Download some inconvenient truths about sex chromosome dosage

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doi:10.1111/j.1558-5646.2011.01316.x
SOME INCONVENIENT TRUTHS ABOUT SEX
CHROMOSOME DOSAGE COMPENSATION
AND THE POTENTIAL ROLE OF SEXUAL
CONFLICT
Judith E. Mank,1,2 David J. Hosken,3 and Nina Wedell3
1
Department of Zoology, Edward Grey Institute, University of Oxford, Oxford OX1 3PS, United Kingdom
2
3
E-mail: [email protected]
Biosciences, University of Exeter, Cornwall Campus, Penryn, Cornwall TR10 9EZ, United Kingdom
Received November 16, 2010
Accepted March 29, 2011
Sex chromosome dosage compensation was once thought to be required to balance gene expression levels between sex-linked and
autosomal genes in the heterogametic sex. Recent evidence from a range of animals has indicated that although sex chromosome
dosage compensation exists in some clades, it is far from a necessary companion to sex chromosome evolution, and is in fact rather
rare in animals. This raises questions about why complex dosage compensation mechanisms arise in some clades when they are
not strictly needed, and suggests that the role of sex-specific selection in sex chromosome gene regulation should be reassessed.
We show there exists a tremendous diversity in the mechanisms that regulate gene dosage and argue that sexual conflict may be
an overlooked agent responsible for some of the variation seen in sex chromosome gene dose regulation.
KEY WORDS:
Evolutionary genomics, sexual conflict, sex.
In diploid sexual species with morphologically distinct sex chromosomes, the heterogametic sex has only half as many copies of
all X- or Z-linked genes outside the pseudoautosomal region compared to the homogametic sex, and only half as many copies of Xor Z-linked genes compared to the autosomes. Reduced gene dose
can result in reduced gene transcription, as fewer copies of a locus
present fewer targets to which the transcriptional machinery can
bind, and the result will be large differences in gene expression
for sex-linked and autosomal genes in the heterogametic sex. This
has the potential to create tensions in gene networks that span sexlinked and autosomal loci (Birchler and Veitia 2010), theoretically
with deleterious phenotypic implications to the heterogametic sex
(Ohno 1967; Charlesworth 1978; Marin et al. 2002).
“Sex chromosome dosage compensation” is the name given
to the regulatory mechanisms that balance gene expression between the autosomes and sex chromosomes in the heterogametic
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C 2011 The Author(s).
Evolution
sex, and although compensation is achieved in a variety of ways,
chromosome-wide dosage compensating mechanisms have been
documented in the major animal model systems, including therian
mammals, Drosophila, and C. elegans. Because of the presence
of dosage compensation in these animal models, and the fact that
gene expression levels are often under selection (Hebbert 1984;
Khaitovich et al. 2006), it has largely become dogma that dosage
compensation is essential and universal to avoid the detrimental effects of unequal levels of gene expression caused by sex
chromosome divergence (Griffin et al. 2008; Pierce 2008; Naurin
et al. 2010).
The universality of sex chromosome dosage compensation
has informed other aspects of evolutionary genetics, most notably sex chromosome evolution. Additionally, sex chromosome
dosage compensation can be used to understand the fitness costs
of hypo- and hyper-expression, an important step in determining
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the relationship between the genome and the organism it encodes.
Studying differences in gene expression between males and females is also increasingly useful for evolutionary examinations
of intralocus sexual antagonism (Innocenti and Morrow 2010;
Wyman et al 2009; Mank and Ellegren 2009c), and therefore understanding selection on sex-specific gene expression patterns is
key to correctly using these data to test evolutionary theory.
As we discuss below, sex chromosome dosage compensation
also illustrates how selection in one sex for altered transcription
rates can negatively affect the transcription rates of the other sex,
and therefore can be studied in the context of intralocus sexual
antagonism. Although traditional models of intralocus sexual conflict result in different gene expression levels between the sexes,
sexually antagonistic selection for sex chromosome dosage compensation is unusual in that the end result is balanced gene expression levels between males and females. Hence, there is clearly
a link between the evolutionary dynamics of sex chromosomes
and their gene expression patterns with sexual conflict, but the
implication of sexual conflict for dosage compensation remains
largely unexplored.
The spread of microarrays and next-generation sequencing of
RNA has made tenable studies of sex chromosome dosage compensation well outside the traditional model organisms, and the
results have challenged the dogma of universal sex chromosome
dosage compensation. Although some nonmodel organisms, such
as Anopheles (Hahn and Lanzaro 2005), show evidence of a nearly
complete mechanism of sex chromosome dosage compensation,
many other animals do not, including birds (Itoh et al. 2007;
Ellegren et al. 2007), stickleback fish (Leder et al. 2010),
monotremes (Deakin et al 2008), and lepidoptera (Arunkumar
et al. 2009; Zha et al. 2009), although see Walters and Hardcastle
(in press).
