X-Chromosome Dosage
Compensation
• Introduction
Xionglei He,
• Ohno’s Hypothesis of X-Chromosome Dosage
Compensation
School of Life Sciences, Sun Yat-sen University, Guangzhou, Guang-
Article Contents
• Testing Mammalian X-Chromosome Dosage
Compensation in mRNA Concentration
dong, China
Jianzhi Zhang,
Introductory article
Department of Ecology and Evolutionary Biology, University of
Michigan, Ann Arbor, Michigan, USA
• Testing Mammalian X-Chromosome Dosage
Compensation in Protein Concentration
• Dosage Compensation of X-Linked Genes
Encoding Members of Large Protein Complexes
• Testing Sex Chromosome Dosage Compensation
in Other Species
• Evolutionary Implications
Online posting date: 16th May 2016
The X and Y chromosomes of placental and marsupial mammals originated from a pair of autosomes.
Ohno hypothesised nearly 50 years ago that the
expression levels of X-linked genes should be
doubled to compensate for the degeneration
of their Y-linked homologues during sex chromosome evolution. The advent of microarray
and RNA (ribonucleic acid) sequencing technologies in the past decade prompted a series of
empirical tests of Ohno’s hypothesis. Surprisingly,
X-chromosome dosage compensation is found to
be largely absent in mammals. Studies of multiple
independently evolved sex chromosome systems
from a variety of species revealed a large variation
in sex-chromosome dosage compensation, ranging
from absence of compensation to complete compensation, although further scrutiny is required
because of the high heterogeneities in expression
data acquisition and analysis methods among
studies. The lack of sex chromosome dosage compensation in at least some lineages has important
implications for understanding gene expression
evolution and sex chromosome evolution.
Introduction
Chromosomal sex determination emerged independently in a
variety of animal and plant lineages (Bull, 1983), with two main
types. In the XY system, females are homogametic and have
eLS subject area: Evolution & Diversity of Life
How to cite:
He, Xionglei and Zhang, Jianzhi (May 2016) X-Chromosome
Dosage Compensation. In: eLS. John Wiley & Sons, Ltd:
Chichester.
DOI: 10.1002/9780470015902.a0026517
two X chromosomes, while males are heterogametic and have
one X and one Y chromosome. In the ZW system, females are
heterogametic and have one Z and one W chromosome, while
males are homogametic and have two Z chromosomes. Although
the extant X and Y (or Z and W) chromosomes of the same
species often have distinct gene content, it is generally believed
that they were originally a pair of homologous autosomes and
that they have gradually diverged through the degeneration of
genes in Y (or W) as a result of suppression of recombination
between homologous chromosomes. A critical issue during sex
chromosome evolution is that each X-linked (or Z-linked) gene
has only one allele in males (or females), while it had two alleles
before the degeneration of the Y-linked (or W-linked) allele. The
apparent success of extant species suggests the possible existence
of genetic mechanisms compensating for the chromosome-wide
halving of gene dosage on the X (or Z). This hypothesis of sex
chromosome dosage compensation has been extensively tested
in many lineages with independent origins of sex chromosomes,
including mammals, birds, fishes, insects, nematodes, plants and
so on. Because the potential dosage compensation has been most
extensively studied in the eutherian XY system, we first focus
on this system in our review of major milestones in dosage compensation research. We then summarise the findings in other sex
chromosome systems and end with a discussion on evolutionary implications and future directions. See also: Mammalian
Sex Chromosome Evolution; Evolution of the Mammalian X
Chromosome; Sex Chromosomes
Ohno’s Hypothesis of
X-Chromosome Dosage
Compensation
The human X and Y chromosome originated from a pair of autosomes ∼170 million years ago after therians (placental and marsupial mammals) diverged from monotremes (Veyrunes et al.,
2008). Evolutionary degeneration of the Y chromosome halved
the dose of nearly all X-linked genes that had been present in
two copies (Charlesworth and Charlesworth, 2000), resulting in X
eLS © 2016, John Wiley & Sons, Ltd. www.els.net
1
X-Chromosome Dosage Compensation
‘monosomy’ in males – a phenomenon that is typically fatal when
it happens to autosomes. In 1967, in his seminal book titled ‘Sex
