Nature Genetics 38, 47 - 53 (2006)
Published online: 11 December 2005; | doi:10.1038/ng1705
Dosage compensation of the active X chromosome in mammalsDi Kim Nguyen1
& Christine M Disteche1, 21 Department of Pathology, University of Washington, Seattle, Washington 98195, USA. 2 Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
Correspondence should be addressed to Christine M Disteche cdistech@u.washington.edu Monosomy of the X chromosome owing to divergence between the sex chromosomes leads to dosage compensation mechanisms to restore balanced expression between the X and the autosomes. In Drosophila melanogaster, upregulation of the male X leads to dosage compensation. It has been hypothesized that mammals likewise upregulate their active X chromosome. Together with X inactivation, this mechanism would maintain balanced expression between the X chromosome and autosomes and between the sexes. Here, we show that doubling of the global expression level of the X chromosome leads to dosage compensation in somatic tissues from several mammalian species. X-linked genes are highly expressed in brain tissues, consistent with a role in cognitive functions. Furthermore, the X chromosome is expressed but not upregulated in spermatids and secondary oocytes, preserving balanced expression of the genome in these haploid cells. Upon fertilization, upregulation of the active X must occur to achieve the observed dosage compensation in early embryos.The X chromosome is unique in the mammalian genome because it is present in one copy in males and two copies in females, whereas each autosome is present in two copies in diploid cells. Divergence between the sex chromosomes and loss of genes from the Y chromosome lead to monosomy of the X chromosome in males1. X inactivation in females is the classical form of dosage compensation that equalizes gene expression between the sexes2. A second form of dosage compensation must have evolved to protect mammals from deleterious effects due to functional monosomy (haploinsufficiency) of the X chromosome. Ohno proposed that "...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"3. One example of such a functional compensation has been identified in D. melanogaster, in which upregulation of the X occurs in males only4,
5.
A corresponding mammalian X chromosome upregulation process and its components have not been identified. We previously found the first indication of X upregulation in mice where the X-linked form of the Clcn4-2 gene from one species was expressed at twice the level of the autosomal copy from another species6. In this study, we used microarray expression data to evaluate the global transcriptional output from the mammalian X chromosome in comparison with the rest of the genome. Array expression profiles can detect dosage-dependent changes in chromosome-specific gene expression in monosomic or trisomic regions of the mouse and human genomes7,
8,
9,
10. Our primary goal was to test Ohno's hypothesis by calculating the ratio of the mean global expression of X-linked genes to that of autosomal genes. This X:autosome expression ratio was predicted to be 1 if there was a doubling of transcription from the X. If there were no such doubling, the X:autosome expression ratio would be 0.5. Based on our analyses, the calculated ratio is indeed close to 1 in adult somatic tissues, consistent with dosage compensation in all six mammalian species examined and in D. melanogaster, which was used as a control.
The mammalian X chromosome undergoes a cycle of inactivation and reactivation during germ cell development and early embryogenesis11,
12. In females, both X chromosomes are active in primary oocytes13,
14, whereas in males, the X chromosome is transiently silenced at meiosis15,
16. In female embryos, imprinted inactivation of the paternal X chromosome is established at the two- to four-cell stage17,
18, followed by random X inactivation at the blastocyst stage19. We determined that the X chromosome was not upregulated in haploid cells, thereby maintaining a balanced expression of the genome. Thus, X upregulation must occur rapidly in early development to achieve the observed dosage compensation in embryos and adult somatic tissues.
Results
X chromosome is upregulated twofold in adult somatic tissues
We compared the global transcriptional output from the X chromosome with that of autosomes using microarray data from public databases as well as data from our own arrays. We analyzed a total of 1,554 microarrays, including cDNA and oligomer arrays (Affymetrix and 60-mer arrays) to demonstrate the consistency of our results (Supplementary Table 1 online). We calculated the mean fluorescence intensity of X-linked versus autosomal genes for each set of arrays hybridized with labeled cDNA. The most complete sets of human and mouse arrays, designed to cover as much as possible of the protein-encoding transcriptome of each species in an unbiased manner, have been hybridized with cDNA from a total of 27 human tissues and 33 mouse tissues (excluding brain and gonadal tissues, described below) from pooled males and females20,
21. We calculated an overall average X:autosome expression ratio of 0.94 in human and 1.01 in mouse (Fig. 1a; Supplementary Table 2 online). Normalized gene expression values followed a normal distribution (Fig. 1b).