In addition to this new data, reevaluation of model systems
that were thought to exhibit universal sex chromosome dosage
compensation has demonstrated that a significant proportion of
the sex chromosomes are not dosage compensated. For example,
in humans about 15% of X-linked genes escape random-X inactivation (Carrel and Willard 2005), as do many noncoding RNAs
(Renius et al. 2010). More importantly, recent evidence suggests
that random-X inactivation, originally thought to be a mechanism
of dosage compensation (Nguyen and Disteche 2006), does not
achieve dosage compensation in eutherian mammals, rather it extends the problem of reduced gene dose to females (Gupta et al
2006; Xiong et al. 2010). In fact differences in gene dosage can
be important in sex determination (Smith et al. 2009a) and lack of
dosage compensation can potentially facilitate sex-specific evolution and defuse intralocus sexual conflict (Bonduriansky and
Chenoweth 2009). In this review, we address some assumptions
that are unsupported to dispel several myths about dosage compensation, ask why dosage compensation exists in some taxa and
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not others, and then discuss potential reasons for variation in the
proportion of genes that are compensated. In particular, we discuss the potential role of sexual conflict in the evolution of dosage
compensation mechanisms.
Before we begin, it is worth defining precisely what is
meant by sex chromosome dosage compensation. Sex chromosome dosage compensation is a mechanism, acting in
the heterogametic sex, to increase transcription of the single X or Z chromosome to that level expected from a
diploid complement. Empirical tests of dosage compensation often assess the gene expression differences for X- or
Z-linked genes between the sexes, with dosage compensation concluded when male/female levels are near one. Although one consequence of sex chromosome dosage compensation mechanisms
in some species is that transcription rates for X- and Z-linked
genes are equalized between males and females, this is not actually the selective cause of dosage compensation, but rather simply
a consequence of it, and balanced transcription rates in males and
females for X- or Z-linked genes is, by itself, not sufficient to
demonstrate the presence of dosage compensation. Because sex
chromosome dosage compensation results from the need to balance transcription between X- or Z-linked genes and autosomal
loci in the heterogametic sex (Mank 2009), the most important
test for sex chromosome dosage compensation is whether the
X:A or Z:A transcriptional ratio = 1 (Fig. 1) in the heterogametic
sex. This X:A and Z:A balance is important for gene networks
and pathways that encompass both sex-linked and autosomal loci,
as the functional interactions between sex-linked and autosomal
genes are different between uncompensated heterogametic individuals and the homogametic sex. Although this distinction is
subtle, it has important implications for organisms that actually do
have sex chromosome dosage compensation (discussed below).
Dosage compensation can be achieved most simply via a
specific mechanism to hyper-express the single sex chromosome
in the heterogametic sex (Fig. 1), such as the mechanism seen
in Drosophila. However, selection for hyper-transcription in the
heterogametic sex can result in overexpression in the homogametic sex, which then results in selection in this sex to downregulate transcription rates from the sex chromosomes (Charlesworth
1978).
Myth No. 1: Dosage Compensation
For Gene Expression Will
Accompany Sex Chromosome
Evolution
As the X and Y chromosomes gradually diverge from one another, the gene content of the Y chromosome degrades, leaving
males with just one functional copy of many X-linked genes.
The single copy results in a more limited transcriptional target
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Figure 1.
(A) In male heterogametic organisms, heteromorphic sex chromosomes produce a X:A ratio < 1 in males, who only have one
copy of X-linked genes for every autosomal loci. This can be fixed via the evolution of dosage compensative mechanisms that increase
transcription from the single male X chromosome. (B) In female heterogametic organisms, the single copy of the Z chromosome in females
produces a Z:A ratio < 1 in this sex. This can be corrected via the hyper-transcription of Z-linked genes in females.
for gene expression machinery, and a reduction in the overall
X:A ratio in males. For female-heterogametic lineages, a similar
process of W chromosome degeneration produces a lower Z:A
ratio in females.
Sex chromosomes in many animals are large, and harbor
a significant portion of the coding content of the genome. In
Drosophila melanogaster, the X is home to more than 15% of
the total coding loci, and the Caenorhabditis elegans X holds
nearly 14% of the genomic tally of coding genes. Vertebrates
have somewhat smaller sex chromosomes, but their contribution
is still significant, with the human X and chicken Z both harboring
around 5% of all coding genes (www.ensembl.org).
Although the process is gradual, the degeneration of the Y
or W coding content would be expected to be deleterious to the
heterogametic sex due to the reduced expression of many genes
on the X or Z chromosome. Genes with critical dosage sensitivity
would need to be compensated in the heterogametic sex, and this
compensation mechanism would theoretically eventually spread
to the entire sex chromosome. In line with this model, early findings from model animals revealed complex chromosome-wide
regulatory machinery counteracting the problems associated with
sex chromosome divergence. This topic has been the subject of
several recent reviews (e.g., see Straub and Becker 2007), so
we will not go into great detail about the regulatory mechanics
of sex chromosome dosage compensation. Briefly, Drosophila
males achieve X:A parity by hyper-transcribing their single X
chromosome (Lucchesi 1973). The mechanism does not affect
expression in females, although chromatin-structure on the X has
been altered for this process and that can affect females (Zhang and
Oliver 2009). The mechanics of sex chromosome dosage compensation is more complex in C. elegans, where the X chromosome
is hyper-transcribed in both sexes during development (Xiong
et al. 2010), resulting in balanced X:A ratio in males and X:A > 1
in hermaphrodites. Over-transcription in hermaphrodites is then
countered by a secondary sex-specific compensatory mechanism
(Ercan et al. 2007; McDonel et al. 2006), returning hermaphrodite
expression of X-linked genes to the ancestral, diploid level.
