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Dosage compensation is less effective in birds than in mammals  [cached]
Itoh Yuichiro,Melamed Esther,Yang Xia,Kampf Kathy
Journal of Biology , 2007, DOI: 10.1186/jbiol53
Abstract: 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.
Decoding dosage compensation
Xinxian Deng, Christine M Disteche
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-2-204
Abstract: In animals in which sex is determined by a divergent pair of sex chromosomes (XY), the resulting imbalance of gene dose between autosomes and sex chromosomes is potentially fatal. This imbalance is redressed by a process termed dosage compensation, which modulates global gene expression on the X chromosome to restore a balanced network of gene expression in the diploid cells in both sexes [1-4]. In Drosophila, dosage compensation is achieved by a twofold upregulation of expression from the single X chromosome in males. In contrast, in mammals and Caenorhabditis elegans, X-chromosome upregulation occurs in both sexes, together with a reduction of X-linked gene expression in the homogametic sex by silencing one of the two X chromosomes in mammalian females or repressing both X chromosomes in C. elegans hermaphrodites. Despite such diverse strategies, a fundamental question in the study of dosage compensation in all these species is how specific recognition of an entire X chromosome occurs. McDonel et al. [5] have recently shed light on this problem. They have discovered two clustered DNA motifs on the C. elegans X chromosome that act as a cis-acting code for recognition by the dosage-compensation complex (DCC), a complex of proteins that is responsible for the repression of the X chromosomes in hermaphrodites. This breakthrough points out the importance of DNA sequence in specifying the target of the DCC.Dosage-compensation mechanisms involve both protein complexes that act in trans and elements that are produced by the X chromosome itself, such as X inactive-specific transcript (XIST) RNA, which is essential for the onset of mammalian X inactivation. The question is how such regulatory complexes become specifically associated with, or stay with, the X chromosome. X inactivation is random in eutherian mammals, with either the paternal or maternal X chromosome silenced; however, in early mouse embryos and in marsupials, the paternal X chromosome is always inactivated.
Widespread Occurrence of Dosage Compensation in Candida albicans  [PDF]
Anatoliy Kravets,Hong Qin,Ausaf Ahmad,Gabor Bethlendy,Qinshan Gao,Elena Rustchenko
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010856
Abstract: The important human pathogen Candida albicans possesses an unusual form of gene regulation, in which the copy number of an entire specific chromosome or a large portion of a specific chromosome changes in response to a specific adverse environment, thus, insuring survival. In the absence of the adverse environment, the altered portion of the genome can be restored to its normal condition. One major question is how C. albicans copes with gene imbalance arising by transitory aneuploid states. Here, we compared transcriptomes from cells with either two copies or one copy of chromosome 5 (Ch5) in, respectively, a diploid strain 3153A and its representative derivative Sor55. Statistical analyses revealed that at least 40% of transcripts from the monosomic Ch5 are fully compensated to a disomic level, thus, indicating the existence of a genome-wide mechanism maintaining cellular homeostasis. Only approximately 15% of transcripts were diminished twofold in accordance with what would be expected for Ch5 monosomy. Another minor portion of approximately 6% of transcripts, unexpectedly, increased up to twofold and higher than the disomic level, demonstrating indirect control by monosomy. Array comparative genome hybridization revealed that only few out of approximately 500 genes on the monosomic Ch5b were duplicated, thus, not causing a global up regulation. Dosage compensation was confirmed with several representative genes from another monosomic Ch5a in the mutant Sor60. We suggest that C. albicans's unusual regulation of gene expression by the loss and gain of entire chromosomes is coupled with widespread compensation of gene dosage at the transcriptional level.
LTR retrotransposons and the evolution of dosage compensation in Drosophila
Lilya V Matyunina, Nathan J Bowen, John F McDonald
BMC Molecular Biology , 2008, DOI: 10.1186/1471-2199-9-55
Abstract: We show that transcription of the Drosophila melanogaster copia LTR (long terminal repeat) retrotransposon is significantly down regulated when in the hemizygous state. DNA digestion and chromatin immunoprecipitation (ChIP) analyses demonstrate that this down regulation is associated with changes in chromatin structure mediated by the histone acetyltransferase, MOF. MOF has previously been shown to play a central role in the Drosophila dosage compensation complex by binding to the hemizygous X-chromosome in males.Our results are consistent with the hypothesis that MOF originally functioned to silence retrotransposons and, over evolutionary time, was co-opted to play an essential role in dosage compensation in Drosophila.Retrotransposons are a major component of the genomes of higher eukaryotes and have been identified as a significant source of loss-of-function and regulatory mutations [1]. Over evolutionary time host genomes have developed mechanisms to mitigate the mutational potential of retrotransposons by transcriptionally silencing or otherwise blocking their transpositional activity [2]. One of the primary mechanisms by which retrotransposons are transcriptionally silenced is by methylation and/or other epigenetic mechanisms. Indeed it has been hypothesized that most, if not all, epigenetic mechanisms originally evolved as a defense against retrotransposons and have subsequently been co-opted for other essential cellular functions [3,4].Approximately 10% of the Drosophila melanogaster genome is comprised of retrotransposons, the majority of which are LTR retrotransposons. LTR retrotransposon insertions are a major source of mutations in D. melanogaster and are believed to have contributed significantly to genome evolution [5]. While histone acetylation and other epigenetic mechanisms are believed to play an essential role in dosage compensation and other vital functions in D. melanogaster, little is known about the role of these mechanisms in the regulation o
An evolutionary consequence of dosage compensation on Drosophila melanogaster female X-chromatin structure?