Chromosomes and Sex-Linked Genes’, Ohno wrote, ‘During the
course of evolution, an ancestor to placental mammals must have
escaped a peril resulting from the hemizygous existence of all
the X-linked genes in the male by doubling the rate of product
output of each X-linked gene’ (Ohno, 1967). The hypothesis of
a twofold upregulation of X-linked genes was later elaborated
in a population genetic framework (Charlesworth, 1978). However, because females have two X chromosomes, if each X-lined
gene expresses twice the original level, females would have the
condition equivalent to ‘X tetrasomy’. This situation is proposed
to have been avoided by the random inactivation of one of the
two X chromosomes in females. The inactivated X chromosome
is cytogenetically known as the Barr body, first discovered by
Moore and Barr in female somatic cells (Moore and Barr, 1953)
and later suggested by Ohno to be an X chromosome (Ohno
et al., 1959) and explained by Lyon to be an inactivated X (Lyon,
1961). Thus, the postulated twofold X-upregulation accompanied by female-specific X-inactivation maintains in both sexes
the expression levels of X-linked genes to the levels prior to the
sex chromosome origination (Figure 1). By the mid-1990s, it was
thought that the primary principles and steps of the evolution of
sex chromosome dosage compensation had been well understood
(Charlesworth, 1996). See also: Ohno, Susumu; Chromosome
X: General Features
Testing Mammalian
X-Chromosome Dosage
Compensation in mRNA
Concentration
Although the female-specific X-inactivation appeared to be
firmly established, the twofold X-upregulation remained
Male
Expression level
Female
Proto-X
Proto-X
Proto-X
Proto-X
Y degeneration
X
Y
X
X
Twofold upregulation (Ohno’s hypothesis)
X
Y
X
X
Female X inactivation
X
Y
X
X
Figure 1 The prevailing evolutionary model of mammalian X-chromosome
dosage compensation that has recently been tested and challenged. Each
arrowhead represents the expression of one allele, with the height of the
arrowhead indicating the expression level of the allele.
2
speculative. In principle, the latter should be tested by comparing the expression levels of the genes on the present-day
mammalian X chromosome with those of the orthologous genes
on the mammalian ancestor’s proto-X (denoted by X), the autosomal progenitor of X. An observation of the gene expression ratio
of 1 between the single active X in human and the two proto-X
chromosomes, or X : XX = 1, would prove this hypothesis. This
test, however, cannot be conducted due to the unavailability of
X, which was present ∼170 million years ago.
In 1997, Adler et al. reported that the chloride channel gene
clcn4-2, which is X-linked in most placental mammals including
human, cow, dog, rat and the wild mouse Mus spretus, had been
relocated to an autosome in the laboratory mouse Mus musculus
(Adler et al., 1997). Expression analysis in the F1 offspring
of a cross between M. spretus and M. musculus showed that
each X-linked M. spretus clcn4-2 allele is twice as active as
each autosomal M. musculus clcn4-2 allele (Adler et al., 1997).
Although this finding was interpreted as evidence for Ohno’s
X-upregulation hypothesis (Adler et al., 1997), it is actually
autosome-downregulation, because the gene migrated from X to
an autosome, and is unrelated to the origin of sex chromosomes
from autosomes, which Ohno’s hypothesis is all about.
In 2006, two groups attempted to test Ohno’s hypothesis using
microarray measures of genome-wide gene expression levels in
humans and mice (Gupta et al., 2006; Nguyen and Disteche,
2006). Because the expression levels of genes on the proto-X
are unknown, these authors used human or mouse autosomes as
proxies of the proto-X under the assumption that the proto-X was
an ordinary autosome and, therefore, can be approximated by
extant autosomes. Both groups reported no significant difference
in overall expression between X-linked genes and autosomal
genes in multiple tissues of humans and mice. Because there is
only one active X and two sets of autosomes in both sexes, this
observation suggests that a single X chromosome expresses as
much as two autosomes (i.e. the expression ratio of X : AA ∼ 1).
This is the first chromosome-wide evidence that, albeit indirect,
supports Ohno’s hypothesis.
However, there is a caveat in comparing microarray-based gene
expression levels between X-linked genes and autosomal genes.
