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Sex chromosome evolution in non-mammalian vertebrates
Manfred Schartl
Birds, reptiles, amphibia and fish have an enormous variety of
chromosomal sex determination mechanisms that apparently
do not follow any phylogenetic or taxonomic scheme. A similar
picture is now emerging at the molecular level. Most genes that
function downstream of the mammalian master sexdetermining gene, Sry, have been found in non-mammalian
vertebrates. Although the components of the machinery that
determines sex seem to be conserved, their interaction and
most importantly the initial trigger is not the same in all
vertebrates. This variety is the consequence of the extremely
dynamic process of the evolution of sex determination
mechanisms and sex chromosomes, which is prone to
create differences rather than uniformity.
Addresses
Physiologische Chemie I, Biozentrum der Universität Würzburg,
Am Hubland, 97074 Würzburg, Germany
e-mail: [email protected]
follows SD — namely, the actual development of testes or
ovaries — is called sex differentiation.)
A similar picture has emerged for the genes that translate
the chromosomal mechanism into molecular action. Sry is
a gene on the Y chromosome that triggers male development in mammals. It has been found only in placental
mammals and marsupials. However, genes that are known
or thought to act downstream of Sry in the SD cascade have
been detected in many vertebrate species. The finding
that a Dmrt1 gene (encoding Doublesex and Mab-3related transcription factor 1) is Z-linked in birds and is
also the male-sex-determining gene in a fish led to the
hypothesis that Dmrt1 is the ‘Sry gene’ of non-mammalian
vertebrates. Thus, the molecules also seemed to represent
a common and stable developmental mechanism. This
view has completely changed over the past few years, as it
has become clear that we have to contend with a wide
variety of SD mechanisms and master SD genes [1].
Current Opinion in Genetics & Development 2004, 14:634–641
This review comes from a themed issue on
Genomes and evolution
Edited by David Haig and Steve Henikoff
Available online 3rd October 2004
0959-437X/$ – see front matter
# 2004 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.gde.2004.09.005
Abbreviations
AMH
anti-Müllerian hormone
Dmrt
doublesex and Mab-3 related transcription factor
FET
female expressed transcript
HIT
histidine triad
MHM
male hypermethylated
NRY
non-combining region of the Y chromosome
SD
sex determination
WPKCI similar to protein kinase C inhibitor (W-linked)
ZPKCI
similar to protein kinase C inhibitor (Z-linked)
Introduction
Whether a mammalian embryo develops into a male or a
female is determined by its chromosomal complement:
XX embryos become females and XY embryos become
males. In birds it is the other way round: the homogametic
sex (ZZ) is the male and the heterogametic sex (WZ) is
the female. Without taking a deeper look into the field,
this observation led many researchers to think that the
chromosomal mechanism of sex determination (SD, the
process that determines whether the bipotential gonad
primordium will develop into testis or ovary) is a widespread and stable system. (Note that the process that
Current Opinion in Genetics & Development 2004, 14:634–641
This review illustrates this variety and gives an update on
some genes that are known, or believed, to play a role in
SD of non-mammalian vertebrates. And — in quoting
Dobshansky that ‘‘nothing in biology makes sense,
except in the light of evolution’’ [2] — the phylogenetic
and evolutionary context will be considered.
A concept for sex chromosome evolution
The gene at the top of the SD cascade, the ‘master sex
regulator’, can have a marked effect on genome evolution,
in particular on the very chromosome on which it is
located. On the basis of many cytogenetic observations
and theoretical considerations, a commonly accepted
model of the process of sex chromosome evolution has
been established [3].
The origin of a master SD gene is supposed to be an
autosomal gene for which two different alleles developed
and for which homozygosity leads to the development
of one sex and heterozygosity to the other. Under this
scheme, the evolution of an XY system occurs when
suppression of recombination maintains one chromosome in a constant heterozygous state and the allele on
this chromosome is dominant in determining male sex.
Suppression of recombination would be most effectively
achieved by a large inversion. Suppression of recombination is the first and crucial step in sex chromosome
evolution: only through this process can the emerging
heterogametic sex chromosome keep its identity.