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We conclude that the global transcriptional output from the X chromosome is doubled in both species to achieve dosage compensation. Despite an apparent tissue-to-tissue variation (Fig. 1a), X:autosome expression ratios were not significantly different between tissues (by Student's t-test). Analyses of a different type of array platform containing cDNAs22 (P. Nelson, Fred Hutchinson Cancer Research Center, Seattle, personal communication) confirmed our data on the larger oligomer arrays, with X:autosome expression ratios of 1.00 for human prostate and 0.91 and 0.98 for mouse liver and kidney, respectively. The rat X chromosome is also upregulated, with an average X:autosome expression ratio of 1.01 in 12 somatic tissues (excluding brain and gonadal tissues)23 (Fig. 2a; Supplementary Table 2). Control analysis of array data sets from pooled male and female D. melanogaster yielded a ratio of 0.98, consistent with the well-known dosage compensation by upregulation of the male X in this species (Fig. 2)24.
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To determine whether X chromosome expression differed between the sexes, we analyzed our own set of eight Affymetrix arrays hybridized with cDNA from human female and male heart, female spleen and male liver, together with deposited array data on heart and muscle for which the sex was specified25,
26. We calculated similar X:autosome expression ratios for male (XY:AA) and female (XX:AA) tissues from human and mouse (Fig. 3). Thus, dosage compensation was consistently achieved, presumably by a combination of overall doubling of transcriptional output from the active X in both sexes and X inactivation in females.
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A number of genes (about 15%) escape X inactivation in human (that is, they are expressed from both X chromosomes), whereas few genes escape in mouse. 'Escape genes' could potentially increase the X:autosome expression ratio in females. However, as described above, we did not observe significant differences between the sexes. To address this paradox, we used microarray data to determine the sex-specific expression of a subset of 27 human genes expressed in at least five of nine rodent hybrid cell lines containing an inactive X (ref. 27) and four mouse escape genes28. The average female-to-male expression ratio of these genes was 1.11 in humans and 1.38 in mouse. The female-to-male ratio varied from 0.10 to 2.94 for 27 individual escape genes examined in three human tissues, indicating that only a few escape genes have a significant increase in expression in females, whereas most show a modest increase, no increase or even a decrease in expression. This is due to low expression from the inactive X and to additional sex-specific effects (such as hormonal effects) on gene expression.
X-linked gene expression higher in brain than in other tissues
The mean X:autosome expression ratios in adult brain tissues were 1.08 in human (24 tissues) and 1.13 in mouse (17 tissues), based on a combination of our own arrays and on deposited data20,
21,
25,
29 (Fig. 1a; Supplementary Table 2). In spite of tissue-to-tissue variation, the differences in X:autosome expression ratios between all brain tissues as a group and all other tissues as another group were significant (Student's t-tests: human P = 1.03  10-10; mouse P = 7.22 10-7). Scatter plots also demonstrated an excess of X-linked genes with high expression in brain tissues (Fig. 4). Indeed, the proportion of genes with a twofold higher expression in the brain tissue group than in the 'other tissue' group was 2.8 and 2.5 times greater for the X chromosome than for the autosomes in human and mouse, respectively. When considering genes selected as brain-specific genes (defined by at least a twofold higher expression in brain than in other tissues), the average X:autosome expression ratios were 1.43 in human and 1.18 in mouse, suggesting a greater proportion of highly expressed X-linked genes in human. The distribution of normalized gene expression in brain tissues also showed a shift toward higher values for X-linked versus autosomal genes in human but not in mouse (Fig. 1b).
