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1.  Progress and prospects toward our understanding of the evolution of dosage compensation 
Chromosome Research  2009;17(5):585-602.
In many eukaryotic organisms, gender is determined by a pair of heteromorphic sex chromosomes. Degeneration of the non-recombining Y chromosome is a general facet of sex chromosome evolution. Selective pressure to restore expression levels of X-linked genes relative to autosomes accompanies Y-chromosome degeneration, thus driving the evolution of dosage compensation mechanisms. This review focuses on evolutionary aspects of dosage compensation, in light of recent advances in comparative and functional genomics that have substantially increased our understanding of the molecular mechanisms of dosage compensation and how it evolved. We review processes involved in sex chromosome evolution, and discuss the dynamic interaction between Y degeneration and the acquisition of dosage compensation. We compare mechanisms of dosage compensation and the origin of dosage compensation genes between different taxa and comment on sex chromosomes that apparently lack compensation mechanisms. Finally, we discuss how dosage compensation systems can also influence the evolution of well-established sex chromosomes.
doi:10.1007/s10577-009-9053-y
PMCID: PMC2758192  PMID: 19626444
Dosage compensation; Sex chromosomes; Evolution; Chromatin; Epigenetics
2.  Dosage Compensation of Sex Chromosome Genes in Eukaryotes  
Acta Naturae  2010;2(4):36-43.
Sex chromosome evolution is accompanied by significant divergence in morphology and gene content and results in most genes of one of the sex chromosomes being present in two dosages in one sex and in one dosage in the other. To eliminate the difference in the expression levels of these genes between sexes and to restore equal expression levels of the genes between sex chromosomes and autosomes, mechanisms of dosage compensation have appeared. Studies of three classical objects,Drosophila melanogaster,Caenorhabditis elegans, and mammals, have shown that dosage compensation of X-linked genes can be achieved through completely different chromosome-wide mechanisms. New data on sex chromosome gene expression demonstrating that many sex chromosome genes can be expressed at different levels in males and females were recently obtained from birds and butterflies. In this review, dosage compensation mechanisms inD. melanogaster,C. elegans, and mammals are considered and the data on sex chromosome gene expression in birds and butterflies, and their influence on our view of dosage compensation, are discussed.
PMCID: PMC3347590  PMID: 22649662
dosage compensation; sex chromosomes; gene expression; X-chromosome inactivation
3.  The worm solution: a chromosome-full of condensin helps gene expression go down 
Dosage compensation in the nematode C. elegans is achieved by the binding of a condensin-like dosage compensation complex (DCC) to both X chromosomes in hermaphrodites to downregulate gene expression two-fold. Condensin IDC, a sub-part of the DCC, differs from the mitotic condensin I complex by a single subunit, strengthening the connection between dosage compensation and mitotic chromosome condensation. The DCC is targeted to X chromosomes by initial binding to a number of recruiting elements, followed by dispersal or spreading to secondary sites. While the complex is greatly enriched on the X chromosomes, many sites on autosomes also bind the complex. DCC binding does not correlate with DCC-mediated repression, suggesting that the complex acts in a chromosome-wide manner, rather than on a gene-by-gene basis. Worm dosage compensation represents an excellent model system to study how condensin-mediated changes in higher order chromatin organization affect gene expression.
doi:10.1007/s10577-009-9061-y
PMCID: PMC2992697  PMID: 19802703
4.  Dosage Compensation of the Sex Chromosomes 
Annual review of genetics  2012;46:537-560.
Differentiated sex chromosomes evolved because of suppressed recombination once sex became genetically controlled. In XX/XY and ZZ/ZW systems, the heterogametic sex became partially aneuploid after degeneration of the Y or W. Often, aneuploidy causes abnormal levels of gene expression throughout the entire genome. Dosage compensation mechanisms evolved to restore balanced expression of the genome. These mechanisms include upregulation of the heterogametic chromosome as well as repression in the homogametic sex. Remarkably, strategies for dosage compensation differ between species. In organisms where more is known about molecular mechanisms of dosage compensation, specific protein complexes containing noncoding RNAs are targeted to the X chromosome. In addition, the dosage-regulated chromosome often occupies a specific nuclear compartment. Some genes escape dosage compensation, potentially resulting in sex-specific differences in gene expression. This review focuses on dosage compensation in mammals, with comparisons to fruit flies, nematodes, and birds.
doi:10.1146/annurev-genet-110711-155454
PMCID: PMC3767307  PMID: 22974302
dosage compensation; X upregulation; X inactivation; epigenetics; evolution; sex chromosomes
5.  Balancing sex chromosome expression and satisfying the sexes 
Fly  2012;6(1):26-29.
Equalizing sex chromosome expression between the sexes when they have largely differing gene content appears to be necessary, and across species, is accomplished in a variety of ways. Even in birds, where the process is less than complete,1 a mechanism to reduce the difference in gene dose between the sexes exists. In early development, while the dosage difference is unregulated and still in flux, it is frequently exploited by sex determination mechanisms. The Drosophila female sex determination process is one clear example, determining the sexes based on X chromosome dose. Recent data show that in Drosophila, the female sex not only reads this gene balance difference, but at the same time usurps the moment. Taking advantage of the transient default state of male dosage compensation, the sex determination master-switch Sex-lethal which resides on the X, has its expression levels enhanced before it works to correct the gene imbalance.2 Intriguingly, key developmental genes which could create developmental havoc if their levels were unbalanced show more exquisite regulation,3 suggesting nature distinguishes them and ensures their expression is kept in the desirable range.
doi:10.4161/fly.18822
PMCID: PMC3365834  PMID: 22388008
dosage compensation; Drosophila; male-specific lethals; sex determination; Sex-lethal; X chromosome
6.  Genome-wide analysis of condensin binding in Caenorhabditis elegans 
Genome Biology  2013;14(10):R112.
