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• W2047962502 abstract "•Males and females experience different gene dosage for sex-linked genes, which can cause differences in expression.•In some species, sex chromosome dosage compensation has evolved to balance out these these differences.•In other species, dosage compensation is incomplete, and expression for many genes differs between females and males.•Complete sex chromosome dosage compensation is limited to X chromosomes and is incomplete on Z chromosomes. Sex chromosomes often entail gene dose differences between the sexes, which if not compensated for, lead to differences between males and females in the expression of sex-linked genes. Recent work has shown that different organisms respond to sex chromosome dose in a variety of ways, ranging from complete sex chromosome dosage compensation in some species to active compensation of only a minority genes in other organisms. Although we still do not understand the implications of the diversity in sex chromosome dosage compensation, its realization has created exciting new opportunities to study the evolution, mechanism, and consequences of gene regulation. However, confusion remains as to what sorts of genes are likely to be dosage compensated, how dosage compensation evolves, and why complete dosage compensation appears to be limited to male heterogametic species. In this review, I survey the status of dosage compensation to answer these questions and identify current controversies in this fast-moving field. Sex chromosomes often entail gene dose differences between the sexes, which if not compensated for, lead to differences between males and females in the expression of sex-linked genes. Recent work has shown that different organisms respond to sex chromosome dose in a variety of ways, ranging from complete sex chromosome dosage compensation in some species to active compensation of only a minority genes in other organisms. Although we still do not understand the implications of the diversity in sex chromosome dosage compensation, its realization has created exciting new opportunities to study the evolution, mechanism, and consequences of gene regulation. However, confusion remains as to what sorts of genes are likely to be dosage compensated, how dosage compensation evolves, and why complete dosage compensation appears to be limited to male heterogametic species. In this review, I survey the status of dosage compensation to answer these questions and identify current controversies in this fast-moving field. In diploid species, sex determination is often linked to sex chromosomes, which follow one of two primary types. In male heterogamety (see Glossary), males have an XY genotype and are the heterogametic sex, and females are XX and are homogametic. Alternatively, many species are female heterogametic, with ZW females and homogametic males with a ZZ genotype. Regardless of which sex is heterogametic, sex chromosome pairs, meaning the X and Y or Z and W chromosomes, usually originate from a pair of autosomes, initially identical, that diverge from each other after recombination between them is suppressed. Once recombination is halted, the sex-limited Y or W chromosome deteriorates in both gene content and activity [1Bachtrog D. Y-chromosome evolution: emerging insights into processes of Y-chromosome degeneration.Nat. Rev. Genet. 2013; 14: 113-124Crossref PubMed Scopus (513) Google Scholar]. The degree of difference between sex chromosome pairs varies among species and, although many species with genetic sex determination show only small differences between the X and Y or Z and W chromosomes [2Kamiya T. et al.A trans-species missense SNP in Amhr2 is associated with sex determination in the tiger pufferfish, Takifugu rubripes (Fugu).PLoS Genet. 2012; 8: e1002798Crossref PubMed Scopus (409) Google Scholar], some sex chromosome pairs show marked divergence from each other when the region of suppressed recombination is large. The decay of genes and gene activity on the Y or W chromosome causes an imbalance between males and females in gene dose; whereas the homogametic sex retains two copies of all X- or Z-linked genes, genes lost from the sex-limited chromosome are present in only one copy in the heterogametic sex. In those species where recombination suppression spreads across the sex chromosomes and a larger share of the Y or W chromosome is gnawed away, dose differences between the sexes emerge for an increasing proportion of X- or Z-linked genes and the heterogametic sex becomes effectively monosomic for the X or Z chromosome. In some species, such as eutherian mammals, Drosophila, and many birds, only a few dozen genes remain on the Y or W chromosome [3Hughes J.F. et al.Strict evolutionary conservation followed rapid gene loss on human and rhesus Y chromosomes.Nature. 