Microarray-based expression profiling is designed primarily for
comparing expression levels of the same genes across different
conditions or tissues rather than comparing expression levels
of different genes. Direct comparisons of microarray signals
from different genes, which necessarily have different probes, are
often inappropriate due to the intrinsic between-probe variations
(Liao and Zhang, 2006). Such probe effects reduce the power
in detecting expression differences between genes. Nevertheless,
there was no other choice at the time because microarray was the
only way to measure gene expressions at the genomic scale.
In just a couple of years, next-generation DNA (deoxyribonucleic acid) sequencing was invented and applied to probing transcriptomes. In the high-throughput experiment known
as mRNA (messenger ribonucleic acid) sequencing or RNA-seq
(ribonucleic acid-sequencing), mRNAs extracted from a biological sample are reverse transcribed to cDNAs (complementary
deoxyribonucleic acids) and then sequenced. Within the same
sample, the relative expression level of a gene is measured by
the number of RNA-seq reads mapped to the gene divided by
eLS © 2016, John Wiley & Sons, Ltd. www.els.net
X-Chromosome Dosage Compensation
AA:AA
X:XX
6
log2 (human : chicken)
4
2
1
0
−1
−2
−4
Testis (M)
Liver (M)
Kidney (M)
Kidney (F)
Heart (M)
Heart (F)
Cerebellum (M)
Cerebellum (F)
Brain (M)
−6
Brain (F)
the number of sites the gene could be sequenced and mapped.
Compared with microarray that represents an analogue measure
of gene expression, RNA-seq provides a digital measure of gene
expression that has a larger dynamic range and higher sensitivity
(Wang et al., 2009). More importantly, RNA-seq-based expression levels of different genes are directly comparable. In 2010,
Xiong et al. analysed the then newly available RNA-seq gene
expression data and found that the ratio of the median expression
of X-linked genes to that of autosomal genes is close to ∼0.5 in
multiple male and female human and mouse tissues (i.e. X : AA
∼ 0.5) (Xiong et al., 2010). Because the twofold upregulation is
presumably needed for only those X-linked genes that existed in
the genome prior to the origin of X, the authors also estimated the
X : AA expression ratio in human and mouse by considering only
those genes that have orthologous genes in chicken, and found
qualitatively similar results (Xiong et al., 2010).
Soon after the publication of the above study, three groups
pointed out that there is a higher fraction of inactive genes on
X than on autosomes and that the X : AA ratio is ∼1 when inactive genes are excluded from the analysis (Deng et al., 2011;
Kharchenko et al., 2011; Lin et al., 2011). This argument reflects
a misunderstanding of Ohno’s hypothesis (He et al., 2011).
Specifically, these authors equated the twofold X-upregulation
hypothesis with equal expressions between X and autosomes. The
expression level varies by orders of magnitude among genes and
there is no expectation that genes with no functional relationships should have comparable expression levels. The expression
comparison between present-day X-linked genes and autosomal
genes (i.e. X : AA) becomes meaningful only in the framework
of sex chromosome evolution, in which the expression levels of
present-day autosomes serve as a proxy of those of X (i.e. AA =
XX). The twofold X-upregulation hypothesis is written as X : XX
∼1, which predicts X : AA ∼1 under the assumption of AA = XX.
Thus, considering only the active genes in the present-day X is a
flawed approach because the extra inactive genes on X could have
originated from the most weakly expressed genes in X as a consequence of the degeneration of the Y-linked allele. Instead, all
X-linked genes that were present in X should be included for a fair
comparison. Although X is no longer available, chicken chromosomes 1 and 4 are known to be homologous to mammalian X with
conserved synteny. By considering all human X-linked genes that
have one-to-one orthologues on chicken chromosomes 1 and 4
and the human autosomal genes that have one-to-one orthologues
on any chicken chromosome except 1 and 4, He et al. confirmed
that X : AA is approximately 0.5 (He et al., 2011).