During subsequent evolution, suppression of recombination between the X and Y chromosomes spreads out from
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Sex chromosome evolution in non-mammalian vertebrates Schartl 635
the SD gene and encompasses larger and larger portions
of the Y. Again, large inversions are thought to be the most
effective means for enlarging the non-recombining region
of the Y chromosome (NRY). Mutations that destroy
genes can accumulate in the NRY, and deletions, insertions, accumulations of transposable elements and expansions of repetitive sequences are the hallmarks of this
process, which has been termed ‘asexual decay’ [3]. Such
molecular changes accumulate to a threshold, at which
point they become visible on the cytological level as two
distinct changes in chromosome morphology: one is an
accumulation of heterochromatin, the other is shrinkage
owing to loss of genetic material. This explains Ohno’s
postulate [4] that the young sex chromosomes — being at
an earlier stage of the decay process — are homomorphic,
whereas the more derived, older sex chromosomes show
clearly visible, morphological differences.
Owing to asexual decay, the recombining (or pseudoautosomal) part of the Y chromosome will become smaller
and even vanish. At some point the SD gene will be the
only gene left on the Y, and at this stage it will also be the
only factor that guarantees persistence of the chromosome. Eventually the Y will be lost, and either a new Y
chromosome can emerge from an autosome or the mode
of SD may change.
There are, however, processes that can stabilize the Y
chromosome. Genes that are male-specific, for example
genes associated with spermatogenesis, can accumulate
on the Y. Sexually antagonistic genes are those that are
beneficial to one sex but harmful to the other. For example,
in species where female mate choice operates, genes
associated with colour make a male attractive (although
they are also harmful because they enhance predation), but
increase predation in females without enhancing attractiveness. The larger the number of ‘male-specific’ genes
on the Y is, the more reasons to keep it.
Suppression of recombination has a severe consequence
— namely, that mutations will accumulate in the NRY
[5]. On the one hand, this is the driving force of asexual
decay. On the other hand, the male-specific genes need to
escape from the acquisition of deleterious mutations. A
single mutation in a spermatogenesis-associated gene can
exclude the respective Y chromosome from transmission
to the next generation. If the effective population size is
small, as it is in most mammalian and many avian species,
this exclusion can become a considerable problem.
An efficient solution to how the Y-linked genes can be
kept in shape has been detected through sequencing of
the male-specific region of the human Y chromosome
[6]. Most of the genes that have a function in testis are
encoded as near identical gene pairs in inverted repeats;
thus, gene conversion can occur between the inverted
sequence pairs and will purge deleterious mutations.
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Of course, all of the above issues concerning the evolution
of the Y chromosome apply in the same way to the other
type of heterogametic sex chromosome — that is, the W
chromosome.
Sex determination in non-mammalian
vertebrates
Birds
The ratitae birds (e.g. ostrich, emu and cassowary), which
are considered to be ‘primitive’ birds, have karyologically
indistinguishable or only slightly differentiated Z and W
chromosomes, whereas all other (carinatae) birds have
generally well distinguishable sex chromosomes, in which
the W is usually small and heterochromatic. This observation seems to defy Ohno’s law [4] because the most
basal group, the ratitae, has the least differentiated sex
chromosomes even though it is evolutionarily ‘older’ than
the carinatae.
Another unexpected finding is that the Z chromosome of
chicken contains the orthologs of genes that are located
on human chromosome 9 [7,8]. This indicates that the
ZW chromosomes of birds and the XY chromosomes of
mammals have evolved from different autosomal pairs.
As yet, it is unclear whether the W chromosome carries a
dominant female-determining gene or the Z chromosome
carries a dosage-dependant male determinant, or whether
both features may apply. Definitive evidence from sex
chromosome aneuploidy (e.g. the sexual development of
ZO or ZZW birds) is lacking [9]. There are two candidate
genes on the W, whose expression patterns are consistent
with a female-determining function.
The first candidate is WPKCI (also known as HINTW or
ASW for avian, sex-specific, W-linked), which encodes a
protein with similarity to the protein kinase C inhibitor.