2012; 483: 82-86Crossref PubMed Scopus (187) Google Scholar, 4Koerich L.B. et al.Low conservation of gene content in the Drosophila Y chromosome.Nature. 2008; 456: 949-951Crossref PubMed Scopus (113) Google Scholar, 5Moghadam H.K. et al.W chromosome expression responds to female-specific selection.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 8207-8211Crossref PubMed Scopus (75) Google Scholar], which leads to gene dose differences between the sexes for hundreds of genes on the X or Z chromosome. Gene dose is often, although not always, correlated with gene transcription and translation levels [6Guo M. et al.Dosage effects on gene expression in a maize ploidy series.Genetics. 1996; 142: 1349-1355PubMed Google Scholar, 7Malone J.H. et al.Mediation of Drosophila autosomal dosage effects and compensation by network interactions.Genome Biol. 2012; 13: R28Crossref PubMed Scopus (71) Google Scholar]. This is because reducing the number of gene copies cuts the number of targets that the transcriptional machinery can work from to generate RNA, which can translate to differences in protein levels. Additionally, because genes do not work in isolation, sex chromosome dose differences between males and females can affect protein titers for not only X- and Z-linked loci, but also the many downstream autosomal genes that they regulate [8Wijchers P.J. Festenstein R.J. Epigenetic regulation of autosomal gene expression by sex chromosomes.Trends Genet. 2011; 27: 132-140Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 9Wijchers P.J. et al.Sexual dimorphism in mammalian autosomal gene regulation is determined not only by Sry but by sex chromosome complement as well.Dev. Cell. 2010; 19: 477-484Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar]. Because eukaryotic genomes have complex interconnected network structures, gene dose differences for a few hundred genes on the sex chromosomes could theoretically affect a large proportion of the genome. Limited deletions of specific genes or restricted regions of autosomes can be tolerated in many cases; however, complete autosomal monosomies are generally lethal. Given the harmful effects of autosomal monosomy, it was assumed until recently (Box 1) that sex chromosome monosomy would need to be actively compensated for by hyperexpression of nearly all genes on the X (or Z) chromosome in the heterogametic sex. The assumption that complete sex chromosome dosage compensation is required to accompany sex chromosome divergence has changed somewhat over the past few years. Although some species, such as Drosophila [10Larschan E. et al.X chromosome dosage compensation via enhanced transcriptional elongation in Drosophila.Nature. 2011; 471: 115-139Crossref PubMed Scopus (150) Google Scholar] and Caenorhabditis elegans [11Ercan S. et al.X chromosome repression by localization of the C. elegans dosage compensation machinery to sites of transcription initiation.Nat. Genet. 2007; 39: 403-408Crossref PubMed Scopus (98) Google Scholar], do regulate the entire sex chromosome as a unit to achieve complete dosage compensation, where all (or nearly all) genes on the sex chromosome are restored to the diploid expression level in the heterogametic sex, it is now clear from the list of species that show incomplete dosage compensation (Table 1) that this sort of complex whole-chromosome regulation is not necessarily expected to accompany all heteromorphic sex chromosomes.Box 1Ohno's theory of sex chromosome dosage compensationAlthough deletions of limited regions of any given chromosome can often be tolerable, monosomy of an entire autosome is frequently catastrophic for an organism. Given that sex chromosome divergence leads to male monosomy of the X or female monosomy of the Z chromosome, Susumu Ohno proposed over 40 years ago that the heterogametic sex would upregulate the single X or Z chromosome to compensate for sex chromosome monosomy [16Ohno S. Sex Chromosomes