Strangely, hyper-transcription abates in adult C. elegans, resulting in X:A < 1 in both males and hermaphrodites (Xiong et al.
2010). The mechanism of compensation is not understood in the
mosquito, Anopheles gambiae, however the X is neither hypertranscribed in males nor hypo-transcribed in females, indicating
some compensatory regulation takes place (Hahn and Lanzaro
2005). Eutherian mammals also show sex chromosome gene regulation. However not all elements of X chromosome regulation in
eutherians may be related to dosage compensation, and therefore
we will address the mechanism and consequences later. The regulatory machineries that affect the Drosophila and C. elegans X
chromosomes act across the entire chromosome at once, and are
remarkably, almost awe-inspiringly, complex.
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The discovery of these regulatory mechanisms affecting entire sex chromosomes confirmed Ohno’s predictions (1967) and
led to the development of a long-standing dogma in molecular
and evolutionary genetics stating that complicated compensation
methods to correct for gene dose across the entire sex chromosome
accompanies sex chromosome differentiation (Straub and Becker
2007). It was accepted that sex chromosome dosage compensation is required for successful development (Payer and Lee, 2008),
as the imbalance in gene dosage between the sex chromosomes
and the autosomes would be potentially fatal in the heterogametic
sex (Deng and Disteche 2007). The genes affected by sex chromosome divergence were all linked, and this was a hypothesis
put forward to explain why dosage compensation mechanisms
regulated the entire sex chromosome together, rather than more
common mechanisms in the rest of the genome of localized regulatory control, where nearby enhancers direct the expression of
individual genes (Larsson and Meller 2006).
Because sex chromosome dosage compensation was concluded to be a required companion of sex chromosome divergence, it was assumed that it would be present in all organisms
with highly dimorphic sex chromosomes. This is why there was
such a surprise when global gene expression studies in the zebra
finch and chicken (Itoh et al. 2007; Ellegren et al. 2007; Itoh
Table 1.
et al. 2010) showed that there was no global mechanism to balance avian Z chromosome gene dose. This was quickly followed
by genome-wide data for the silkworm (Zha et al., 2009; Arunkumar et al. 2009) indicating that the lepidopteran Z is also not
dosage compensated. Studies in the platypus (Deakin et al. 2008;
2009) indicate incomplete X chromosome dosage compensation
in the monotremes, and data from stickleback fish show that the
X is expressed more in females than males (Leder et al. 2010),
consistent with a lack of sex chromosome dosage compensation.
Following this, a recent reappraisal of model organisms
(Xiong et al. 2010) indicates that dosage compensation is present
in Drosophila, is developmentally transient in C. elegans, and is
not present in therian mammals (discussed in more detail below).
Combining the new data from model and nonmodel organisms
suggests that chromosome-wide dosage compensation is actually
rather rare in animals, and is present in the truest sense only in
Drosophila and possibly Anopheles (Table 1).
These examples clearly indicate that dosage compensation
of the entire X or Z chromosome is not required for sex chromosome evolution. In retrospect, there were hints that complete
sex chromosome dosage compensation might not be a requirement for life. At the phenotypic level, the difference in expression in females and males for Z-linked genes that affect plumage
The current status of dosage compensation in animals.
Clade or species
Type of sex
chromosomes
Dosage compensation
Results
Most recent citation
Drosophila
XY
Yes
Xiong et al. (2010)
Therian mammals
XY
No
C. elegans
XO
Partial, during
development
Anopheles
XY
Birds
ZW
Probably, but must be
confirmed with
next-generation data
Partial, gene-by-gene
Xmale = Xfemale
Xmale = Autosomes
Xmale = Xfemale
Xmale < Autosomes
Xfemale < Autosomes
During development:
Xmale = Xfemale
Xmale = Autosomes Adults:
Xmale = Xfemale
Xmale < Autosome
Xfemale < Autosomes
Xmale = Xfemale
Xmale = Autosomes
Itoh et al. (2007)
Lepidoptera
ZW
Partial, gene by gene
Sticklebacks
Platypus
XY
XY
Absent or partial
Partial, gene-by gene
Zmale > Zfemale
Zfemale < autosomes
Zmale > Zfemale
Zfemale < autosomes
Xmale < Xfemale
Xmale < Xfemale
Tribolium
XY
In males, not females
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Xmale < Xfemale
Xmale = autosomes
Xfemale > autosomes
Xiong et al. (2010)
Xiong et al. (2010)
Hahn and Lanzarro
(2005)
Zha et al. (2009)
Leder et al. (2010)
Deakin et al. (2008,
2009)
Prince et al. (2010)
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has been known for more than a century by poultry fanciers
(Spillman 1908; Punnett 1923), although at the genetic level,
a lack of dosage compensation for some genes was reported as
far back as the 1950s, with similar reports trickling into the literature since then (e.g., Stehr 1959; Cock 1964; Johnson and Turner
1979; Hebbert 1984).