Background
Condensins are multi-subunit protein complexes that are essential for chromosome condensation during mitosis and meiosis, and play key roles in transcription regulation during interphase. Metazoans contain two condensins, I and II, which perform different functions and localize to different chromosomal regions. Caenorhabditis elegans contains a third condensin, IDC, that is targeted to and represses transcription of the X chromosome for dosage compensation.
Results
To understand condensin binding and function, we performed ChIP-seq analysis of C. elegans condensins in mixed developmental stage embryos, which contain predominantly interphase nuclei. Condensins bind to a subset of active promoters, tRNA genes and putative enhancers. Expression analysis in kle-2-mutant larvae suggests that the primary effect of condensin II on transcription is repression. A DNA sequence motif, GCGC, is enriched at condensin II binding sites. A sequence extension of this core motif, AGGG, creates the condensin IDC motif. In addition to differences in recruitment that result in X-enrichment of condensin IDC and condensin II binding to all chromosomes, we provide evidence for a shared recruitment mechanism, as condensin IDC recruiter SDC-2 also recruits condensin II to the condensin IDC recruitment sites on the X. In addition, we found that condensin sites overlap extensively with the cohesin loader SCC-2, and that SDC-2 also recruits SCC-2 to the condensin IDC recruitment sites.
Conclusions
Our results provide the first genome-wide view of metazoan condensin II binding in interphase, define putative recruitment motifs, and illustrate shared loading mechanisms for condensin IDC and condensin II.
doi:10.1186/gb-2013-14-10-r112
PMCID: PMC3983662  PMID: 24125077
7.  Three Distinct Condensin Complexes Control C. elegans Chromosome Dynamics 
Current biology : CB  2009;19(1):9-19.
Summary
Background
Condensin complexes organize chromosome structure and facilitate chromosome segregation. Higher eukaryotes have two complexes, condensin I and condensin II, each essential for chromosome segregation. The nematode Caenorhabditis elegans was considered an exception, because it has a mitotic condensin II complex but appeared to lack mitotic condensin I. Instead, its condensin I-like complex (here called condensin IDC) dampens gene expression along hermaphrodite X chromosomes during dosage compensation.
Results
Here we report the discovery of a third condensin complex, condensin I, in C. elegans. We identify new condensin subunits and show that each complex has a conserved five-subunit composition. Condensin I differs from condensin IDC by only a single subunit. Yet condensin I binds to autosomes and X chromosomes in both sexes to promote chromosome segregation, whereas condensin IDC binds specifically to X chromosomes in hermaphrodites to regulate transcript levels. Both condensin I and II promote chromosome segregation, but associate with different chromosomal regions during mitosis and meiosis. Unexpectedly, condensin I also localizes to regions of cohesion between meiotic chromosomes before their segregation.
Conclusions
We demonstrate that condensin subunits in C. elegans form three complexes, one that functions in dosage compensation and two that function in mitosis and meiosis. These results highlight how the duplication and divergence of condensin subunits during evolution may facilitate their adaptation to specialized chromosomal roles and illustrate the versatility of condensins to function in both gene regulation and chromosome segregation.
doi:10.1016/j.cub.2008.12.006
PMCID: PMC2682549  PMID: 19119011
8.  The T-Box Transcription Factor SEA-1 Is an Autosomal Element of the X 
Developmental cell  2005;9(3):339-349.
Summary
Sex is determined in C. elegans by a chromosome-counting mechanism that tallies X chromosome dose relative to the sets of autosomes, the X:A ratio. A group of genes on X called X signal elements (XSEs) communicates X chromosome number by repressing the activity of the master sex-determination switch gene xol-1 in a dose-dependent manner. xol-1 is repressed by transcriptional and posttranscriptional mechanisms and is inactive in XX animals (hermaphrodite) but active in XO animals (male). Prior to our work, the nature of the autosomal signal and its target(s) were unknown. Here we show the signal includes discrete, trans-acting autosomal signal elements (ASEs) that counter XSEs to coordinately control both sex determination and dosage compensation. sea-1, the first autosomal signal element, encodes a T-box transcription factor that opposes XSEs by activating transcription of xol-1. Hence, xol-1 integrates both X and autosomal signals to determine sexual fate.
doi:10.1016/j.devcel.2005.06.009
PMCID: PMC2649673  PMID: 16139225
9.  Sex-dimorphic gene expression and ineffective dosage compensation of Z-linked genes in gastrulating chicken embryos 
BMC Genomics  2010;11:13.
Background
Considerable progress has been made in our understanding of sex determination and dosage compensation mechanisms in model organisms such as C. elegans, Drosophila and M. musculus. Strikingly, the mechanism involved in sex determination and dosage compensation are very different among these three model organisms. Birds present yet another situation where the heterogametic sex is the female. Sex determination is still poorly understood in birds and few key determinants have so far been identified. In contrast to most other species, dosage compensation of bird sex chromosomal genes appears rather ineffective.