Yu Zhang, Brian Oliver
BMC Genomics , 2010, DOI: 10.1186/1471-2164-11-6
Abstract: We find that the general chromatin structure of female X chromosomes is distinct from autosomes. Additionally, specific histone marks associated with dosage compensation and active chromatin marks on the male X chromosome are also enriched on the X chromosomes of females, albeit to a lesser degree.Our data indicate that X chromatin structure is fundamentally different from autosome structure in both sexes. We suggest that the differences between the X chromosomes and autosomes in females are a consequence of mechanisms that have evolved to ensure sufficient X chromosome expression in the soma of males.Drosophila X chromosomes show peculiar features in both gene expression [1] and gene evolution [2]. One of the most striking consequences of X chromosome hemizygosity in males, is dosage compensation, a process which brings X chromosome and autosome expression into balance [3-5]. Dosage compensation was probably acquired gradually in the course of sex chromosome evolution, as sex chromosomes are thought to arise by divergence of an ancestral autosome pair [6]. Gene loss from the Y chromosome creates an increasingly aneuploid condition in males and is thought to be the driving force in the evolution of global X-chromosome dosage compensation. In the absence of dosage compensation genomic imbalance results in male lethality.It has long been known that selective pressures applied to just one of the sexes can effect change in the other [7]. For example, the coloration of certain birds or the nipples of mammals are advantageous to one of the sexes and are likely to be present as an evolutionary side-effect in the other. X chromosome dosage compensation might also show evidence of this type of sexual selection. X chromosome dosage compensation requires both cis and trans components [1]. Cis changes resulting from selection of the compensation system in males will also be present in females, and might alter the character of the X chromosome in females as a secondary consequen
Expression in Aneuploid Drosophila S2 Cells  [PDF]
Yu Zhang,John H. Malone,Sara K. Powell,Vipul Periwal,Eric Spana,David M. MacAlpine,Brian Oliver
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000320
Abstract: Extensive departures from balanced gene dose in aneuploids are highly deleterious. However, we know very little about the relationship between gene copy number and expression in aneuploid cells. We determined copy number and transcript abundance (expression) genome-wide in Drosophila S2 cells by DNA-Seq and RNA-Seq. We found that S2 cells are aneuploid for >43 Mb of the genome, primarily in the range of one to five copies, and show a male genotype (~ two X chromosomes and four sets of autosomes, or 2X;4A). Both X chromosomes and autosomes showed expression dosage compensation. X chromosome expression was elevated in a fixed-fold manner regardless of actual gene dose. In engineering terms, the system “anticipates” the perturbation caused by X dose, rather than responding to an error caused by the perturbation. This feed-forward regulation resulted in precise dosage compensation only when X dose was half of the autosome dose. Insufficient compensation occurred at lower X chromosome dose and excessive expression occurred at higher doses. RNAi knockdown of the Male Specific Lethal complex abolished feed-forward regulation. Both autosome and X chromosome genes show Male Specific Lethal–independent compensation that fits a first order dose-response curve. Our data indicate that expression dosage compensation dampens the effect of altered DNA copy number genome-wide. For the X chromosome, compensation includes fixed and dose-dependent components.
Expression in Aneuploid Drosophila S2 Cells  [PDF]
Yu Zhang,John H. Malone,Sara K. Powell,Vipul Periwal,Eric Spana,David M. MacAlpine,Brian Oliver
PLOS Biology , 2010, DOI: 10.1371/journal.pbio.1000320
Abstract: Extensive departures from balanced gene dose in aneuploids are highly deleterious. However, we know very little about the relationship between gene copy number and expression in aneuploid cells. We determined copy number and transcript abundance (expression) genome-wide in Drosophila S2 cells by DNA-Seq and RNA-Seq. We found that S2 cells are aneuploid for >43 Mb of the genome, primarily in the range of one to five copies, and show a male genotype (~ two X chromosomes and four sets of autosomes, or 2X;4A). Both X chromosomes and autosomes showed expression dosage compensation. X chromosome expression was elevated in a fixed-fold manner regardless of actual gene dose. In engineering terms, the system “anticipates” the perturbation caused by X dose, rather than responding to an error caused by the perturbation. This feed-forward regulation resulted in precise dosage compensation only when X dose was half of the autosome dose. Insufficient compensation occurred at lower X chromosome dose and excessive expression occurred at higher doses. RNAi knockdown of the Male Specific Lethal complex abolished feed-forward regulation. Both autosome and X chromosome genes show Male Specific Lethal–independent compensation that fits a first order dose-response curve. Our data indicate that expression dosage compensation dampens the effect of altered DNA copy number genome-wide. For the X chromosome, compensation includes fixed and dose-dependent components.