and Sex-linked Genes. Springer-Verlag, 1967Crossref Google Scholar]. This would return expression for genes on the X or Z chromosome in the heterogametic sex to the diploid level observed before gene activity decayed on the sex-limited Y or W chromosome. This theory of dosage compensation was supported by subsequent empirical work in the main model organisms, placental mammals [42Gupta V. et al.Global analysis of X-chromosome dosage compensation.J. Biol. 2006; 5: 3Crossref PubMed Scopus (237) Google Scholar, 43Nguyen D.K. Disteche C.M. High expression of the mammalian X chromosome in brain.Brain Res. 2006; 1126: 46-49Crossref PubMed Scopus (85) Google Scholar], Caenorhabditis elegans [11Ercan S. et al.X chromosome repression by localization of the C. elegans dosage compensation machinery to sites of transcription initiation.Nat. Genet. 2007; 39: 403-408Crossref PubMed Scopus (98) Google Scholar, 44Reinke V. et al.Genome-wide germline-enriched and sex-biased expression profiles in Caenorhabditis elegans.Development. 2004; 131: 311-323Crossref PubMed Scopus (344) Google Scholar], and Drosophila, all of which appeared to exhibit complete X chromosome dosage compensation as Ohno predicted. This in turn led to the widespread and long-standing assumption that complete sex chromosome dosage compensation was a requirement for any species with divergent sex chromosomes.The first real crack in the theory of complete sex chromosome dosage compensation occurred in 2007 with the publication of two papers from separate groups showing that birds lacked complete Z chromosome dosage compensation [12Itoh Y. et al.Dosage compensation is less effective in birds than in mammals.J. Biol. 2007; 6: 2Crossref PubMed Scopus (265) Google Scholar, 45Ellegren H. et al.Faced with inequality: chicken does not have general dosage compensation of sex-linked genes.BMC Biol. 2007; 5: 40Crossref PubMed Scopus (196) Google Scholar] and, as a result, most Z-linked genes were expressed at lower levels in females because of reduced gene dose. At this point, it was not clear whether birds were simply the inevitable exception to every biological rule, or dosage compensation was less common than previously assumed. Since then, however, studies on a wide range of other organisms (Table 1, main text) have overturned the view that complete sex chromosome dosage compensation necessarily accompanies sex chromosome evolution. This has in turn led to a re-evaluation of the model organisms originally thought to exhibit dosage compensation, with some surprising results (see Box 3).Table 1Current status of dosage compensationaRecent studies have assessed the presence or absence of complete dosage compensation by comparing the average X or Z expression to the average autosomal expression in the heterogametic (Xmale:AAmale or Zfemale:AAfemale) and homogametic (XXfemale:AAfemale or ZZmale:AAmale) sex, and/or comparing average X and Z expression in females and males (XXfemale:Xmale or Zfemale:ZZmale).Species or cladeXmale:AAmale or Zfemale:AAfemaleXXfemale:AAfemale or ZZmale:AAmaleXXfemale:Xmale or Zfemale:ZZmaleAverage sex chromosome dosage compensationRefsMale heterogametic speciesCaenorhabditis elegans111Complete11Ercan S. et al.X chromosome repression by localization of the C. elegans dosage compensation machinery to sites of transcription initiation.Nat. Genet. 2007; 39: 403-408Crossref PubMed Scopus (98) Google Scholar, 44Reinke V. et al.Genome-wide germline-enriched and sex-biased expression profiles in Caenorhabditis elegans.Development. 2004; 131: 311-323Crossref PubMed Scopus (344) Google Scholar, 46Straub T. Becker P.B. Dosage compensation: the beginning and end of generalization.Nat. Rev. Genet. 2007; 8: 47-57Crossref PubMed Scopus (166) Google ScholarDrosophila melanogaster111Complete46Straub T. Becker P.B. Dosage compensation: the beginning and end of generalization.Nat. Rev. Genet. 2007; 8: 47-57Crossref PubMed Scopus (166) Google Scholar, 47Gelbart M.E. Kuroda M.I. Drosophila dosage compensation: a complex voyage to the X chromosome.Development. 2009; 136: 1399-1410Crossref PubMed Scopus (186) Google ScholarTeleopsis dalmanni111Complete34Wilkinson G.S. et al.Sex-biased gene expression during head development in a sexually dimorphic stalk-eyed fly.PLoS ONE. 2013; 8: e59826Crossref PubMed Scopus (17) Google ScholarAnopheles gambiae111Complete48Baker D.A. et al.A comprehensive gene expression atlas of sex- and tissue-specificity in the malaria vector, Anopheles gambiae.BMC Genomics. 