Results
By comparing microarrays from microdissected primitive streak from single chicken embryos, we identified a large number of genes differentially expressed between male and female embryos at a very early stage (Hamburger and Hamilton stage 4), long before any sexual differentiation occurs. Most of these genes are located on the Z chromosome, which indicates that dosage compensation is ineffective in early chicken embryos. Gene ontology analyses, using an enhanced annotation tool for Affymetrix probesets of the chicken genome developed in our laboratory (called Manteia), show that among these male-biased genes found on the Z chromosome, more than 20 genes play a role in sex differentiation.
Conclusions
These results corroborate previous studies demonstrating the rather inefficient dosage compensation for Z chromosome in birds and show that this sexual dimorphism in gene regulation is observed long before the onset of sexual differentiation. These data also suggest a potential role of non-compensated Z-linked genes in somatic sex differentiation in birds.
doi:10.1186/1471-2164-11-13
PMCID: PMC2821371  PMID: 20055996
10.  Unexpected Role for Dosage Compensation in the Control of Dauer Arrest, Insulin-Like Signaling, and FoxO Transcription Factor Activity in Caenorhabditis elegans 
Genetics  2013;194(3):619-629.
During embryogenesis, an essential process known as dosage compensation is initiated to equalize gene expression from sex chromosomes. Although much is known about how dosage compensation is established, the consequences of modulating the stability of dosage compensation postembryonically are not known. Here we define a role for the Caenorhabditis elegans dosage compensation complex (DCC) in the regulation of DAF-2 insulin-like signaling. In a screen for dauer regulatory genes that control the activity of the FoxO transcription factor DAF-16, we isolated three mutant alleles of dpy-21, which encodes a conserved DCC component. Knockdown of multiple DCC components in hermaphrodite and male animals indicates that the dauer suppression phenotype of dpy-21 mutants is due to a defect in dosage compensation per se. In dpy-21 mutants, expression of several X-linked genes that promote dauer bypass is elevated, including four genes encoding components of the DAF-2 insulin-like pathway that antagonize DAF-16/FoxO activity. Accordingly, dpy-21 mutation reduced the expression of DAF-16/FoxO target genes by promoting the exclusion of DAF-16/FoxO from nuclei. Thus, dosage compensation enhances dauer arrest by repressing X-linked genes that promote reproductive development through the inhibition of DAF-16/FoxO nuclear translocation. This work is the first to establish a specific postembryonic function for dosage compensation in any organism. The influence of dosage compensation on dauer arrest, a larval developmental fate governed by the integration of multiple environmental inputs and signaling outputs, suggests that the dosage compensation machinery may respond to external cues by modulating signaling pathways through chromosome-wide regulation of gene expression.
doi:10.1534/genetics.113.149948
PMCID: PMC3697968  PMID: 23733789
Caenorhabditis elegans; dosage compensation; dauer; insulin signaling; DAF-16/FoxO
11.  Restricting Dosage Compensation Complex Binding to the X Chromosomes by H2A.Z/HTZ-1 
PLoS Genetics  2009;5(10):e1000699.
Dosage compensation ensures similar levels of X-linked gene products in males (XY or XO) and females (XX), despite their different numbers of X chromosomes. In mammals, flies, and worms, dosage compensation is mediated by a specialized machinery that localizes to one or both of the X chromosomes in one sex resulting in a change in gene expression from the affected X chromosome(s). In mammals and flies, dosage compensation is associated with specific histone posttranslational modifications and replacement with variant histones. Until now, no specific histone modifications or histone variants have been implicated in Caenorhabditis elegans dosage compensation. Taking a candidate approach, we have looked at specific histone modifications and variants on the C. elegans dosage compensated X chromosomes. Using RNAi-based assays, we show that reducing levels of the histone H2A variant, H2A.Z (HTZ-1 in C. elegans), leads to partial disruption of dosage compensation. By immunofluorescence, we have observed that HTZ-1 is under-represented on the dosage compensated X chromosomes, but not on the non-dosage compensated male X chromosome. We find that reduction of HTZ-1 levels by RNA interference (RNAi) and mutation results in only a very modest change in dosage compensation complex protein levels. However, in these animals, the X chromosome–specific localization of the complex is partially disrupted, with some nuclei displaying DCC localization beyond the X chromosome territory. We propose a model in which HTZ-1, directly or indirectly, serves to restrict the dosage compensation complex to the X chromosome by acting as or regulating the activity of an autosomal repellant.
Author Summary
In organisms where females have two X chromosomes and males only have one, a mechanism called dosage compensation ensures that both sexes receive the same amount of information from their X chromosomes. Disruption of dosage compensation leads to lethality in the affected sex. While the precise mechanisms of dosage compensation differ between organisms, changes to the structure of the X chromosomes are involved in each case. The DNA of all chromosomes is packaged into a complex protein–DNA structure called chromatin. The most basic level of packaging involves wrapping DNA around a group of small proteins called histones. In both mammals and flies, dosage compensation is associated with specific changes to the histones on the dosage compensated X chromosome. Until now, no such change has been associated with dosage compensation in worms. Here we present evidence that the histone variant HTZ-1/H2A.Z plays a role in dosage compensation in the worm. Specifically, we suggest that HTZ-1 functions to ensure that only the X chromosomes, and not the other chromosomes, are subjected to dosage compensation. This suggests that, despite different mechanisms, one common theme of dosage compensation is a change at the level of the histones associated with the chromosomal DNA.
doi:10.1371/journal.pgen.1000699
PMCID: PMC2760203  PMID: 19851459
12.  Mechanisms and Evolutionary Patterns of Mammalian and Avian Dosage Compensation 
PLoS Biology  2012;10(5):e1001328.