There are roughly 40 copies of the WPKCI gene on the W
of carinatae (but not ratitae) birds [10]. The Z carries a
single copy of this gene (ZPKCI). WPKCI is strongly
expressed in female chicken embryos, specifically in
the gonad, whereas ZPKCI is expressed at similarly low
levels in both sexes. There is a major structural difference
in the gene products of the W- and Z-encoded genes:
WPKCI lacks the histidine triad (HIT) motif, which is
essential for the protein’s function as a protein kinase C
inhibitor. The HIT motif is present in ZPCKI; thus, the Z
encodes a bona fide enzyme. Enzymes with HIT motifs
function as homodimers, which has led to the hypothesis
that WPKCI functions as a dominant-negative factor in
avian SD by inhibiting ZPKCI activity in heterodimers
[11].
The second candidate is FET1 (female-expressed transcript 1), which has no homolog on the Z chromosome.
FET1 is expressed almost exclusively in the female
urogenital system, and its expression is especially strong
Current Opinion in Genetics & Development 2004, 14:634–641
636 Genomes and evolution
in the developing gonads before differentiation. Interestingly, expression is higher in the left gonad, which in
female chicken develops to ovary as the right anlage
regresses. The predicted amino acid sequence of FET1
does not correspond to any known domain that would be
informative to infer a function and, similar to WPKCI, no
ortholog has been found outside birds [12].
The high degree of conservation of synteny between
human chromosome 9 and chicken Z immediately has
put the spotlight on Dmrt1 as a Z-linked candidate male
SD gene [7,8]. The human gene is located at the tip of
chromosome 9 (9p24.3). Haploinsufficency for this region
is connected to a male-to-female sex reversal with normal
XY chromosomes. Thus, Dmrt1 seems to be a dosagesensitive SD gene in birds. There is no copy of Dmrt1
on the W chromosome, and thus males have a double
gene dosage. Whether there is a dosage compensation
mechanism for Z-linked genes in birds as there is for
X-linked in mammals is the subject of ongoing debate.
Quantitative RT–PCR data have indicated that six
Z-linked genes are expressed at similar levels in both
males and females [13], whereas fluorescent in situ hybridization studies on nascent mRNAs have demonstrated
the transcription of five genes from both Z chromosomes
in males [14].
Regardless of whether one or two copies of Dmrt1 are
expressed in male chicken, an interesting observation
seems to indicate that Dmrt1 is downregulated in females.
Dmrt1 is located close to a region of roughly 460 kb on the
Z chromosome, termed the MHM (male hypermethylated) locus, which is hypermethylated in males starting
from day 1 of embryonic development [15]. In females,
this region is hypomethylated and the MHM locus is
transcribed into a non-coding RNA. This RNA, being
produced only in female cells, stays in the nucleus around
the MHM locus and the Dmrt1 locus [16]. Mizuno et al.
[16] have speculated that this accumulation of MHM
RNA, similar to the role of Xist RNA in X-chromosome
inactivation in female mammals, may silence the Dmrt1
gene in female chicken. Such a silencing would explain
the observed expression pattern of Dmrt1: it is expressed
exclusively in the gonad of both sexes, but is more highly
expressed in males than in females before (in the medullary cord cells, where a testis-determining gene is
expected to be expressed) and during gonadal sex differentiation [17,18]. The repression is probably only partial,
because in WZ sex-reversed chicken Dmrt1 is upregulated in the gonad, although it is expressed later and
at lower levels than in ordinary males [19].
Direct evidence to suggest a possible role for these genes,
which could come from one of three lines of investigation, is still lacking. None of the candidate genes has
been reported to generate, following gene transfer, the
expected effect of sex reversal in genetically altered
Current Opinion in Genetics & Development 2004, 14:634–641
chicken. Similarly, mutations in these genes — either
naturally occurring or artificially induced — should cause
a sex reversal and yet also have not been observed. The
second functional test would be a knock-down experiment that affects gonad development, for example, by
injecting antisense oligonucleotides or morpholinos into
chicken embryos. Such experiments have not been
reported.
Reptiles
The incubation temperature of the eggs regulates the
development of the embryonic gonad towards testis or
ovary in all crocodilians and marine turtles examined so
far, and is common in terrestrial turtles and some lizards.
In crocodiles the higher temperature is male-determining, whereas in turtles a higher temperature promotes
female development. By contrast, snakes have a firm
genetic SD of the WZ type. Some lizards are also WZ,
but others have an XY system.