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The global transcriptional output from the X was also high in brain tissues of other mammalian species, including chimpanzee, gorilla, macaque, and rat (Fig. 2b; Supplementary Table 2)23,
29. The higher expression of X-linked genes in brain versus other tissues was independent of gender (Fig. 3)25. X: autosome expression ratios were 1.12 and 1.16 in human male and female brain tissues, respectively, and 1.19 and 1.19 in mouse male and female brain tissues, respectively (Fig. 3; Supplementary Table 2). Taken together, our data indicate a high expression of X-linked genes in mammalian brain tissues.
X chromosome reactivated but not upregulated in spermatids
The mammalian X chromosome is silenced in male germ cells, specifically in spermatocytes at meiosis I (refs. 15,16). Some X-linked genes are reactivated in spermatids30,
31,
32,
33, but the global transcriptional output from the X chromosome was unknown in these haploid cells (X:A or Y:A). We observed low X:autosome expression ratios in whole adult testis from mouse, rat, and human, which represent a mixture of supporting cells and germ cells (Fig. 5a; Supplementary Table 2)21,
34,
35,
36. The adult testis contains 75% haploid cells (spermatids and sperm), 9% diploid cells (somatic cells, spermatogonia) and 12% tetraploid cells (meiotic primary spermatocytes)34,
37. In postpartum mouse testes, the global transcriptional output from the X chromosome selectively decreased with age from postnatal day 11 onward, coincident with the progressive onset of spermatogenesis, as previously reported (Supplementary Fig. 1 online)38.
| | Figure 5. X chromosome expression in male and female sex-specific tissues and germ cells and in embryos. | | |  | (a) X:autosome expression ratios (mean  s.d.) are shown for mouse (square), rat (circle) and human (diamond). Male-specific somatic tissues are Leydig and Sertoli cells, testicular somatic cells and prostate. Female-specific somatic tissues are uterus and mammary gland. (b) Distribution histograms of normalized expression values for the X chromosomes (filled bars) and autosomes (open bars) for various tissues. Gene expression levels were transformed into log2 and binned before graphing the data in arbitrary units. (c) X:autosome expression ratios (mean s.d.) are shown for mouse embryonic tissues at specific stages. (d) Schematic of X chromosome upregulation in relation to the number of autosomal sets (AA, diploid; A, haploid). The schematic summarizes hypothetical changes in the X chromosome(s) in female and male germ cells, zygotes and soma. In female primary oocytes, secondary oocytes, and zygotes, the X chromosome(s) are active (Xa) but partially repressed or not upregulated (one downward black arrow), whereas in female soma, one X is active and upregulated (large X) and the other is inactivated (Xi, two downward black arrows). In male spermatocytes, the X chromosome is inactive; in spermatids, it is active but partially repressed or not upregulated; in zygotes and soma, it is upregulated. The X:autosome expression ratios (X:A) for each stage are shown.
 Full Figure and legend (61K) |
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To sort out the X chromosome transcriptional output in different cell types, we examined data from purified rat spermatocytes36, which had a very low X:autosome expression ratio (0.22), consistent with repression of the X chromosome in late pachytene. In contrast, spermatogonia and somatic tissues (Sertoli, Leydig and other interstitial cells) had ratios of 1.00 and 1.22, respectively (Fig. 5a; Supplementary Table 2). Early spermatids purified to 90% (ref. 36) and presumably representing equal numbers of X chromosome– and Y chromosome–bearing cells had a ratio of 0.46. Thus, X chromosome–bearing spermatids would have a ratio close to 0.9, the ratio being theoretically 0 in Y chromosome–bearing spermatids. This implies that the X chromosome is active and not upregulated in X chromosome–bearing early spermatids (Fig. 5a,b; Supplementary Table 2). We found a marked shift towards X-linked genes with low expression in spermatocytes and early spermatids (Fig. 5b), in agreement with overall decreased expression from the X chromosome and depletion for genes expressed in late spermatogenesis38. Similar results were obtained in mouse, albeit with a higher ratio in spermatocytes purified by attachment in culture37 than in rat cells purified by centrifugation and thus more representative of the in vivo state36.