A large-scale comparative gene expression study reveals the different ways in which the chromosome-wide gene dosage reductions resulting from sex chromosome differentiation events were compensated during mammalian and avian evolution.
As a result of sex chromosome differentiation from ancestral autosomes, male mammalian cells only contain one X chromosome. It has long been hypothesized that X-linked gene expression levels have become doubled in males to restore the original transcriptional output, and that the resulting X overexpression in females then drove the evolution of X inactivation (XCI). However, this model has never been directly tested and patterns and mechanisms of dosage compensation across different mammals and birds generally remain little understood. Here we trace the evolution of dosage compensation using extensive transcriptome data from males and females representing all major mammalian lineages and birds. Our analyses suggest that the X has become globally upregulated in marsupials, whereas we do not detect a global upregulation of this chromosome in placental mammals. However, we find that a subset of autosomal genes interacting with X-linked genes have become downregulated in placentals upon the emergence of sex chromosomes. Thus, different driving forces may underlie the evolution of XCI and the highly efficient equilibration of X expression levels between the sexes observed for both of these lineages. In the egg-laying monotremes and birds, which have partially homologous sex chromosome systems, partial upregulation of the X (Z in birds) evolved but is largely restricted to the heterogametic sex, which provides an explanation for the partially sex-biased X (Z) expression and lack of global inactivation mechanisms in these lineages. Our findings suggest that dosage reductions imposed by sex chromosome differentiation events in amniotes were resolved in strikingly different ways.
Author Summary
Mammalian sex chromosomes (the X and Y) evolved from an ordinary pair of ancestral somatic chromosomes (the proto-sex chromosomes). The process that led to emergence of distinct sex chromosomes involved the degeneration of the Y chromosome, leaving males with only one copy of most proto-sex chromosomal genes on their single X chromosome. It has remained unclear whether mechanisms evolved that compensate for this dosage reduction. Here we trace the evolution of sex chromosomal expression levels in all major mammalian lineages and in birds. We find that the X has become globally upregulated in response to the dosage reduction in marsupials, whereas in placental mammals, genes resident on autosomal (non-sex) chromosomes that interact with X-linked genes have instead become downregulated. These mechanisms restore ancestral gene expression balances and also presumably drove the evolution of secondary compensation mechanisms (i.e., female X-inactivation) in these mammalian lineages. In egg-laying mammals and birds, sex chromosomes have become partially upregulated specifically in the heterogametic sex, i.e., in male monotremes (which are XY) and female birds (which are WZ). This probably explains why the evolution of inactivation mechanisms in the homogametic sexes in these lineages (XX and ZZ, respectively) was not necessary. Our findings suggest that gene dosage alterations associated with the emergence of sex chromosome systems can be compensated in various different ways.
doi:10.1371/journal.pbio.1001328
PMCID: PMC3352821  PMID: 22615540
13.  Getting a Full Dose? Reconsidering Sex Chromosome Dosage Compensation in the Silkworm, Bombyx mori 
Dosage compensation—equalizing gene expression levels in response to differences in gene dose or copy number—is classically considered to play a critical role in the evolution of heteromorphic sex chromosomes. As the X and Y diverge through degradation and gene loss on the Y (or the W in female-heterogametic ZW taxa), it is expected that dosage compensation will evolve to correct for sex-specific differences in gene dose. Although this is observed in some organisms, recent genome-wide expression studies in other taxa have revealed striking exceptions. In particular, reports that both birds and the silkworm moth (Bombyx mori) lack dosage compensation have spurred speculation that this is the rule for all female-heterogametic taxa. Here, we revisit the issue of dosage compensation in silkworm by replicating and extending the previous analysis. Contrary to previous reports, our efforts reveal a pattern typically associated with dosage compensated taxa: the global male:female expression ratio does not differ between the Z and autosomes. We believe the previous report of unequal male:female ratios on the Z reflects artifacts of microarray normalization in conjunction with not testing a major assumption that the male:female global expression ratio was unbiased for autosomal loci. However, we also find that the global Z chromosome expression is significantly reduced relative to autosomes, a pattern not expected in dosage compensated taxa. This combination of male:female parity with an overall reduction in expression for sex-linked loci is not consistent with the prevailing evolutionary theory of sex chromosome evolution and dosage compensation.
doi:10.1093/gbe/evr036
PMCID: PMC3296447  PMID: 21508430
sex chromosomes; lepidoptera; microarray; female heterogamety
14.  Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster 
Nature genetics  2011;43(12):1179-1185.
Many animal species use a chromosome-based mechanism of sex determination, which has led to the coordinate evolution of dosage-compensation systems. Dosage compensation not only corrects the imbalance in the number of X chromosomes between the sexes but also is hypothesized to correct dosage imbalance within cells that is due to monoallelic X-linked expression and biallelic autosomal expression, by upregulating X-linked genes twofold (termed ‘Ohno’s hypothesis’). Although this hypothesis is well supported by expression analyses of individual X-linked genes and by microarray-based transcriptome analyses, it was challenged by a recent study using RNA sequencing and proteomics. We obtained new, independent RNA-seq data, measured RNA polymerase distribution and reanalyzed published expression data in mammals, C. elegans and Drosophila. Our analyses, which take into account the skewed gene content of the X chromosome, support the hypothesis of upregulation of expressed X-linked genes to balance expression of the genome.
doi:10.1038/ng.948
PMCID: PMC3576853  PMID: 22019781
15.  The role of LINEs and CpG islands in dosage compensation on the chicken Z chromosome 
Chromosome Research  2009;17(6):727-736.