2011; 12: 296Crossref PubMed Scopus (149) Google Scholar, 49Hahn M.W. Lanzaro G.C. Female-biased gene expression in the malaria mosquito Anopheles gambiae.Curr. Biol. 2005; 15: R192-R193Abstract Full Text Full Text PDF PubMed Scopus (52) Google ScholarTribolium castaneum1>1>1Complete in males, females show overexpression27Prince E.G. et al.Hyperexpression of the X chromosome in both sexes results in extensive female bias of X-linked genes in the Flour Beetle.Genome Biol. Evol. 2010; 2: 336-346Crossref PubMed Scopus (77) Google ScholarGasterosteus aculeatus<11>1Incomplete33Leder E.H. et al.Female-biased expression on the X chromosome as a key step in sex chromosome evolution in threespine sticklebacks.Mol. Biol. Evol. 2010; 27: 1495-1503Crossref PubMed Scopus (69) Google ScholarOrnithorhynchus anatinus<11>1Incomplete15Julien P. et al.Mechanisms and evolutionary patterns of mammalian and avian dosage compensation.PLoS Biol. 2012; 10: e1001328Crossref PubMed Scopus (142) Google ScholarMonodelphis domestica111Complete15Julien P. et al.Mechanisms and evolutionary patterns of mammalian and avian dosage compensation.PLoS Biol. 2012; 10: e1001328Crossref PubMed Scopus (142) Google ScholarEutherian mammalsbAssessed in human, chimpanzee, bonobo, gorilla, orangutan, Rhesus macaque, and mouse [15].<1<11Complete for dosage sensitive geneseSee Box 3.15Julien P. et al.Mechanisms and evolutionary patterns of mammalian and avian dosage compensation.PLoS Biol. 2012; 10: e1001328Crossref PubMed Scopus (142) Google Scholar, 21Pessia E. et al.Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 5346-5351Crossref PubMed Scopus (140) Google Scholar, 22Lin F.Q. et al.Expression reduction in mammalian X chromosome evolution refutes Ohno's hypothesis of dosage compensation.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 11752-11757Crossref PubMed Scopus (85) Google ScholarSilene latifolia??1Complete17Muyle A. et al.Rapid de novo evolution of X chromosome dosage compensation in Silene latifolia, a plant with young sex chromosomes.PLoS Biol. 2012; 10: e1001308Crossref PubMed Scopus (115) Google ScholarFemale heterogametic speciesSchistosoma mansoni<11<1Incomplete13Vicoso B. Bachtrog D. Lack of global dosage compensation in Schistosoma mansoni, a female-heterogametic parasite.Genome Biol. Evol. 2011; 3: 230-235Crossref PubMed Scopus (60) Google ScholarLepidopteracAssessed in silk moth [31,50] and Indian meal moth [14].<11<1Incomplete14Harrison P. et al.Incomplete sex chromosome dosage compensation in the Indian meal moth, Plodia interpunctella, based on de novo transcriptome assembly.Genome Biol. Evol. 2012; 4: 1118-1126Crossref PubMed Scopus (59) Google Scholar, 31Zha X. et al.Dosage analysis of Z chromosome genes using microarray in silkworm, Bombyx mori.Insect Biochem. Mol. Biol. 2009; 35: 315-321Crossref Scopus (64) Google Scholar, 50Arunkumar K.P. et al.The silkworm Z chromosome Is enriched in testis-specific genes.Genetics. 2009; 182: 493-501Crossref PubMed Scopus (64) Google ScholarAvesdAssessed in chicken [12,45], Kentish plover [52], zebra finch [12], white throated warbler [53], and crow [54].<11>1Incomplete12Itoh Y. et al.Dosage compensation is less effective in birds than in mammals.J. Biol. 2007; 6: 2Crossref PubMed Scopus (265) Google Scholar, 51Arnold A.P. et al.A bird's-eye view of sex chromosome dosage compensation.Annu. Rev. Genomics Hum. Genet. 2008; 9: 109-127Crossref PubMed Scopus (71) Google Scholar, 52Moghadam H.K. et al.The plover neurotranscriptome assembly: transcriptomic analysis in an ecological model species without a reference genome.Mol. Ecol. Res. 2013; 13: 696-705Crossref PubMed Scopus (24) Google Scholar, 53Naurn S. et al.The sex-biased brain: sexual dimorphism in gene expression in two species of songbirds.BMC Genomics. 2011; 12: 37Crossref PubMed Scopus (50) Google Scholar, 54Wolf J.B.W. Bryk J. General lack of global dosage compensation in ZZ/ZW systems? Broadening the perspective with RNA-seq.BMC Genomics. 