Furthermore, many animal clades show incredible turnover
of the sex chromosomes. This process, whereby ancestral sex
chromosomes are replaced by new proto-sex chromosomes
carrying nascent sex-determining mechanisms, results in heteromorphic nonhomologous sex chromosomes in closely related lineages. The best known examples are in fish, including the sticklebacks (Peichel et al., 2004; Ross et al., 2009; Shapiro et al., 2009),
salmon (Woram et al., 2003; 2004), and ricefish (Matsuda et al.,
2002; 2003; Takehana et al., 2007; 2008; Tanaka et al., 2007), although there are also examples in reptiles (Ezaz et al., 2005, 2009),
and insects (Bachtrog 2004; Carvalho and Clark 2005). Many
more examples are probably only waiting to be identified. Global
mechanisms to balance gene dose are extraordinarily complex,
and the requirement of a similar and independent mechanism for
all sex chromosome systems presents a substantial evolutionary
barrier to sex chromosome evolution. Yet we know that nonhomologous sex chromosomes occur in countless lineages, and it is
difficult to see how sex chromosomes could arise, decay, and be
replaced rapidly if chromosome-wide dosage compensation was
obligatory. Although we do not know how often the origin of new
sex chromosomes is accompanied by dosage compensation, we
already know that it is not an absolute relationship, adding further
weight to the conclusion that total dosage compensation is not
compulsory.
Myth No. 2: Regulating the Gene
Expression of An Entire Sex
Chromosome is Simpler Than
Regulating Specific Genes
One of the reasons for myth that global dosage compensation was
necessary for sex chromosome evolution was the assumption that
halving gene copy number resulted in halved gene expression.
Additionally, genes do not do their work in isolation, but rather
together in networks (Falconer 1981; Carroll 2000; Oliver 2007),
and the reduced gene expression of X- or Z-linked genes was
expected to perturb all the other interacting genes throughout the
genome. The relative expression of interacting genes is important
for phenotypes and fitness (e.g., Smith et al., 2009b), therefore
because the reduction in transcription from X-linked genes might
disrupt gene networks in the heterogametic sex, large deletions or
rapid loss of Y chromosome homologs were thought to cause total
network collapse in the absence of compensation mechanisms.
All of this was incorporated into the model that chromosomewide regulatory machinery was needed for sex chromosome
compensation. These chromosome-level regulatory mechanisms
are complex, which implied that selection for sex chromosome
dosage compensation must be very strong during sex chromosome
evolution—how else could such complicated apparati evolve?
There are several lines of evidence contradicting these assumptions. To understand the transcriptional and phenotypic consequences of halving gene dose in the heterogametic sex, we can
look to studies of autosomal monosomy, which is functionally
equivalent (Birchler et al. 2005). Although studies indicate that
monosomy is often deleterious in large blocks (Dallapiccola et
al. 1978), there are reasons to think that the uncompensated X
chromosome itself is not largely deleterious for most genes. This
is because those complex gene networks actually buffer gene
dose, as studies of monosomy indicate that regulatory buffering
reduces the expression-level effect for many genes undergoing a
1
-fold reduction in gene dose (Vietia et al. 2008; McAnally and
2
Yampolsky 2010; Stenberg et al. 2009). For those genes that do
show expression reductions associated with gene dose reduction,
many will fall under the Kascer–Burns model of dominance for
enzymatic and metabolic genes (Kascer and Burns 1981). This
model suggests that 12 -fold reduction in protein titers will not
greatly affect functionality, and therefore the phenotypic effects
would be negligible. However, it should be noted that we do not
know at this point what percentage of genes are described by the
Kascer–Burns model.
Studies of gene expression patterns from sex chromosomes
systems lacking complete dosage compensation show many similar patterns to autosomal monosomy. Consistent with reports that
gene expression is not necessarily an additive trait (Auger et al.
2005), studies of dosage compensation in birds indicate that 12 -fold
reduction in gene dose in the heterogametic sex does not result in
halved gene expression. Rather, when averaged across all genes
on the Z, the single dose in females results in a 0.7- to 0.8-fold
decrease in gene expression (Itoh et al. 2007), but within these
numbers is a complex pattern of different regulatory machineries.
Some genes on the avian Z chromosome are equally transcribed
in the sexes (Itoh et al. 2007; Mank and Ellegren 2009a), and this
is primarily due to increased transcription in females (Mank et al.
2008). Hyper-transcription of Z-linked loci in females varies by
tissue and ontogenetically (Mank and Ellegren 2009a; Itoh et al.
2010), and it appears that the genes on the Z chromosome are locally dosage compensated when and where balanced transcription
is needed in the heterogametic sex.