The expression of the reptile homologs of several mammalian SD genes has been studied during temperaturedependent SD. In the American alligator, expression of
Sox9 (a transcription factor of HMG Box family), AMH
(anti-Müllerian hormone) and Dmrt1 is testis-specific.
Expression of Sox9 in the developing Sertoli cells of
the male gonad begins up to 10 days after the first signs
of testis differentiation are visible. Expression of AMH
starts some days earlier in the same type of cells, but again
does not precede testis formation [20]. Thus, at least
one temperature-dependent mediator of SD functions
upstream of AMH and Sox9. Notably, Sox9 upregulates
AMH expression in mammals [21]. In reptiles, however, it
looks as though the sequence of events is turned around.
Although Dmrt1 is initially expressed in both the developing ovary and the testis, expression becomes higher
in testis as development proceeds [18]. In the red-eared
slider turtle, Dmrt1 mRNA is more abundant in the
genital ridge and mesonephros complex at the maledetermining temperature [22,23]. Dmrt1 is still the only
gene that shows temperature-dependent expression
before or around the stage when sexual differentiation
starts. It is reasonable to assume that Dmrt1 has a key role
in sexual development; however, how temperature —
either directly or indirectly — regulates its expression is
unknown.
Amphibians
All amphibians that have been tested so far possess a
genetic mechanism of SD. Male or female heterogamety
has been repeatedly found in anurans and urodeles. Most
species have homomorphic sex chromosomes, but there
are also some species with heteromorphic gonosomes
[24]. The chromosomal mechanisms in action do not
apparently follow any systematic scheme. In the Japanese
frog Rana rugosa, populations with heteromorphic XY,
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Sex chromosome evolution in non-mammalian vertebrates Schartl 637
homomorphic XY and heteromorphic WZ sex chromosomes have been identified even in the same species [25].
Sex can be reverted by hormone or temperature treatment or even occurs spontaneously. Heat and cold treatment can be either masculinizing or feminizing in XY or
WZ systems, depending on the species. There is no
indication, however, that the temperature during embryo
and larval development under natural conditions has a SD
effect as it does in some reptiles [24].
Not much is known about candidate SD genes. Dmrt1 has
been studied in Rana rugosa and found to be an autosomal
gene. During development, Dmrt1 is expressed in interstitial and Sertoli cells in the testis of tadpoles just before
metamorphosis. In young tadpoles, in which the testis is
already differentiated, no expression has been found. In
adult frogs, the gene is expressed in interstitial, Sertoli
and germ cells of the testis. When XX tadpoles were
masculinized by testosterone injection, Dmrt1 expression
started in the sex-reverted gonad. The rather late expression assigns a role to Dmrt1 in testis differentiation, but
not necessarily in testis determination [26,27].
Fish
With roughly 25 000 species, fishes are by far the largest
group of vertebrates. They show the widest variety of
adaptation responses to a universe of aquatic habitats and
ecological constraints. With respect to SD, fishes also
have the most variety. Unlike the situation in higher
vertebrates, where the male and female sexes are always
represented by two different individuals (gonochorism),
several hundred species of fish are known to be hermaphrodites [28], most of them from the order Perciformes.
Either they are males first and become females subsequently (protandric), or vice versa (protogynic). The sex
change can be triggered by age, social factors or temperature. The most extreme situation known so far is found in
a single species, the cyprinodont Rivulus marmoratus,
which is a self-fertilizing simultaneous hermaphrodite.
chromosomes exist in a population. One of the best
studied species is the platyfish (Xiphophorus maculatus),
in which three types of sex chromosomes, X, W and Y,
coexist in a population. Depending on their chromosomal
complement WX, XX and WY fish become females,
whereas XY and YY fish become males. The different
‘strength’ of the X and the W in inducing female development may indicate that different genes or at least
copies of SD genes are involved, although complex
regulatory networks or dosage models for a single gene
have been also proposed to be involved in sex determination [30,31].
Most orthologs of the common set of downstream sex
determinators have been found in fish. Analysis of Sox9
and Dmrt1 in several species has shown differential
expression in testis, consistent with an important role
in SD and/or testis differentiation [32–35]. In a protandrous hermaphroditic fish, expression of Dmrt1 parallels
the development and regression of the testes [36]. So far,
there is no report of a fish gene that could be the ortholog
of the AMH hormone. If it exists, then it may have a
different function, because in fish the genital ducts are
not derived from the renal duct system, but from the
somatic cells of the gonad and/or the coelomic epithelium
[37,38].