Most avian Z genes are expressed more highly in ZZ males than ZW females, suggesting that chromosome-wide mechanisms of dosage compensation have not evolved. Nevertheless, a small percentage of Z genes are expressed at similar levels in males and females, an indication that a yet unidentified mechanism compensates for the sex difference in copy number. Primary DNA sequences are thought to have a role in determining chromosome gene inactivation status on the mammalian X chromosome. However, it is currently unknown whether primary DNA sequences also mediate chicken Z gene compensation status. Using a combination of chicken DNA sequences and Z gene compensation profiles of 310 genes, we explored the relationship between Z gene compensation status and primary DNA sequence features. Statistical analysis of different Z chromosomal features revealed that long interspersed nuclear elements (LINEs) and CpG islands are enriched on the Z chromosome compared with 329 other DNA features. Linear support vector machine (SVM) classifiers, using primary DNA sequences, correctly predict the Z compensation status for >60% of all Z-linked genes. CpG islands appear to be the most accurate classifier and alone can correctly predict compensation of 63% of Z genes. We also show that LINE CR1 elements are enriched 2.7-fold on the chicken Z chromosome compared with autosomes and that chicken chromosomal length is highly correlated with percentage LINE content. However, the position of LINE elements is not significantly associated with dosage compensation status of Z genes. We also find a trend for a higher proportion of CpG islands in the region of the Z chromosome with the fewest dosage-compensated genes compared with the region containing the greatest concentration of compensated genes. Comparison between chicken and platypus genomes shows that LINE elements are not enriched on sex chromosomes in platypus, indicating that LINE accumulation is not a feature of all sex chromosomes. Our results suggest that CpG islands are not randomly distributed on the Z chromosome and may influence Z gene dosage compensation status.
Electronic supplementary material
The online version of this article (doi:10.1007/s10577-009-9068-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s10577-009-9068-4
PMCID: PMC2759020  PMID: 19672682
dosage compensation; Z chromosome; DNA sequence; LINEs; CpG; chicken; sex chromosome; X chromosome
16.  Incomplete Sex Chromosome Dosage Compensation in the Indian Meal Moth, Plodia interpunctella, Based on De Novo Transcriptome Assembly 
Genome Biology and Evolution  2012;4(11):1118-1126.
Males and females experience differences in gene dose for loci in the nonrecombining region of heteromorphic sex chromosomes. If not compensated, this leads to expression imbalances, with the homogametic sex on average exhibiting greater expression due to the doubled gene dose. Many organisms with heteromorphic sex chromosomes display global dosage compensation mechanisms, which equalize gene expression levels between the sexes. However, birds and Schistosoma have been previously shown to lack chromosome-wide dosage compensation mechanisms, and the status in other female heterogametic taxa including Lepidoptera remains unresolved. To further our understanding of dosage compensation in female heterogametic taxa and to resolve its status in the lepidopterans, we assessed the Indian meal moth, Plodia interpunctella. As P. interpunctella lacks a complete reference genome, we conducted de novo transcriptome assembly combined with orthologous genomic location prediction from the related silkworm genome, Bombyx mori, to compare Z-linked and autosomal gene expression levels for each sex. We demonstrate that P. interpunctella lacks complete Z chromosome dosage compensation, female Z-linked genes having just over half the expression level of males and autosomal genes. This finding suggests that the Lepidoptera and possibly all female heterogametic taxa lack global dosage compensation, although more species will need to be sampled to confirm this assertion.
doi:10.1093/gbe/evs086
PMCID: PMC3514961  PMID: 23034217
dosage compensation; Lepidoptera; sex chromosomes; de novo transcriptome assembly; orthology
17.  Regional differences in dosage compensation on the chicken Z chromosome 
Genome Biology  2007;8(9):R202.
Microarray data analysis revealed a cluster of well compensated genes in the MHM (male-hypermethylated) region on chicken chromosome Zp, whereas Zq is enriched in non-compensated genes. The non-coding MHM RNA may therefore play a role in dosage compensation in the female.
Background
Most Z chromosome genes in birds are expressed at a higher level in ZZ males than in ZW females, and thus are relatively ineffectively dosage compensated. Some Z genes are compensated, however, by an unknown mechanism. Previous studies identified a non-coding RNA in the male hypermethylated (MHM) region, associated with sex-specific histone acetylation, which has been proposed to be involved in dosage compensation.
Results
Using microarray mRNA expression analysis, we find that dosage compensated and non-compensated genes occur across the Z chromosome, but a cluster of compensated genes are found in the MHM region of chicken chromosome Zp, whereas Zq is enriched in non-compensated genes. The degree of dosage compensation among Z genes is predicted better by the level of expression of Z genes in males than in females, probably because of better compensation of genes with lower levels of expression. Compensated genes have different functional properties than non-compensated genes, suggesting that dosage compensation has evolved gene-by-gene according to selective pressures on each gene. The group of genes comprising the MHM region also resides on a primitive mammalian (platypus) sex chromosome and, thus, may represent an ancestral precursor to avian ZZ/ZW and monotreme XX/XY sex chromosome systems.
Conclusion
The aggregation of dosage compensated genes near the MHM locus may reflect a local sex- and chromosome-specific mechanism of dosage compensation, perhaps mediated by the MHM non-coding RNA.
doi:10.1186/gb-2007-8-9-r202
PMCID: PMC2375040  PMID: 17900367
18.  Sex-Specific Embryonic Gene Expression in Species with Newly Evolved Sex Chromosomes 
PLoS Genetics  2014;10(2):e1004159.