This local pattern of hyper-transcription represents a much
simpler method to balance gene dose for those genes that
have critical expression titers (Mank 2009). Sex-specific gene
regulation affects large proportions of autosomal genes in animals (Ranz et al. 2003; Reinke et al. 2004; Cutter and Ward
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2005; Reinius et al. 2008; Mank et al. 2010), and because this
mechanism was in place before the evolution of any specific set
of sex chromosomes and is clearly effective at regulating dosagesensitive genes on the sex chromosomes of some animals, it raises
the question as to why complex chromosome-wide mechanisms
evolved in some organisms at all.
Put another way, female birds simply increase transcription
for those genes that require dosage compensation, and do not seem
to suffer any cost due to the unbalanced expression of other genes.
Although the fitness consequences of incomplete dosage compensation need to be confirmed empirically, it nevertheless suggests
that we may have been asking the wrong questions. Instead of
asking why birds, therian mammals, monotremes, sticklebacks,
and lepidopterans lack complete sex chromosome dosage compensation, we should be asking why this complex and seemingly
unnecessary adaptation exists in flies, developing nematodes, and
mosquitoes.
Additionally, the gradual process of Y and W chromosome
degeneration cannot have an immediate and strongly deleterious effect on the heterogametic sex. If it did individuals bearing
strongly deleterious deletions or disintegrations on the Y and
W chromosomes would be removed from the gene pool, arresting the process of sex chromosome divergence and presenting
a significant barrier to the origin of any heteromorphic pair of
sex chromosomes. The fact that the Y and W do slowly degenerate suggests that the process is at most mildly deleterious to
the heterogametic sex. Therefore, selection for dosage compensation cannot be terribly strong, as the uncompensated phenotypes
are not at a large disadvantage. This leads to the question of how
complex chromosome-wide mechanisms of dosage compensation
arise if they are not the focus of strong selection.
Myth No. 3: Most Sex-Specific
Regulation of The Sex
Chromosomes is a Product Of
Selection for Dosage Compensation
Dosage compensation has become an umbrella term, and is applied to aspects of sex chromosome gene regulation that may not
have anything to do with the need to balance the transcription
in the heterogametic sex. Additionally, a great deal of confusion
exists about what exactly dosage compensation achieves. Simply
put, sex chromosome dosage compensation is the result of the
need to balance transcription between the sex chromosomes and
the autosomes in the heterogametic sex (Ohno 1967). This results
in a Z:A or X:A ratio of 1 in the heterogametic sex. The confusion
exists because compensation of the X or Z chromosome in the
heterogametic sex also has the side-effect of balancing X or Z
chromosome transcription between males and females. However,
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balanced transcription between males and females alone does
not constitute dosage compensation, and, in some cases, can run
counter to it.
Applying this precise definition, some sex chromosome regulatory mechanisms that were classified as dosage compensating
possibly are not. The best example of this is the pattern of X
chromosome inactivation in therian mammals. In marsupial and
placental mammals, one X chromosome is inactivated in females
(X chromosome inactivation, or XCI). In marsupials, the paternal X is always inactivated (Sharman 1971). In placentals, the
process is somewhat more baroque, with the initial paternal XCI
reversed at the blastocyst stage and replaced with random XCI
(reviewed in Payer and Lee 2008), resulting in females that are
chimeric for the functional X chromosome. This process extends
the problems of hemizygosity and X:A imbalance, confined to
males in all other XY animals, to females (Oliver 2007). Results
and interpretation conflict among studies, with some reports that
the single X chromosome is upregulated in both sexes to achieve
X:A parity (Nguyen and Disteche 2006; Lin et al. 2007), and other
reports that X chromosome inactivation in females results in an
X:A ratio < 1 in both sexes (Gupta et al. 2006; Xiong et al. 2010).
Interestingly, the locus-specific hyper-transcription patterns bear
some resemblance to the gene-by-gene hyper-transcription seen
on the female Z chromosome (Deng et al. 2009). XCI in Eutheria
therefore may not balance X:A ratios in males so much as drag
females away from a balanced X:A. Despite this, eutherian XCI
is typically described as fulfilling the needs of sex chromosome
dosage compensation because it balances transcription for most
genes on the X between males and females.
Similarly, sexual dimorphism in gene expression on the sex
chromosomes can be confused with dosage compensation if precise definitions are not used. For example, there is a region of
the chicken Z chromosome that is hyper-methylated in males
(Male Hypermethylated Region, or MHM), and therefore expressed more in females despite the fact that female birds have
only one copy of the Z (Melamed and Arnold 2007). Although
there is a sex-specific mechanism to regulate gene expression in
MHM of the chicken Z chromosome, this is not strictly speaking a dosage compensation mechanism because the Z:A ratio of
the MHM is < 1 in females and << 1 in males (Mank and
Ellegren 2009b). This ratio reflects the fact that the MHM is not
hyper-transcribed in females, but is instead hypo-transcribed in
males. Therefore it does not balance gene dose between the Z and
autosomes in females, but rather represents some other form of
sex-specific gene regulation.
