomes saturated.
This causes a deficit of highly expressed male-biased
genes on the Drosophila X chromosome (Vicoso &
Charlesworth, 2009), exactly the type of genes we
might expect to be key to male phenotypes.
For those species that lack complete sex chromosome
dosage compensation, the predicted role of the sex chromosomes in dimorphism is even less clear, and several
questions remain unanswered. For example, does the
increase in expression of sex-linked genes due to dose
effects have a sex-specific phenotypic effect? If so, we
might expect the role of the sex chromosomes in sexual
dimorphism to be greater in species with incomplete sex
chromosome dosage compensation. Also, there is evidence that selection correlates positively with expression
1449
level (Castillo-Davis et al., 2002; Subramanian & Kumar,
2004; Van Dyken & Wade, 2010). If there is a similar
relationship between the strength of sex-specific selection and expression level, we might expect X- or
Z-linked loci to be under weaker selection in the
heterogametic sex in species with incomplete dosage
compensation compared with those species where
hypertranscription in the heterogametic sex compensates for reduced gene dose. This could lead to the accumulation of alleles benefiting the homogametic sex to be
slower in species with complete dosage compensation.
Dosage compensation is a largely unexplored issue in
regards to the evolution of sexual dimorphism. The
recent realization that the efficacy of sex chromosome
dosage compensation varies extensively across species
may prove important in our ultimate understanding of
the role of sex chromosomes in sex differences.
Where do we go from here?
To better understand this discordance between phenotypic and molecular studies of sex chromosomes and
sexual dimorphism, we suggest several future directions
that may prove profitable. First, moving towards
broadly synthetic meta-analyses of multiple species or
multiple traits is a helpful way to present a less-biased
view of the role of sex chromosomes vs. autosomes in
sexual dimorphism. In particular, studies of this sort
should also account for the relative size of the sex chromosomes in their analysis, as we might expect a fair
percentage of traits to be linked to the sex chromosomes by chance in species, such as many invertebrates, with relatively large sex chromosomes. As the
tide of available phenotypic and genomic data grows,
this approach becomes increasingly viable.
Another way to bridge the gap in our understanding
of the discordance between molecular and phenotypic
studies could be to look for the genomic location of
regions that regulate sex-biased gene expression (i.e.
eQTL approaches). Although eQTL studies may still suffer from some of the same problems as traditional QTL
studies, studying a less complex trait (i.e. expression of
a specific locus) increases the chances of detecting
fewer, but stronger signals. Knowledge of the location
of sex-biased genes, their trans-acting regulation and
the resulting phenotype would present a fuller picture
of the importance of sex chromosomes for sexual
dimorphism. Given the growing evidence that complex
traits are probably regulated by many loci of small
effect (Rockman, 2012), techniques to assess the role of
sex chromosomes in shaping phenotypic sexual dimorphism could be at the chromosome level, rather than
approaches used to find individual loci. Such
approaches that might give useful future advances
include chromosome partitioning techniques and whole
chromosome substitutions, such as those possible in
Drosophila (e.g. Rice et al., 2005).
ª 2014 THE AUTHORS. J. EVOL. BIOL. 27 (2014) 1443–1453
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R. DEAN AND J. E. MANK
Many studies of sex-biased expression assume that
sex-biased genes are the biochemical basis of sexual
dimorphism. Although there is indeed some evidence
for this (Connallon & Clark, 2011; Pointer et al., 2013),
the relationship between sex-biased genes, sexually
dimorphic phenotypes and sex-specific fitness remains
rather hazy. We therefore do not really know whether
the patterns of masculinization and feminization of
gene expression on the sex chromosomes actually have
definitive phenotypic implications. Studies with stronger links between phenotype, fitness and gene expression are clearly needed.
Finally, the elegant theory that predicts a large role
of the sex chromosomes in sexual dimorphism, sexual
selection and sexual conflict, such as Rice (1984),
Albert & Otto (2005) and Kirkpatrick and Hall (2004),
among many others, may not have the necessary
genetic complexity. Integrating the role of pleiotropy,
cis- vs. trans-regulation and sex chromosome dosage
compensation into the mathematics remains to be carried out. Doing so may offer a revised and more
nuanced understanding of the conditions under which
sex chromosomes do, and do not, punch above their
weight in the production of sexually dimorphic forms.
Acknowledgments
This work was supported by the BBSRC and the ERC
(grant agreement 260233), and by a fellowship from
the Wissenschaftskolleg zu Berlin to JEM and Lars Hiertas Minne to RD. We thank P.W. Harrison, S.H. Montgomery, J.C. Perry, F. Zimmer and A.E. Wright for
helpful comments.
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