The medaka case
The medaka is a small aquarium model fish species that is
comparable to the more widely known zebrafish. Tools
similar to those used for zebrafish have been developed to
make it a complementary system for studying developmental biological issues or for generating disease models
for biomedical research [39]. In addition, medaka is a
classical system for genetic studies of sexual development
[40]. In fact, in 1921 it was the first vertebrate to be found
to show crossing over between the sex chromosomes [41].
In several gonochoristic species, environmental factors
can influence the sex ratio even if the species has a
genetic SD system. The most prominent factor is the
incubation temperature of the embryos and larvae. It
should be noted, however, that all studies have been
performed under laboratory conditions. Only for a few
fish species can circumstantial evidence be presented that
these fish might use this mechanism for SD under natural
conditions [28,29].
Medaka has an XX–XY SD system. In independent
studies using candidate gene [42] and positional cloning
[43] approaches, a gene with high similarity to Dmrt1 was
found to be an excellent candidate for the master male SD
gene. It was shown that a region on the autosomal linkage
group 9, which contains Dmrt1, was duplicated and the
whole fragment was inserted into another chromosome.
That chromosome became the proto-Y, whereas its wildtype homolog (the progenitor chromosome without the
insertion) became the proto-X. This is in perfect agreement with Ohno’s hypothesis that sex chromosomes are
derived from a pair of autosomes [4].
The chromosomal mechanisms of SD show an amazing
variety. XY and WZ systems are most common, but there
are several examples of polygenic SD (i.e. the SD factors
are distributed over several chromosomes). In addition,
XO, ZO, X1X2Y, XY1Y2 and Y–autosome fusion have
been described [28], and systems in which multiple sex
According to the nomenclature for duplicated genes, the
autosomal copy is dmrt1a and the Y-chromosomal copy is
dmrt1bY (the suffix Y indicates its sex chromosomal
location; the gene is also called dmY by some authors).
dmrt1bY is expressed before gonad differentiation.
Naturally occurring mutations in the gene lead to
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Current Opinion in Genetics & Development 2004, 14:634–641
638 Genomes and evolution
male-to-female sex reversal. Both features are expected
for a master SD gene. Simliar to its autosomal counterpart
[44], dmrt1bY is expressed exclusively in the Sertoli cells
in adults [42,43].
In the Y-specific insertion, all co-duplicated genes except
dmrt1bY are corrupted by frameshift mutations and deletions. The region also contains an unusual high density
of transposable elements and repetitive DNA. Notably,
the male-specific region is only 260 kb, which constitutes
less than 1% of the sex chromosome [45]. It is flanked
by a direct repeat of 20 kb, which is present only once on
the X chromosome. The Y repeat is obviously a tandem
duplication generated during the process of insertion of
the fragment derived from linkage group 9. Outside the
tandem duplication, the X and the Y chromosomes are
homologous.
The age of the medaka Y chromosome has been determined by a comparative analysis of several species of the
same genus. A sister species of medaka contains a homologous Y chromosome with a male-determining dmrt1bY
gene, but other more distantly related species have only
the autosomal dmrt1 gene. Calculations based on the
timing of the divergence of Oryzias species with or without dmrt1bY and on nucleotide substitution rates have
shown that the medaka Y is about 10 million years old
[46]. This makes it the youngest vertebrate male-determining chromosome known so far. Studies on the genomic organization of the male-specific region will aid our
understanding of the initial processes that occurred during the early evolution of heterogametic sex chromosomes, which will be impossible to infer from almost
terminally differentiated and genetically highly degenerated ‘old’ sex chromosomes such as the mammalian Y.
is not known, but environmental factors are not likely to
be involved: obviously, other genes can substitute for the
function of dmrt1bY.
Because dmrt1bY originated during evolution of the genus
Oryzias, it may not be surprising that this gene has not
been found to be the master SD gene of other fish species
[48–50]. It is possible, however, that a gene duplication
event involving dmrt1 might have also occurred independently in another lineage, leading to the convergent
evolution of a SD system similar to that observed in
medaka.