Because it is clear that sex chromosome dosage compensation is not required for life, we cannot assume that all sex-specific
gene regulation of sex chromosomes achieves dosage compensation. This is increasingly important with the recent trend of
using sex-biased gene expression to test sexual conflict theory
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(Mank and Ellegren 2009c; Wyman et al. 2009; Innocenti Morrow 2010), a topic we address in more detail later.
Myth No. 4. The Need for Dosage
Compensation Will Prevent Sex
Chromosome Turnover
The final myth that we address is that sex chromosome turnover,
where ancestral sex chromosomes are replaced by new nonhomologous ones, will be retarded by the need for dosage compensation.
This makes intuitive sense under the old paradigm: if sex chromosome dosage compensation is an absolute requirement, then
turnover of sex chromosomes would be impeded by the need
for complex (and rare) chromosome-wide regulatory machinery.
As we have mentioned above, in many clades, sex chromosome
turnover is rapid, and therefore the need for complex dosage compensating mechanisms is clearly no hindrance to sex chromosome
evolution.
Perhaps however the presence of sex-chromosome regulatory machinery in some instances can explain why some clades
exhibit strong conservation of sex chromosomes and others undergo rapid turnover. It has been argued that dosage compensation
mechanisms can retard the invasion of new sex chromosomes as
the heterogametic sex with a newly arisen Y (or W) chromosome
would now have two upregulated ancestral X or Z chromosomes
(van Doorn and Kirkpatrick 2007, Fig. 2).
Closer examination suggests that although this may explain
some of the data, there are some examples that contradict the
Figure 2.
How the invasion of a new male-determining factor
may be retarded by chromosome-wide dosage compensation. In
the ancestral state, the single male X is upregulated, and as a
result, the single male X is expressed at twice that of each female
X (upper panel). However, as a new male-determining factor (the
star in the lower panel) arises on the neo-Y, males can now carry
two (ancestral) X chromosomes that are upregulated. Any cost
associated with this double upregulation will select against the
new male-determining factor and, hence, will select against sexchromosome turnover.
prediction. For example, although the X is largely conserved in
Drosophila (Drosophila 12 Genomes Consortium 2007) and therian mammals (Veyrunes et al. 2008), both of which regulate their
entire respective X chromosomes, the extreme conservation of
the avian Z (Shetty et al. 1999) is clearly not explained by a
sex chromosome regulatory mechanism. More data are needed to
determine general trends of this prediction.
Toward A New Synthesis
Studies of sex chromosome dosage compensation can illuminate the fundamental connection between genes and phenotypes.
More important for an evolutionary biologist, correctly classifying dosage compensation versus more generalized sex-specific
gene regulation is needed to understand the relationship between
sex-specific selection, sex-biased gene expression, and sexually
dimorphic phenotypes. This is especially imperative for the sex
chromosomes, as the X and Z chromosomes are predicted to play
a disproportionately large role in the evolution of sexually dimorphic phenotypes (Rice 1984; 1996), through mechanisms that
include the evolution of sex-biased gene expression. Is it possible
that in ZW taxa, where the sex-determination system is predicted
to favor the evolution of exaggerated male ornaments through female choice (e.g., birds and butterflies: Reeve and Pfennig 2003;
Kirkpatrick and Hall 2004; Albert and Otto 2005), incomplete
dosage compensation has enabled differential gene expression in
males and females of other Z-linked loci important in sexual dimorphism to occur? To date, there are no data available linking
gene expression levels of such sexually selected traits in butterflies
and birds to examine this possibility.
Much sex-biased gene expression is thought to result from
sexually antagonistic selection for fitness optima (Connallon and
Knowles 2005; Bondurianky and Chenoweth 2009), and sexual
conflict is expected to play out in an unusual way on the sex chromosomes (Rice 1984). For example in XY systems, dominant
female benefit alleles are expected to accumulate on the X as the
X has a longer residence time in females. Male benefit recessive
alleles will also accumulate on the X as these genes will always be
expressed in the hemizygous male, but will only be expressed in
homozygous females (Rice 1984). Furthermore, selection could
favor the movement of male-specific alleles that originally accumulate on the Y to the X because the Y is degenerate (Rice 1996;
Gibson et al. 2002). In Drosophila, there is also evidence of extensive gene traffic on the Y chromosome to and from the autosomes,
with more Y chromosome gene gains from the autosomes than
gene losses (Carvalho et al. 2009). Thus there are good reasons to
predict an association between sexually selected phenotypes and
the sex chromosomes (assuming no X chromosome inactivation
in females). There is also phenotypic and gene expression data
consistent with this. For example, the X-chromosome has been
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shown to harbor almost all the genome-wide ontogenetic sexually
antagonistic variation in D. melanogaster (Gibson et al. 2002),
and gene expression patterns are consistent with dominant female,
but not male, benefit alleles accumulating on the Drosophila X
(Connallon and Knowles 2005; Bachtrog et al. 2010, but see Gallach et al. 2011 and Zhang et al. 2010 for a more nuanced view).
Furthermore, the sex determination system can have profound
effects on the fixation of sexually antagonistic alleles when females choose their mates (Albert and Otto 2005). In ZW systems,
dominant male benefit alleles are predicted to fix on the Z even
if they cause some harm to females, whereas in XY systems it
should be dominant female benefit alleles that are preferentially
selected for on the X even if they cause some harm to males.