As discussed, the X : AA ratio is an indirect test of the twofold
X-upregulation hypothesis. The ultimate test requires a direct
comparison of one-to-one orthologues on X and X (He et al.,
2011). While the expression data of X can no longer be obtained,
one may substitute X with its autosomal homologue in a close
outgroup of mammals such as birds, on the basis of the presumption that the overall expressions of an autosome, which X was,
does not change in evolution. In 2012, two groups compared
the expressions of one-to-one orthologous genes in chicken and
human (Julien et al., 2012; Lin et al., 2012), two species that
diverged ∼300 million years ago. This comparison circumvented
the problem of defining comparable gene sets. Both groups
found X : XX ∼ 0.5 and AA : AA ∼ 1, where X : XX represents
Figure 2 Comparison of expression levels of orthologous genes from
human and chicken. (A) Human X : chicken XX expression ratios for
one-to-one orthologues in six male (M) or four female (F) tissues, when the
medians of human AA : chicken AA expression ratios are normalised to 1.
The null hypothesis of X : XX = AA : AA is rejected in each tissue (P < 10−9 ,
Mann–Whitney U-test). There are 325 gene pairs for calculating X : XX and
10 171 gene pairs for calculating AA : AA. The central bold line shows the
median, the box encompasses 50% of genes, and the error bars include 90%
of genes. Reproduced with permission from Lin et al. (2012) © Proceedings
of the National Academy of Sciences of the United States of America.
human : chicken orthologous gene pairs of human X-linked
genes and AA : AA represents human : chicken orthologous
gene pairs of human autosomal genes (Figure 2). This result
provides the most direct evidence possible that the hypothesis
of chromosome-wide expression doubling of X-linked genes in
therian mammals after the degeneration of their Y counterparts
is false.
Testing Mammalian
X-Chromosome Dosage
Compensation in Protein
Concentration
Although mammalian X-chromosome dosage compensation is
not found at the mRNA level, dosage compensation could in
principle still occur at the protein level, because ultimately it is
the protein concentration that matters functionally. In addition to
analysing RNA-seq data, Xiong et al. also analysed a proteomic
dataset from mouse (Xiong et al., 2010). Because the dataset is
relatively small, the authors combined the data from multiple
tissues and reported an X : AA ratio of 0.47. More recently, Chen
and Zhang analysed a much larger proteomic dataset from 22
human tissues, including 17 non-sex-specific tissues (e.g. heart
and liver) and 5 sex-specific tissues (e.g. ovary and testis) (Chen
and Zhang, 2015). They found the X : AA ratio to be smaller
than 1 in every tissue, with the mean of these ratios among the
eLS © 2016, John Wiley & Sons, Ltd. www.els.net
3
X-Chromosome Dosage Compensation
17 non-sex-specific tissues being 0.50 and that among all 22
tissues being 0.56. Both of these mean ratios are significantly
lower than 1 but not significantly different from 0.5. By dividing
the protein concentration by the corresponding mRNA concentration for each gene, Chen and Zhang demonstrated the lack
of post-transcriptional X-chromosome dosage compensation in
humans.
Dosage Compensation of X-Linked
Genes Encoding Members of Large
Protein Complexes
Genes encoding members of large protein complexes (≥7 proteins) are known to be sensitive to dosage balance, likely because
of a strict stoichiometric requirement in protein complex assembly (Lehner, 2008; Papp et al., 2003). It was reported that human
genes encoding components of large protein complexes have a
median X : AA mRNA expression ratio of ∼1, whereas the corresponding ratio for small protein complexes (<7 proteins) is
∼0.5 (Pessia et al., 2012). This result was subsequently confirmed
in the human–chicken comparison (Lin et al., 2012). Nonetheless, these upregulated X-linked genes constitute only ∼5% of
all X-linked genes (Lin et al., 2012). Note that the mRNA level
upregulation could not be validated in the human proteomic data,
which could be due to the smaller coverage of the proteomic data,
compared with the transcriptomic data (Chen and Zhang, 2015).