Conclusions
The evolution of the gene cascade that regulates SD has
been explained to happen from the bottom to the top, and
new SD systems arise through the addition of each new
component [51]. Thus, the downstream genes should be
more highly conserved. This prediction is confirmed by
the facts that Dmrt1 is a conserved SD gene from flies
and worms [52], Sox9, WT1 and SF1 are conserved from
fish to mammals and AMH is conserved from reptiles to
mammals.
The large variety of SD mechanisms that exist even in
closely related species of lower vertebrates could suggest
that there are permanently new top SD genes emerging.
The idea that SD cascades grow constantly from the
bottom upwards immediately raises the issue of whether
this will continue ad infinitum or whether there are
mechanisms that limit the process or even trim the
cascade. Below, I put forward a hypothesis on the basis
of the situation in medaka that may provide answers and
that also underscores the importance of gene duplication
in the evolution of SD genes.
Some features of the medaka Y do not coincide with
common expectations. The medaka male-determining
gene did not arise from a stepwise allelic diversification
at one locus but from a chromosomal segment duplication
that also included other genes. The new copy (dmrt1bY)
was free from selective pressure and could acquire a new
or altered function, whereas the original copy (dmrt1a)
on linkage group 9 continued to fulfill its physiological
function. The insertion of the duplicated fragment into
another chromosome per se and ab initio excluded pairing
in meiosis. This situation was fixed by enlarging the insert
through the expansion of repetitive DNAs, the accumulation of transposable elements and the insertion of
duplicated pieces from elsewhere in the genome [42]
and not by a chromosomal inversion.
We can consider the SD cascade as a gene hierarchy in
which, at certain points, genes will be upregulated above
a threshold by their controlling gene so that they can
transmit a signal, for example, for male development
(Figure 1). If one gene becomes duplicated, the additional copy will add its basal expression to the basal levels
of the pre-existing copies. This increase in expression
might shift the amount of transcripts of this gene above
the threshold that would be normally reached only after
the upstream controller transcriptionally had activated it.
Thus, the duplicated copy will make all upstream components unnecessary and become the new ‘master SD
gene’. The upstream genes will then loose their SD
function, and — if they have no other function — will
decay and eventually will be lost completely.
The SD system of medaka seems not to be totally stable.
In several laboratory strains there is a considerable proportion of XX males (up to 20%) [47]. Their uncompromised fertility shows that dmrt1bY is not always necessary
for SD. What triggers male development in these XX fish
Mutations in regulatory regions, which could occur either
concomitantly with or after the duplication event, could
confer constitutive activity to the duplicated copy in the
cells of the primordial gonad. This would strengthen its
function as the dominant SD gene or would make it the
Current Opinion in Genetics & Development 2004, 14:634–641
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Sex chromosome evolution in non-mammalian vertebrates Schartl 639
Figure 1
A
A
A
B
B
B
C
C
C
D
D
E
E
E
E
F
F
F
F
F
(a)
( b)
(c)
(d)
(e)
D
D
X
Mutation
D
D
D′
D′
E
Current Opinion in Genetics & Development
Evolution of the sex-determining gene cascade by gene duplication. (a) A sex-determining gene cascade, in which each component transcriptionally
activates a downstream gene above a threshold so that it can activate the next downstream gene. (b) Gene duplication generates a second
copy of gene D with a basal level of gene expression. (c) The basal transcript levels of both copies of D are sufficient to activate E without the necessity
of C activating D. The upstream components of the cascade become obsolete. (d) One of the copies of D becomes mutated, D0 , so that
its expression alone is sufficient to activate E. (e) A new gene is added to the cascade and becomes the new master regulator.
Arrows indicate transcriptional activation of a downstream gene; the size of the arrow represents the degree of activation.
master SD gene in those cases where there is no basal
level of gene expression. Such an hypothesis might help
to explain how a gene that starts out at a downstream
position of the SD cascade can become the master regulator at the top, as has happened with the dmrt1bY gene
in medaka.
Acknowledgements
I thank Monika Niklaus-Ruiz for help in preparing the manuscript, and
Jean-Nicolas Volff and Indrajit Nanda for critical comments on the review.
This work was funded by the European Commission and the Deutsche
Forschungsgemeinschaft.
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