Again, these predictions are predicated on the assumption of no
Z/X inactivation.
As sex chromosome dosage compensation becomes more
complete, the predictions associating the sex chromosomes to sexual dimorphism break down as the gene expression from the X and
Z chromosome are increasingly constrained by chromosome-wide
regulatory mechanisms rather than locus-specific sex-specific selection. However, thought of from a different perspective, the
evolution of dosage compensation, and all sex-specific gene regulation, is the result of sexual conflict over optimal trait values
for males and females.
Does Conflict Explain Sex-Specific
Gene Regulation?
Sex-specific regulation of the sex chromosomes, either for dosage
compensation or other reasons, can be thought of in terms of
sex-specific selection (Engelstadter and Haig 2008; Rice 1987b).
When sex-specific selection to increase transcription and counterreduced chromosome dose in the heterogametic sex does not affect expression in the homogametic sex, dosage compensation is
not antagonistic. The hyper-transcription of the X in Drosophila
males is an example of a sex chromosome dosage compensating
mechanism that is not sexually antagonistic, as it does not affect
female expression (Vicoso and Charlesworth 2009). The same is
true of the locus-by-locus hyper-transcription of the Z in female
birds (Mank and Ellegren 2009a).
However, selection in the heterogametic sex can have sexually antagonistic consequences when the evolutionary response
in gene regulation affects the homogametic sex (Rice 1987b).
This is likely the case in C. elegans, where the initial evolution
of X chromosome hyper-transcription affected both sexes, resulting in X:A = 1 in males, but X:A > 1 in hermaphrodites. Although any negative consequences of X:A > 1 in hermaphrodites
were outweighed by the effects of an uncompensated X in
males, they were apparently sufficiently harmful to result in a
8
EVOLUTION 2011
compensatory hermaphrodite-specific regulatory apparatus that
counters the hyper-transcription, returning X:A to 1 in
hermaphrodites (Ercan et al. 2007; McDonel et al. 2006). Tribolium beetles have progressed through the first stage of the C.
elegans dosage compensation pathway, with hyper-transcription
affecting the X chromosome in both sexes, resulting in balanced
X:A ratios in males and elevated X:A in females (Prince et al.
2010). However, the female-specific countering mechanism is
not present, either because the effects of X:A > 1 in females are
not sufficiently harmful, or because the hyper-transcription mechanism is nascent and a compensatory mechanism in females has
not yet arisen.
Where the deleterious effects of incomplete dosage in the
heterogametic sex result in the upregulation of the gene in both
sexes, this will benefit the hemizygous sex (which experiences
compensation), but be detrimental to the homogametic sex (which
experiences over-compensation). However, assuming the effects
are mild in both sexes, because the allele is on a sex chromosome,
it will spread in the population even if the harm suffered by the
homogametic sex outweighs the gain to the heterogametic one
(Rice 1996; Connallon and Clark 2010), as reduced gene dose
would act in the same manner as a recessive sexually antagonistic
allele. This will proceed until the average transcription from Zand X- linked loci is greater than that from autosomal genes in both
sexes. At this point, the heterogametic sex is dosage compensated,
but the homogametic sex experiences hyper-transcription of the
majority of genes on the sex chromosomes (Charlesworth 1978).
Over time, sex-specific regulatory mutations in the homogametic
sex would develop to counter this hyper-transcription, and X:A
or Z:A balance will be restored in both sexes.
This scenario is subtly different than the traditional concept of
intralocus sexual antagonism, which extended to gene regulation,
results in greater differences between female and male expression
(Lande 1980; Rice 1984). In the case of dosage compensation,
sexually antagonistic selection ultimately results in similar gene
expression levels in both sexes for sex-linked genes, however
the rate of transcription is different, as females and males have
different copy numbers.
Even though it may have little to do with dosage compensation, it is possible mammalian XCI can be reinterpreted in light of
sexual conflict as well. If the marsupial model of paternal XCI is
the ancestral form, which seems likely as placental mammals recapitulate paternal XCI early in development before progressing
to random XCI and the paternal X remains inactivated in extraembryonic tissues (reviewed in Payer and Lee 2008), then XCI is
simply a form of genomic imprinting (Iwasa and Pomiankowski
2001). Imprinting can represent the resolution of sexual conflict
(Day and Bonduriansky 2004), and as the conflict between the
mother and father over fetal growth rates for internally gestating animals would be particularly fierce, it is possible that XCI
PERSPECTIVE
is simply genomic imprinting on a vast scale, with the epigenetic regulation affecting the entire chromosome rather than the
more traditional model of single-gene imprinting (Haig 2006;
Engelstadter and Haig 2008).
What Do We Expect If Sex-Specific
Sex Chromosome Regulation Is A
Product Of Sexual Conflict?