Testing Sex Chromosome Dosage
Compensation in Other Species
While X-chromosome dosage compensation is apparently absent
in placental mammals, its status in other species with independently evolved sex chromosomes is less clear. Sex chromosome
dosage compensation has been examined in over a dozen lineages (Table 1), but with the exception of a few model organisms
such as Drosophila melanogaster, analysis is often less complete and conclusion less certain. The patterns are complex in
two aspects. First, about 20% of the lineages show X : AA (or
Z : AA) ∼ 1 in the heterogametic sex, suggesting complete dosage
compensation of the X- (or Z-) linked genes, while the rest 80%
show partial or no dosage compensation. Second, the XX : AA
(or ZZ : AA) ratio in the homogametic sex also varies among
lineages and sometimes differs from the ratio in the heterogametic sex, leading to male : female dosage imbalance. Notably,
these observations are made on the basis of highly heterogeneous expression data and analytical approaches in a diverse set
of studies. It would not be surprising if some of these results
are biased by the same problems encountered in the study of
mammalian X-chromosome dosage compensation. In particular,
microarray-based gene expression data were used in many lineages showing X : AA ∼ 1. In addition, the quality of genome
annotation and the number of X- (or Z-) linked genes under examination can affect the estimation substantially. For instance, only
∼200 X-linked genes were suitable in the analysis of an opossum dataset, and the median expression ratio between opossum
4
X and chicken XX is close to 0.8 in some tissues. This has led to
the suggestion of a general X-upregulation in marsupials (Julien
et al., 2012). Because the upregulation hypothesis is most meaningful to active genes on X, Lin et al. considered only genes that
are active in chicken tissues and revealed an X : XX ratio close to
0.5 in all male tissues except the brain (Lin et al., 2012). Thus, a
systematic analysis with unbiased analytical approaches and reliable expression data is required to make a firm inference about
sex chromosome dosage compensation in these lineages.
Evolutionary Implications
Although Ohno’s dosage compensation hypothesis was proposed
and has been studied and discussed in the context of sex chromosome evolution, it has broader relevance. Dosage compensation is
actually about how a twofold change in gene/protein expression
level affects fitness. If this amount of expression change alters
fitness appreciably, evolutionary emergence of dosage compensation is expected; otherwise, dosage compensation is unlikely to
occur. A couple of pieces of evidence suggest that, for most genes,
a twofold expression change is likely to be nearly neutral. First,
laboratory yeast experiments showed that ∼97% of genes are haplosufficient (Deutschbauer et al., 2005), which means that the loss
of one allele of a gene in a diploid cell has a minimal fitness
consequence. Second, 65% of autosomal one-to-one orthologues
between human and chicken have a more than twofold expression
difference in kidney; the corresponding number is 41% between
two individuals of the same species (Lin et al., 2012). Because
these genes are subject to neither hemizygosity nor gene duplication, the most likely explanation is that, for most genes, a twofold
expression change has no appreciable fitness impact. Because X(or Z-) linked genes became hemizygous individually during evolution as a result of the stepwise decay of the Y (or W) chromosome, dosage compensation, even if it is required, is unlikely to be
realised by a chromosome-wide upregulation mechanism. Thus,
for the small fraction of genes that are dosage-sensitive, we may
expect different dosage compensation mechanisms for different
genes. For example, a dosage-sensitive gene may retain a functional copy on the Y (or W) chromosome. In fact, a few X-linked
housekeeping genes are known to have their functionally equivalent homologues retained in the non-recombining region of the
Y chromosome in mammals (Lahn et al., 2001). Alternatively, a
dosage-sensitive gene may be relocated from the X (or Z) chromosome to an autosome, be subject to twofold upregulation, or
have their interacting partners downregulated. The analysis in
humans and related mammals revealed that only a tiny fraction of
X-linked genes evolved upregulation (Lin et al., 2012). Whether
this is also true in most other lineages that independently evolved
sex chromosomes requires further studies. If sex-chromosome
dosage compensation indeed varies among lineages, it would be
interesting to understand its proximate and ultimate causes. See
also: Haploinsufficiency
As mentioned, the current understanding of why one of the
two X chromosomes is inactivated in female mammals is based
on Ohno’s hypothesis of twofold X-upregulation. If the twofold
upregulation never happened, as the expression data have now
shown, what was the reason behind the X-inactivation? Is it a
eLS © 2016, John Wiley & Sons, Ltd. www.els.net
X-Chromosome Dosage Compensation
Table 1 Gene expression ratios between sex chromosomes and autosomes across evolutionary lineages
Species or clade
X♂ : AA♂ or XX♀ : AA♀ or XX♀ : X♂ or Sex chromosome
Z♀ : AA♀
ZZ♂ : AA♂
Z♀ : ZZ♂
dosage
compensation
References
Male heterogametic species
Nematodesa
Fliesb
<1
1
<1
1
?