X chromosome not upregulated in primary and secondary oocytes
Both X chromosomes are reactivated in primary oocytes, which arrest at prophase I until puberty, when they complete meiosis I to form secondary oocytes13,
14. Meiosis II is completed only upon fertilization. Based on array data21,
39,
40,
41, the X:autosome expression ratio was 0.67 in primary mouse oocytes (diploid, XX:AA) and 0.87 in secondary mouse oocytes (haploid, X:A; Fig. 5a; Supplementary Table 2). Notably, a large number of X-linked genes showed low expression in primary oocytes, as indicated by a shift in the distribution of expression values compared with autosomes (Fig. 5b). Thus, neither the two active X chromosomes in primary diploid oocytes nor the single X chromosome in secondary haploid oocytes was upregulated. The absence of doubling of transcriptional output from the X chromosome in primary and secondary oocytes would maintain balanced expression with the autosomes. There may even be partial repression of the X chromosome in these cells, which will need to be confirmed by additional analyses.
X:autosome expression ratios were high in human and mouse ovary (1.18 and 1.21) and in human and mouse uterus (1.13 and 1.09), indicating a possible role for the X chromosome in these female-specific organs20,
21,
25 (Supplementary Table 2).
X chromosome upregulation during early mouse embryogenesis
As the X chromosome in haploid spermatids (X:A or Y:A) and secondary oocytes (X:A) was found to be active but not upregulated, the observed X upregulation in adult somatic tissues must be initiated in embryos (XY:AA or XX:AA). To follow the expression of the X chromosome during development, we examined mouse array data for these stages21,
39,
40,
41 (Supplementary Table 1). The gender of the fertilized eggs and embryos was not known for any of these sets of array data. However, 30 to 500 zygotes or embryos, presumably representing equal number of males and females, had been pooled for each stage.
The X:autosome expression ratio in mouse fertilized eggs and embryos up to blastocysts ranged from 0.87 to 1.02 (Fig. 5c; Supplementary Table 2). From 6.5 days post coitum (d.p.c.) embryos onward, the mean X:autosome ratio remained fairly constant and was slightly but not significantly higher (1.09 to 1.12) than in earlier stages (Fig. 5c). Our results indicate that dosage compensation of the X chromosome to maintain balanced expression of the genome is achieved immediately at zygote formation. Potential differences in X-linked gene expression between male and female zygotes and/or embryos would not be detected in our analyses of pooled male and female embryos. To resolve this issue, sexed zygotes and embryos will need to be purified.
Discussion
Gene expression from the mammalian X chromosome is upregulated in somatic tissues of males and females, a process that achieves dosage compensation by a doubling of the X transcriptional output, as shown by our analyses of microarray data. In haploid germ cells, the balance of expression between the X chromosome and autosomes is maintained by a lack of X upregulation. These findings indicate a need to achieve dosage compensation for X-linked genes in most cells. A notable exception includes spermatocytes, in which global expression of the X chromosome is very low owing to silencing at meiosis I. Our findings in mammals mirror those in D. melanogaster in which microarray analyses have also shown that dosage compensation is achieved both in somatic and germ cells42.
An obvious question is how X upregulation is established in mammals. One possibility is that the basal expression level of each X-linked gene may have become upregulated via modifications of the DNA sequence to compensate for the loss of the corresponding Y-linked gene during evolution. Promoter or enhancer functions may have changed to increase gene expression. The microarray expression data analyzed in our study represent steady-state RNA, which could also be increased by an enhancement of mRNA stability due to changes at the 3' end or another region of the gene. Although our study indicates that dosage compensation is established at the transcriptional level, further regulation may be at the translational level. A second possibility is that upregulation is an active process that involves epigenetic changes, similar to those mediated by the MSL complex in D. melanogaster43. Mouse orthologs of the D. melanogaster msl-1, msl-2 and msl-3 genes showed high expression in zygotes and early two-cell embryos, followed by a decrease in late two-cell and four-cell embryos, based on our analysis of array data (data not shown)21,
39,
40,
41. This transient burst of expression of msl-related genes coincides with the overall high expression of chromatin remodeling genes in early embryos39,
40,
44. Whether upregulation of the mammalian X involves the formation of a protein complex remains to be determined. At present, there is no evidence that the chromatin structure of the active X chromosomes in mammals differs in any way from that of autosomes, which argues in favor of a gene-by-gene evolutionary process resulting in enhanced basal expression or mRNA stability.