Targeting Determinants of Dosage Compensation in Drosophila  [PDF]
Ina K Dahlsveen,Gregor D Gilfillan,Vladimir I Shelest,Rosemarie Lamm,Peter B Becker
PLOS Genetics , 2006, DOI: 10.1371/journal.pgen.0020005
Abstract: The dosage compensation complex (DCC) in Drosophila melanogaster is responsible for up-regulating transcription from the single male X chromosome to equal the transcription from the two X chromosomes in females. Visualization of the DCC, a large ribonucleoprotein complex, on male larval polytene chromosomes reveals that the complex binds selectively to many interbands on the X chromosome. The targeting of the DCC is thought to be in part determined by DNA sequences that are enriched on the X. So far, lack of knowledge about DCC binding sites has prevented the identification of sequence determinants. Only three binding sites have been identified to date, but analysis of their DNA sequence did not allow the prediction of further binding sites. We have used chromatin immunoprecipitation to identify a number of new DCC binding fragments and characterized them in vivo by visualizing DCC binding to autosomal insertions of these fragments, and we have demonstrated that they possess a wide range of potential to recruit the DCC. By varying the in vivo concentration of the DCC, we provide evidence that this range of recruitment potential is due to differences in affinity of the complex to these sites. We were also able to establish that DCC binding to ectopic high-affinity sites can allow nearby low-affinity sites to recruit the complex. Using the sequences of the newly identified and previously characterized binding fragments, we have uncovered a number of short sequence motifs, which in combination may contribute to DCC recruitment. Our findings suggest that the DCC is recruited to the X via a number of binding sites of decreasing affinities, and that the presence of high- and moderate-affinity sites on the X may ensure that lower-affinity sites are occupied in a context-dependent manner. Our bioinformatics analysis suggests that DCC binding sites may be composed of variable combinations of degenerate motifs.
Targeting determinants of dosage compensation in Drosophila.  [cached]
Dahlsveen Ina K,Gilfillan Gregor D,Shelest Vladimir I,Lamm Rosemarie
PLOS Genetics , 2006,
Abstract: The dosage compensation complex (DCC) in Drosophila melanogaster is responsible for up-regulating transcription from the single male X chromosome to equal the transcription from the two X chromosomes in females. Visualization of the DCC, a large ribonucleoprotein complex, on male larval polytene chromosomes reveals that the complex binds selectively to many interbands on the X chromosome. The targeting of the DCC is thought to be in part determined by DNA sequences that are enriched on the X. So far, lack of knowledge about DCC binding sites has prevented the identification of sequence determinants. Only three binding sites have been identified to date, but analysis of their DNA sequence did not allow the prediction of further binding sites. We have used chromatin immunoprecipitation to identify a number of new DCC binding fragments and characterized them in vivo by visualizing DCC binding to autosomal insertions of these fragments, and we have demonstrated that they possess a wide range of potential to recruit the DCC. By varying the in vivo concentration of the DCC, we provide evidence that this range of recruitment potential is due to differences in affinity of the complex to these sites. We were also able to establish that DCC binding to ectopic high-affinity sites can allow nearby low-affinity sites to recruit the complex. Using the sequences of the newly identified and previously characterized binding fragments, we have uncovered a number of short sequence motifs, which in combination may contribute to DCC recruitment. Our findings suggest that the DCC is recruited to the X via a number of binding sites of decreasing affinities, and that the presence of high- and moderate-affinity sites on the X may ensure that lower-affinity sites are occupied in a context-dependent manner. Our bioinformatics analysis suggests that DCC binding sites may be composed of variable combinations of degenerate motifs.
Regional differences in dosage compensation on the chicken Z chromosome
Esther Melamed, Arthur P Arnold
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-9-r202
Abstract: 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.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.In birds, males are homogametic (ZZ) and females are heterogametic (ZW), in contrast to the mammalian pattern of female XX homogamety and male XY heterogamety. Like the mammalian X and Y chromosomes, the euchromatic Z is large (over 500 genes) and the heterochromatic W small (probably containing tens of genes) [1-4]. In both groups, the difference in copy number of the Z or X chromosomes results in one sex having a higher genomic dose of Z or X genes.Gene dosage is considered to be critical, at least for a significant number of genes, and an imbalance in chromosomal number (aneuploidy) can result in conditions such as Turner syndrome (XO), Klinefelter syndrome (XXY), Down syndrome (Trisomy 21), and cancer [5-7]. Aneuploidy for an entire chromosome is usually lethal [8]. Because a delicate balance in gene dosage is important for proper functioning and organismal survival, numerous species have evolved mechani
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