Sex chromosome dosage differences between females and males are a significant form of natural genetic variation in many species. Like many species with chromosomal sex determination, Drosophila females have two X chromosomes, while males have one X and one Y. Fusions of sex chromosomes with autosomes have occurred along the lineage leading to D. pseudoobscura and D. miranda. The resulting neo-sex chromosomes are gradually evolving the properties of sex chromosomes, and neo-X chromosomes are becoming targets for the molecular mechanisms that compensate for differences in X chromosome dose between sexes. We have previously shown that D. melanogaster possess at least two dosage compensation mechanisms: the well- characterized MSL-mediated dosage compensation active in most somatic tissues, and another system active during early embryogenesis prior to the onset of MSL-mediated dosage compensation. To better understand the developmental constraints on sex chromosome gene expression and evolution, we sequenced mRNA from individual male and female embryos of D. pseudoobscura and D. miranda, from ∼0.5 to 8 hours of development. Autosomal expression levels are highly conserved between these species. But, unlike D. melanogaster, we observe a general lack of dosage compensation in D. pseudoobscura and D. miranda prior to the onset of MSL-mediated dosage compensation. Thus, either there has been a lineage-specific gain or loss in early dosage compensation mechanism(s) or increasing X chromosome dose may strain dosage compensation systems and make them less effective. The extent of female bias on the X chromosomes decreases through developmental time with the establishment of MSL-mediated dosage compensation, but may do so more slowly in D. miranda than D. pseudoobscura. These results also prompt a number of questions about whether species with more sex-linked genes have more sex-specific phenotypes, and how much transcript level variance is tolerable during critical stages of development.
Author Summary
Many animals have sex-specific combinations of chromosomes. In humans, for example, females have two X chromosomes while males have one X and one Y. In most species with XX:XY systems, the Y chromosome is degenerate and gene-poor while the X encodes a large number of functional genes. A variety of systems have evolved to ensure that males with one X chromosome and females with two X chromosomes have the same gene expression level for X-linked genes. The vinegar fly D. melanogaster has at least two dosage compensation systems: one that acts early in development, and another active in later stages. In this paper, we determine expression levels for thousands of genes in male and female embryos at different developmental stages in two species, D. pseudoobscura and D. miranda, that have unusually large fractions of their genomes in X or X-like chromosomes. We show that dosage compensation is established slowly during embryogenesis, and that in these species, dosage compensation appears to be absent in early development. This may be due to a lineage-specific loss or gain of compensation mechanism, or possibly because the machinery of dosage compensation cannot effectively handle the increased demand in these species.
doi:10.1371/journal.pgen.1004159
PMCID: PMC3923672  PMID: 24550743
19.  The W, X, Y and Z of sex-chromosome dosage compensation 
Trends in genetics : TIG  2009;25(5):226-233.
In species with highly differentiated sex chromosomes, imbalances in gene dosage between the sexes can affect overall organismal fitness. Regulatory mechanisms were discovered in several unrelated animals, which counter gene-dose differences between females and males, and these early findings suggested that dosage-compensating mechanisms were required for sex-chromosome evolution. However, recent reports in birds and moths contradict this view because these animals locally compensate only a few genes on the sex chromosomes, leaving the majority with different expression levels in males and females. These findings warrant a re-examination of the evolutionary forces underlying dosage compensation.
doi:10.1016/j.tig.2009.03.005
PMCID: PMC2923031  PMID: 19359064
20.  Large-Scale Population Study of Human Cell Lines Indicates that Dosage Compensation Is Virtually Complete 
PLoS Genetics  2008;4(1):e9.
X chromosome inactivation in female mammals results in dosage compensation of X-linked gene products between the sexes. In humans there is evidence that a substantial proportion of genes escape from silencing. We have carried out a large-scale analysis of gene expression in lymphoblastoid cell lines from four human populations to determine the extent to which escape from X chromosome inactivation disrupts dosage compensation. We conclude that dosage compensation is virtually complete. Overall expression from the X chromosome is only slightly higher in females and can largely be accounted for by elevated female expression of approximately 5% of X-linked genes. We suggest that the potential contribution of escape from X chromosome inactivation to phenotypic differences between the sexes is more limited than previously believed.
Author Summary
The males and females of many species are distinguished by their inheritance of different sets of sex chromosomes. This creates a significant imbalance in gene number between the sexes. Dosage compensation is the correction for this imbalance and is achieved by regulating gene activity across entire sex chromosomes. For example, human females have two X chromosomes and males have only one. Dosage compensation in humans involves X chromosome inactivation, which is the silencing of one X chromosome in female cells. Some genes are known to escape the silencing process and so are expressed at higher levels in females than males. We have investigated the extent to which such genes disrupt dosage compensation by comparing the activity of X chromosome genes in a large number of human male and female cell lines. We have shown that gene expression from the X chromosome pair in female cell lines is only slightly higher than from the single X in males. The small difference can be accounted for by increased female expression of approximately 5% of X chromosome genes. We conclude therefore that dosage compensation in these human cell lines is virtually complete, and we suggest that differences in X chromosome gene expression between males and females may be less extensive than previously thought.
doi:10.1371/journal.pgen.0040009
PMCID: PMC2213701  PMID: 18208332
21.  Large-Scale Population Study of Human Cell Lines Indicates that Dosage Compensation Is Virtually Complete 
PLoS Genetics  2008;4(1):e9.