If X upregulation results from permanent DNA sequence modifications, the low transcriptional output we observed in spermatids and oocytes would imply an X-specific partial repression process in these cells. In embryos, removal of these repressive marks would be necessary to initiate X upregulation. On the other hand, if X upregulation results from epigenetic modifications and/or the formation of a protein complex on the active X, this complex would presumably be removed in germ cells to account for the observed lower expression, which would then represent the basal expression. Our study suggests that there must be epigenetic mechanisms either to decrease specifically expression of the X chromosome(s) in diploid oocytes with two active X chromosomes (XX:AA) and haploid germ cells (X:A or Y:A) or to increase specifically expression of the single active X chromosome in diploid somatic cells (XY:AA or XX:AA). Both scenarios imply dynamic changes in the global transcriptional output of the X chromosome or possibly the autosomes at transitions between germ cells and somatic cells and vice versa (Fig. 5d). Changes in specific sets of expressed X-linked genes may also have a role in the observed modulations of global expression in these cell types.
Regulation of the active X chromosome probably differs depending on the sex of the embryo. At conception, X upregulation might take place immediately in males, whereas both X chromosomes might be partially repressed before X inactivation in females (Fig. 5d). X inactivation provides a mechanism to protect the organism from functional 'tetrasomy' of upregulated X-linked genes. If X upregulation were an early event in female embryos, silencing should be as well, as recently reported for early imprinted paternal X inactivation in mouse17,
18. However, as imprinted X inactivation is apparently incomplete and may not occur in other mammalian species17, X upregulation could be progressive in female embryos. At the blastocyst stage in mouse, the paternal X becomes reactivated and random X inactivation takes place in the inner cell mass19; we did not detect a significant change in X:autosome expression ratios at this stage, perhaps owing to the small number of cells involved, the timing of this event and/or other regulatory mechanisms. It will be interesting to determine expression from the X chromosome in sexed zygotes and early embryos.
The global transcriptional output from the X chromosome was similar in adult male and female tissues, although larger sets of data ultimately may demonstrate sex-specific differences. A significant contribution from genes that escape X inactivation in females was not detected in our study. This could be explained by the modest increase in expression of individual escape genes in females, consistent with low expression from the inactive X chromosome27,
45. As determined by allele-specific RT-PCR, only one-fifth of human escape genes show expression from the inactive X chromosome that reaches 50% of that of the active X chromosome27. Factors that influence individual gene expression such as tissue-specific, hormonal and metabolic differences between the sexes must also be considered.
We found that X-linked genes were highly expressed in brain tissues of several mammalian species. Our results are consistent with previous estimates of the proportion of X-linked genes involved in human brain function, based on the frequency of X-linked mental retardation46,
47. The data also suggest a greater proportion of highly expressed X-linked genes in human versus mouse brain. During evolution, the X chromosome seems to have become a repository for genes specifically and highly expressed in brain. Such genes may have a role in enhancing cognitive functions, thereby providing a selective advantage to males in sexual reproduction46.
Our findings of X upregulation in mammals unify the concept of balanced expression in a given genome. Haploinsufficiency owing to monosomy of a whole chromosome is not well tolerated in most organisms48. We report on the balanced expression of X-linked genes in diploid somatic tissues and haploid germ cells from several mammalian species and in somatic tissues from D. melanogaster. Similar results have been obtained in somatic tissues and germ cells from D. melanogaster and in somatic tissues from C. elegans and mouse42. Hence, the evolution of mechanisms to protect from deleterious effects of haploinsufficiency are found in several organisms in conjunction with sex chromosome differentiation. Whether these mechanisms evolved piecemeal, on a gene-by-gene basis or for an entire chromosome at a given time remains to be determined49.
Methods
Microarrays.