Dosage compensation has been assumed to be a prerequisite for
sex chromosome evolution, and in some organisms, selection for
equalizing X:A ratios in males has clearly resulted in the evolution
of dosage compensating mechanisms. However, the data in birds,
sticklebacks and Tribolium beetles unequivocally show that sex
chromosomes need not always be dosage compensated in both
sexes, and that when dosage is critical for any single sex-linked
gene, chromosome-wide regulatory mechanisms are not always
the result (see Table 1). This means that we must reinterpret sexspecific gene regulation of sex chromosomes, and incorporate
models of sexual conflict into the reanalysis. Doing so results in
several predictions:
(1) Random X-inactivation in eutherian females, and paternal X-inactivation in marsupials, is possibly not a mechanism to
achieve dosage compensation. Some reports indicate that transcription of X-linked genes is less than that from autosomes in
both sexes, and therefore X-inactivation actually takes females
further away from X:A balance and does nothing to restore it in
males (Gupta et al. 2006), although not all studies support this
(Nguyen and Disteche 2006; Lin et al. 2007). Other theoretical
explanations for X-inactivation have been presented (Iwasa and
Pomiankowski 2001; Haig 2006; Engelstadter and Haig 2008),
stemming from the parental conflict over foetal growth rates in
taxa with internal gestation, suggesting that XCI, although potentially not related to dosage compensation, may be the product of
sexual conflict.
(2) Dosage compensation of sex chromosomes is less likely
in organisms that can tolerate aneuploidy and polyploidy, as there
will be few phenotypic consequences in either sex of incomplete
gene dose. This predicts that dosage compensation will be rare
in fish and plants, both of which tolerate variation in ploidy, but
does not explain the lack of compensation in birds that suffer
embryonic lethality from variations in chromosome copy number
(Forstmeier and Ellegren 2010).
(3) Uncompensated phenotypes cannot be strongly deleterious or sex chromosomes would simply not diverge, therefore
selection for dosage compensation is relatively weak and sexlimited. This may suggest that the evolution of dosage compensation is a relatively slow process, although expression data from
the Drosophila neo-X chromosome indicate that existing dosage
compensating machineries can quickly engulf new additions to
the X chromosome (Bachtrog 2005; Steinemann and Steinemann
2007).
(4) Selection for dosage compensation results in equalized
expression levels for females and males for genes residing on the
sex chromosomes. This means that traditional theories predicting
the sex chromosomes to foster the evolution of sexual dimorphism
(Lande 1980; Rice 1984) via gene expression differences between
the sexes may not be directly applicable to systems with complete
sex chromosome dosage compensation.
(5) Unequal gene expression can resolve sexual conflict involving sexually antagonistic alleles (but see Harano et al. 2010).
Hence the lack of dosage compensation of many genes or even
whole sex chromosomes in many animals may represent one resolution to sexual conflict. In these cases, we expect the genes
involved to bear the hallmark of sexually antagonistic alleles (i.e.,
male-benefit female-detriment alleles or vice versa). This may
suggest an overall association between sexually antagonistic variation and the incidence of dosage compensation.
(6) The most informative taxa to test ideas about the adaptive nature of dosage compensation are clearly those that have
recently acquired new sex chromosomes (e.g., some fish and insects), which appear to be frequent targets of sexually antagonistic
selection. It has recently been proposed that sexually antagonistic
selection can directly favor the establishment of new sex chromosomes by acting on loci that become linked to the new sexdetermination genes (van Doorn and Kirkpatrick 2010). Alternatively, sexually antagonistic alleles accumulated only once the
establishment of the new sex chromosomes had occurred (Rice
1987a). However, it s not clear to what extent local versus complete chromosome gene dosage may either aid or perturb evolution of sexual dimorphism in gene expression in response to
sex-specific selection stemming from sexual conflict.
This review is intended to dispel current dogma about dosage
compensation and to additionally clarify some misconceptions
about precisely what dosage compensation is. By showing that
dosage compensation is not as imperative as current tenets suggest, we can now move beyond this blinkered position and turn our
attention to new research questions, including why complicated
chromosome-wide dosage compensation mechanisms evolved in
some taxa whereas in other taxa gene dosage is regulated on a
more local scale, and what precise role sexually antagonistic selection has in the evolution of dosage compensation. Furthermore,
one or two potentially thorny issues remain to be resolved. Arguably the most pressing of these is a transcription/translation
issue, because although lack of dosage compensation has been
documented at the translation level for a handful of genes, typically allozymes (e.g., Johnson and Turner 1979), for the most
part the patterns described above are transcriptional. Although
it is fully expected that genome-wide translational patterns will
EVOLUTION 2011
9
PERSPECTIVE
resemble those seen in transcription, this remains to be established, and as such it remains possible that the review to follow
this one will be able to reinstate the orthodoxy of dosage compensation. We look forward to reading about it.
ACKNOWLEDGMENTS
We thank A. Agrawal, M. Kirkpatrick, D. Punzalan, J. Walters, and A.
Wright for discussion and helpful comments on previous drafts of this
manuscript. The authors gratefully acknowledge support by NERC (DJH,
NW), BBSRC (JEM), and the ERC under the European Community’s 7th
Framework Programme (grant agreement no 260233 to JEM)
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Associate Editor: M. Wayne