X chromosome inactivation in female mammals results in dosage compensation of X-linked gene products between the sexes. In humans there is evidence that a substantial proportion of genes escape from silencing. We have carried out a large-scale analysis of gene expression in lymphoblastoid cell lines from four human populations to determine the extent to which escape from X chromosome inactivation disrupts dosage compensation. We conclude that dosage compensation is virtually complete. Overall expression from the X chromosome is only slightly higher in females and can largely be accounted for by elevated female expression of approximately 5% of X-linked genes. We suggest that the potential contribution of escape from X chromosome inactivation to phenotypic differences between the sexes is more limited than previously believed.
Author Summary
The males and females of many species are distinguished by their inheritance of different sets of sex chromosomes. This creates a significant imbalance in gene number between the sexes. Dosage compensation is the correction for this imbalance and is achieved by regulating gene activity across entire sex chromosomes. For example, human females have two X chromosomes and males have only one. Dosage compensation in humans involves X chromosome inactivation, which is the silencing of one X chromosome in female cells. Some genes are known to escape the silencing process and so are expressed at higher levels in females than males. We have investigated the extent to which such genes disrupt dosage compensation by comparing the activity of X chromosome genes in a large number of human male and female cell lines. We have shown that gene expression from the X chromosome pair in female cell lines is only slightly higher than from the single X in males. The small difference can be accounted for by increased female expression of approximately 5% of X chromosome genes. We conclude therefore that dosage compensation in these human cell lines is virtually complete, and we suggest that differences in X chromosome gene expression between males and females may be less extensive than previously thought.
doi:10.1371/journal.pgen.0040009
PMCID: PMC2213701  PMID: 18208332
22.  Nuclear Organization and Dosage Compensation 
Dosage compensation is a strategy to deal with the imbalance of sex chromosomal gene products relative to autosomes and also between the sexes. The mechanisms that ensure dosage compensation for X-chromosome activity have been extensively studied in mammals, worms, and flies. Although each entails very different mechanisms to equalize the dose of X-linked genes between the sexes, they all involve the co-ordinate regulation of hundreds of genes specifically on the sex chromosomes and not the autosomes. In addition to chromatin modifications and changes in higher order chromatin structure, nuclear organization is emerging as an important component of these chromosome-wide processes and in the specific targeting of dosage compensation complexes to the sex chromosomes. Preferential localization within the nucleus and 3D organization are thought to contribute to the differential treatment of two identical homologs within the same nucleus, as well as to the chromosome-wide spread and stable maintenance of heterochromatin.
X-chromosome inactivation/up-regulation ensures balanced expression of sex-linked genes both between the sexes and relative to autosomal genes. Subnuclear localization and compartmentalization mechanisms help coordinately regulate the hundreds of genes involved.
doi:10.1101/cshperspect.a000604
PMCID: PMC2964184  PMID: 20943757
23.  The Epigenome of Evolving Drosophila Neo-Sex Chromosomes: Dosage Compensation and Heterochromatin Formation 
PLoS Biology  2013;11(11):e1001711.
This study shows how young sex chromosomes have altered their chromatin structure in Drosophila, and what genomic changes have led to silencing of the Y, and hyper-transcription of the X.
Sex chromosomes originated from autosomes but have evolved a highly specialized chromatin structure. Drosophila Y chromosomes are composed entirely of silent heterochromatin, while male X chromosomes have highly accessible chromatin and are hypertranscribed as a result of dosage compensation. Here, we dissect the molecular mechanisms and functional pressures driving heterochromatin formation and dosage compensation of the recently formed neo-sex chromosomes of Drosophila miranda. We show that the onset of heterochromatin formation on the neo-Y is triggered by an accumulation of repetitive DNA. The neo-X has evolved partial dosage compensation and we find that diverse mutational paths have been utilized to establish several dozen novel binding consensus motifs for the dosage compensation complex on the neo-X, including simple point mutations at pre-binding sites, insertion and deletion mutations, microsatellite expansions, or tandem amplification of weak binding sites. Spreading of these silencing or activating chromatin modifications to adjacent regions results in massive mis-expression of neo-sex linked genes, and little correspondence between functionality of genes and their silencing on the neo-Y or dosage compensation on the neo-X. Intriguingly, the genomic regions being targeted by the dosage compensation complex on the neo-X and those becoming heterochromatic on the neo-Y show little overlap, possibly reflecting different propensities along the ancestral chromosome that formed the sex chromosome to adopt active or repressive chromatin configurations. Our findings have broad implications for current models of sex chromosome evolution, and demonstrate how mechanistic constraints can limit evolutionary adaptations. Our study also highlights how evolution can follow predictable genetic trajectories, by repeatedly acquiring the same 21-bp consensus motif for recruitment of the dosage compensation complex, yet utilizing a diverse array of random mutational changes to attain the same phenotypic outcome.