Array characteristics are listed in Supplementary Table 1. Data were obtained in part from public array databases. We analyzed the following Affymetrix arrays: human HG-U95 set A, B, C, D, E; human HG-U133A; human HG-U133 set; human HG-U133 2.0 plus; mouse MG-U74 set A, B, C; mouse 430 set A, B; rat 230 set A, B; rat RG-U34 set A,B; and Drosophila melanogaster genome array. Other types of arrays were 60-oligomer arrays custom-made at the US National Institutes of Health and GNF-1H and GNF-1M custom-made 25-oligomer arrays21. In addition, we acquired eight HG-U133 2.0 plus arrays from Affymetrix for hybridization to gender-specific total RNA (Stratagene). Probe labeling, array hybridization and scanning were done by the University of Washington Microarray Center. Mouse and human cDNA array data were provided by P. Nelson (Fred Hutchinson Cancer Research Center, Seattle). Mouse and human cDNA arrays contained cDNAs from the Research Genetics sequence-verified set of IMAGE clones.
Microarray data analysis.
Data downloaded from public databases were not uniformly deposited in terms of format. It was critical for our purpose and for consistency in the analysis that the chromosome location and raw fluorescent intensity for each spot on the array be available for each set of data. In the case of Affymetrix arrays, we reanalyzed the raw data files using the Affymetrix software (GCOS 1.1) based on the annotation files available at the Affymetrix website. In the case of cDNA arrays or other types of 60-oligomer arrays, the authors provided annotation files as well as their preferred cut-off point for genes with low expression; without this information, the spots could not be normalized and sorted. Each set of array data was initially extracted and analyzed differently depending on the format in which they were originally deposited. For example, some data were extracted in .CEL file format (reanalyzed using GCOS 1.1, Affymetrix), whereas others were in .XLS format (Microsoft Excel) or .TXT format. After data extraction, all arrays were analyzed in a similar manner. After elimination of background and genes with a low level of expression, the mean fluorescence intensity of duplicated spots representing the same gene was calculated and normalized to the mean fluorescence intensity of the whole array. Genes were then sorted by chromosome location. The ratio of the mean expression of X-linked genes to that of autosomal genes was calculated, as well as the average of the above ratios for all arrays hybridized with cDNA prepared from the same tissue type.
Statistical analyses.
From each set of arrays extracted from the databases, a gene expression distribution histogram (Microsoft Excel) was created to determine whether expression values (log2 based and binned) for all genes surveyed followed a normal distribution. The percentage of X-linked spots on the arrays ranged between 3.8–4.0% of the total numbers of spots, consistent with the percentage of X-linked genes in the mammalian genome, 3.8–4.4%, depending on the species. For example, using the GNF-1H and GH-U133A arrays, we compared 743 X-linked genes to 18,193 autosomal genes. X:autosome expression ratios remained similar when we compared genes on the X chromosome and on a single autosome of similar size, chromosome 3, which had 1,143 genes available for analysis.
Accession codes.
Gene Expression Omnibus: GSE3413
URLs.
Cardiogenomics database, http://www.cardiogenomics.org; National Center for Biotechnology Information (NCBI) Gene Expression Omnibus, http://www.ncbi.nlm.nih.gov/geo/; European Bioinformatics Institute ArrayExpress, http://www.ebi.ac.uk/arrayexpress/; Stanford MicroArray Database, http://genome-www5.stanford.edu/; National Institute of Aging Laboratory of Genetics microarray data, http://lgsun.grc.nia.nih.gov/microarray/data.html; Gene Expression Atlas, http://expression.gnf.org/; Biozentrum Swiss Institute of Bioinformatics, http://www.biozentrum.unibas.ch/personal/primig/rat_spermatogenesis/; Prostate Expression Database, http://www.pedb.org/; University of Washington Microarray Center, http://ra.microslu.washington.edu/; Affymetrix, http://www.affymetrix.com; Array Expression Database, http://www.ebi.ac.uk/arrayexpress/.
Note: Supplementary information is available on the Nature Genetics website.
Received 20 June 2005; Accepted 11 October 2005; Published online: 11 December 2005.
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