1
Beetle Tribolium castaneum
1
>1
>1
<1
<1
>1
<1
<1
?
Incomplete
Jaquiery et al. (2013)
<1
1
>1
Incomplete
Mank (2013)
?
?
>1
Incomplete
Gammerdinger et al. (2014)
<1
1
>1
Incomplete
Mank (2013)
<1
<1
1
Incomplete
<1
<1
1
Incomplete
?
?
?
?
>1
1
Incomplete
Complete
Julien et al. (2012) and Lin et al.
(2012)
Julien et al. (2012) and Lin et al.
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Hough et al. (2014)
Mank (2013)
<1
1
<1
Incomplete
Mank (2013)
<1
<1
1
<1
1
1
1
<1
<1
<1
1
<1
Incomplete
Incomplete
Complete
Incomplete
Mank (2013)
Mank (2013)
Smith et al. (2014)
Walters et al. (2015)
<1
1
<1
Incomplete
Shao et al. (2014)
<1
1
<1
Incomplete
Vicoso et al. (2013)
<1
1
?
Incomplete
Mank (2013), Uebbing et al.
(2013) and Wright et al. (2012)
Parasitic insect Xenos
vesparum
Pea aphid Acyrthosiphon
pisum
Stickleback Gasterosteus
aculeatus
Tilapia Oreochromis
niloticus
Platypus Ornithorhynchus
anatinus
Opossum Monodelphis
domesticac
Eutherian mammalsd
Herbs in the genus Rumexe
White campion Silene
latifolia
Female heterogametic species
Trematode Schistosoma
mansoni
Moth Plodia interpunctella
Moth Bombyx mori
Hornworm Manduca sexta
Butterflies in the genus
Heliconiusf
Tonguefish Cynoglossus
semilaevis
Rattlesnake Sistrurus
miliarius
Birdsg
a Caenorhabditis
Incomplete
Complete
Complete in males;
females show
overexpression
Incomplete
Albritton et al. (2014)
Jiang et al. (2015), Mank (2013),
Nozawa et al. (2014) and
Vicoso and Bachtrog (2015)
Mank (2013)
Mahajan and Bachtrog (2015)
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b Anopheles gambiae (Mank, 2013), Anopheles stephensi (Jiang et al., 2015), Aedes aegypti (Jiang et al., 2015), Drosophila melanogaster (Mank, 2013),
Drosophila pseudoobscura (Nozawa et al., 2014), Teleopsis dalmanni (Mank, 2013), Mayetiola destructor (Vicoso and Bachtrog, 2015), Phortica
variegata (Vicoso and Bachtrog, 2015), Glossina morsitans (Vicoso and Bachtrog, 2015), Themira minor (Vicoso and Bachtrog, 2015), Ephydra hians
(Vicoso and Bachtrog, 2015) and Liriomyza trifolii (Vicoso and Bachtrog, 2015). Dosage compensation is incomplete in D. pseudoobscura.
c Results differ quantitatively between studies.
d Homo sapiens, Pan troglodytes, Pan paniscus, Gorilla gorilla, Macaca mulatta, Pongo abelii and Mus musculus (Mank, 2013).
e Rumex hastatulus and Rumex bucephalophorus (Hough et al., 2014).
f Heliconius melpomene and Heliconius cydno (Walters et al., 2015).
g Gallus gallus (Mank, 2013; Wright et al., 2012), Charadrius alexandrinus (Mank, 2013), Taeniopygia guttata (Mank, 2013), Sylvia communis (Mank,
2013), Corvus brachyrhynchos (Mank, 2013) and Ficedula albicollis (Uebbing et al., 2013).
eLS © 2016, John Wiley & Sons, Ltd. www.els.net
5
X-Chromosome Dosage Compensation
result of selection for a male–female dosage balance? If so, why
is it that male–female dosage balance is not found in all lineages
and why would a between-sex dosage balance be beneficial if
a twofold expression difference is nearly neutral? Studies of
sex-chromosome dosage compensation in the last few years have
raised more questions than they answered. As such, this field may
prove exciting for the foreseeable future.
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6
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Lucchesi JC and Kuroda MI (2015) Dosage compensation in
Drosophila. Cold Spring Harbor Perspectives in Biology 7.
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