Author Summary
Sex chromosomes differ from non-sex chromosomes (“autosomes”) at the genomic, transcriptomic, and epigenomic level, yet the X and Y share a common evolutionary origin. The Drosophila Y chromosome is gene-poor and associated with a compact and transcriptionally inactive form of genetic material called heterochromatin. The X, in contrast, is enriched for activating chromatin marks and is consequently hyper-transcribed, a process thought to be an adaptation to decay and silencing of genes on the Y, resulting in “dosage compensation.” How sex chromosomes have altered their chromatin structure, and what genomic changes led to this dramatically different epigenetic makeup, however, has remained a mystery. By studying the genome, epigenome, and transcriptome of a species with a very recently evolved pair of sex chromosomes (the neo-X and neo-Y of a fruit fly, Drosophila miranda), we here recapitulate how both dosage compensation and heterochromatin formation evolve in Drosophila and establish several novel and important principles governing the evolution of chromatin structure. We dissect the evolutionary history of over 60 novel binding sites for the dosage compensation complex that evolved by natural selection on the neo-X within the last one million years. We show that the 21-bp consensus motifs for recruiting the dosage compensation complex were acquired by diverse molecular mechanisms along the neo-X, while the onset of heterochromatin formation is triggered by the accumulation of transposable elements, leading to silencing of adjacent neo-Y genes. We find that spreading of these chromatin modifications results in massive mis-expression of neo-sex linked genes, and that little correspondence exists between functional activity of genes on the neo-Y and whether they are dosage-compensated on the neo-X. Intriguingly, the genomic regions being targeted by the dosage compensation complex on the neo-X and those that are heterochromatic on the neo-Y show little overlap, possibly reflecting different propensities of the ancestral chromosome that formed the sex chromosome to evolve active versus repressive chromatin configurations. These findings have broad implications for current models of sex chromosome evolution.
doi:10.1371/journal.pbio.1001711
PMCID: PMC3825665  PMID: 24265597
24.  Noncanonical Compensation of Zygotic X Transcription in Early Drosophila melanogaster Development Revealed through Single-Embryo RNA-Seq 
PLoS Biology  2011;9(2):e1000590.
Mmany genes from the X chromosome are expressed at the same level in female and male embryos during early Drosophila development, prior to the establishment of MSL-mediated dosage compensation, suggesting the existence of a novel mechanism.
When Drosophila melanogaster embryos initiate zygotic transcription around mitotic cycle 10, the dose-sensitive expression of specialized genes on the X chromosome triggers a sex-determination cascade that, among other things, compensates for differences in sex chromosome dose by hypertranscribing the single X chromosome in males. However, there is an approximately 1 hour delay between the onset of zygotic transcription and the establishment of canonical dosage compensation near the end of mitotic cycle 14. During this time, zygotic transcription drives segmentation, cellularization, and other important developmental events. Since many of the genes involved in these processes are on the X chromosome, we wondered whether they are transcribed at higher levels in females and whether this might lead to sex-specific early embryonic patterning. To investigate this possibility, we developed methods to precisely stage, sex, and characterize the transcriptomes of individual embryos. We measured genome-wide mRNA abundance in male and female embryos at eight timepoints, spanning mitotic cycle 10 through late cycle 14, using polymorphisms between parental lines to distinguish maternal and zygotic transcription. We found limited sex-specific zygotic transcription, with a weak tendency for genes on the X to be expressed at higher levels in females. However, transcripts derived from the single X chromosome in males were more abundant that those derived from either X chromosome in females, demonstrating that there is widespread dosage compensation prior to the activation of the canonical MSL-mediated dosage compensation system. Crucially, this new system of early zygotic dosage compensation results in nearly identical transcript levels for key X-linked developmental regulators, including giant (gt), brinker (brk), buttonhead (btd), and short gastrulation (sog), in male and female embryos.
Author Summary
Variation in gene dose can have profound effects on animal development. Yet every generation, animals must cope with differences in sex chromosome numbers. Drosophila compensate for the difference in X chromosome dosage (two in females, one in males) with a mechanism that allows for more transcription of the single X chromosome in males. But this mechanism is not established until over an hour after the embryo begins transcription, during which time a number of important events in development occur such as cellularization and segmentation. Here we use an mRNA sequencing method to characterize gene expression in individual female and male embryos before the onset of the previously characterized dosage compensation system. While we find more transcripts from X chromosomal genes in females, we also find many genes with equal transcript levels in males and females. These results indicate that there is an alternate mechanism to compensate for dosage acting earlier in development, prior to the onset of the previously characterized dosage compensation system.
doi:10.1371/journal.pbio.1000590
PMCID: PMC3035605  PMID: 21346796
25.  Dosage compensation is less effective in birds than in mammals 
Journal of Biology  2007;6(1):2.
Background
In animals with heteromorphic sex chromosomes, dosage compensation of sex-chromosome genes is thought to be critical for species survival. Diverse molecular mechanisms have evolved to effectively balance the expressed dose of X-linked genes between XX and XY animals, and to balance expression of X and autosomal genes. Dosage compensation is not understood in birds, in which females (ZW) and males (ZZ) differ in the number of Z chromosomes.
Results
Using microarray analysis, we compared the male:female ratio of expression of sets of Z-linked and autosomal genes in two bird species, zebra finch and chicken, and in two mammalian species, mouse and human. Male:female ratios of expression were significantly higher for Z genes than for autosomal genes in several finch and chicken tissues. In contrast, in mouse and human the male:female ratio of expression of X-linked genes is quite similar to that of autosomal genes, indicating effective dosage compensation even in humans, in which a significant percentage of genes escape X-inactivation.
Conclusion
Birds represent an unprecedented case in which genes on one sex chromosome are expressed on average at constitutively higher levels in one sex compared with the other. Sex-chromosome dosage compensation is surprisingly ineffective in birds, suggesting that some genomes can do without effective sex-specific sex-chromosome dosage compensation mechanisms.
doi:10.1186/jbiol53
PMCID: PMC2373894  PMID: 17352797

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