2011; 12: 91Crossref PubMed Scopus (64) Google Scholara Recent studies have assessed the presence or absence of complete dosage compensation by comparing the average X or Z expression to the average autosomal expression in the heterogametic (Xmale:AAmale or Zfemale:AAfemale) and homogametic (XXfemale:AAfemale or ZZmale:AAmale) sex, and/or comparing average X and Z expression in females and males (XXfemale:Xmale or Zfemale:ZZmale).b Assessed in human, chimpanzee, bonobo, gorilla, orangutan, Rhesus macaque, and mouse 15Julien P. et al.Mechanisms and evolutionary patterns of mammalian and avian dosage compensation.PLoS Biol. 2012; 10: e1001328Crossref PubMed Scopus (142) Google Scholar.c Assessed in silk moth 31Zha X. et al.Dosage analysis of Z chromosome genes using microarray in silkworm, Bombyx mori.Insect Biochem. Mol. Biol. 2009; 35: 315-321Crossref Scopus (64) Google Scholar, 50Arunkumar K.P. et al.The silkworm Z chromosome Is enriched in testis-specific genes.Genetics. 2009; 182: 493-501Crossref PubMed Scopus (64) Google Scholar and Indian meal moth 14Harrison P. et al.Incomplete sex chromosome dosage compensation in the Indian meal moth, Plodia interpunctella, based on de novo transcriptome assembly.Genome Biol. Evol. 2012; 4: 1118-1126Crossref PubMed Scopus (59) Google Scholar.d Assessed in chicken 12Itoh Y. et al.Dosage compensation is less effective in birds than in mammals.J. Biol. 2007; 6: 2Crossref PubMed Scopus (265) Google Scholar, 45Ellegren H. et al.Faced with inequality: chicken does not have general dosage compensation of sex-linked genes.BMC Biol. 2007; 5: 40Crossref PubMed Scopus (196) Google Scholar, Kentish plover 52Moghadam H.K. et al.The plover neurotranscriptome assembly: transcriptomic analysis in an ecological model species without a reference genome.Mol. Ecol. Res. 2013; 13: 696-705Crossref PubMed Scopus (24) Google Scholar, zebra finch 12Itoh Y. et al.Dosage compensation is less effective in birds than in mammals.J. Biol. 2007; 6: 2Crossref PubMed Scopus (265) Google Scholar, white throated warbler 53Naurn S. et al.The sex-biased brain: sexual dimorphism in gene expression in two species of songbirds.BMC Genomics. 2011; 12: 37Crossref PubMed Scopus (50) Google Scholar, and crow 54Wolf J.B.W. Bryk J. General lack of global dosage compensation in ZZ/ZW systems? Broadening the perspective with RNA-seq.BMC Genomics. 2011; 12: 91Crossref PubMed Scopus (64) Google Scholar.e See Box 3. Open table in a new tab Although deletions of limited regions of any given chromosome can often be tolerable, monosomy of an entire autosome is frequently catastrophic for an organism. Given that sex chromosome divergence leads to male monosomy of the X or female monosomy of the Z chromosome, Susumu Ohno proposed over 40 years ago that the heterogametic sex would upregulate the single X or Z chromosome to compensate for sex chromosome monosomy [16Ohno S. Sex Chromosomes and Sex-linked Genes. Springer-Verlag, 1967Crossref Google Scholar]. This would return expression for genes on the X or Z chromosome in the heterogametic sex to the diploid level observed before gene activity decayed on the sex-limited Y or W chromosome. This theory of dosage compensation was supported by subsequent empirical work in the main model organisms, placental mammals [42Gupta V. et al.Global analysis of X-chromosome dosage compensation.J. Biol. 2006; 5: 3Crossref PubMed Scopus (237) Google Scholar, 43Nguyen D.K. Disteche C.M. High expression of the mammalian X chromosome in brain.Brain Res. 2006; 1126: 46-49Crossref PubMed Scopus (85) Google Scholar], Caenorhabditis elegans [11Ercan S. et al.X chromosome repression by localization of the C. elegans dosage compensation machinery to sites of transcription initiation.Nat. Genet. 2007; 39: 403-408Crossref PubMed Scopus (98) Google Scholar, 44Reinke V. et al.Genome-wide germline-enriched and sex-biased expression profiles in Caenorhabditis elegans.Development. 2004; 131: 311-323Crossref PubMed Scopus (344) Google Scholar], and Drosophila, all of which appeared to exhibit complete X chromosome dosage compensation as Ohno predicted. This in turn led to the widespread and long-standing assumption that complete sex chromosome dosage compensation was a requirement for any species with divergent sex chromosomes. The first real crack in the theory of complete sex chromosome dosage compensation occurred in 2007 with the publication of two papers from separate groups showing that birds lacked complete Z chromosome dosage compensation [12Itoh Y. et al.Dosage compensation is less effective in birds than in mammals.J. Biol. 2007; 6: 2Crossref PubMed Scopus (265) Google Scholar, 45Ellegren H. et al.Faced with inequality: chicken does not have general dosage compensation of sex-linked genes.BMC Biol. 2007; 5: 40Crossref PubMed Scopus (196) Google Scholar] and, as a result, most Z-linked genes were expressed at lower levels in females because of reduced gene dose. At this point, it was not clear whether birds were simply the inevitable exception to every biological rule, or dosage compensation was less common than previously assumed. Since then, however, studies on a wide range of other organisms (Table 1, main text) have overturned the view that complete sex chromosome dosage compensation necessarily accompanies sex chromosome evolution. This has in turn led to a re-evaluation of the model organisms originally thought to exhibit dosage compensation, with some surprising results (see Box 3). Studies in birds [12Itoh Y. et al.Dosage compensation is less effective in birds than in mammals.J. Biol. 2007; 6: 2Crossref PubMed Scopus (265) Google Scholar], Schistosoma [13Vicoso B. Bachtrog D. Lack of global dosage compensation in Schistosoma mansoni, a female-heterogametic parasite.Genome Biol. Evol. 2011; 3: 230-235Crossref PubMed Scopus (60) Google Scholar], and other species illustrate that many organisms are resilient to dose effects. In these and other species with incomplete dosage compensation, the transcriptional differences between males and females resulting from reduced dose in the heterogametic sex persist for most genes on the sex chromosome, with no obvious deleterious effects. Moreover, in a sharp turnaround from previous assumptions about the necessity of complete dosage compensation, a spate of recent studies on a wide range of organisms suggests that species with complete sex chromosome dosage compensation may be in the minority. Furthermore, some species that were previously thought to exhibit complete dosage compensation may, in fact, not (Box 3). At the same time that these new results overturned the assumption that complete sex chromosome dosage compensation is required, they also led to several new questions. Why is sex chromosome dosage compensation complete in some organisms but not in others? For species with incomplete dosage compensation, is there a cost to the heterogametic sex for reduced expression of X- and Z-linked genes? These questions have recently been explored using different approaches, and the results have built a more nuanced picture of sex chromosome dosage compensation. There is still some confusion as to what level of expression to expect as a result of halving gene dose in the heterogametic sex. Although it may seem reasonable to assume that halving gene dose should result in halved expression, copy number variation studies tell us that this is far from true in many cases. For many genes, halving the gene dose does not produce any observable changes in expression, or dose effect. Dose effects are the difference in RNA or protein abundance in response to changes in gene dose (or copy number). In other words, dose effects are the difference in expression observed when copy number (or dose) of a gene is varied. It is increasingly clear that many loci, on or off the sex chromosomes, do not show dose effects, and expression is the same whether an individual has one or two copies. For example, genes with lower expression levels are less likely to show dose effects on the autosomes [7Malone J.H. et al.Mediation of Drosophila autosomal dosage effects and compensation by network interactions.Genome Biol. 2012; 13: R28Crossref PubMed Scopus (71) Google Scholar] as well as on sex chromosomes [14Harrison P. et al.Incomplete sex chromosome dosage compensation in the Indian meal moth, Plodia interpunctella, based on de novo transcriptome assembly.Genome Biol. Evol. 2012; 4: 1118-1126Crossref PubMed Scopus (59) Google Scholar, 15Julien P. et al.Mechanisms and evolutionary patterns of mammalian and avian dosage compensation.PLoS Biol. 2012; 10: e1001328Crossref PubMed Scopus (142) Google Scholar]. This may be because the rate of transcription is not saturated at lower expression levels. Additionally, dose effects are less likely for genes with higher levels of feedback regulation through genetic networks [7Malone J.H. et al.Mediation of Drosophila autosomal dosage effects and compensation by network interactions.Genome Biol. 2012; 13: R28Crossref PubMed Scopus (71) Google Scholar]. In these cases, regulatory interactions theoretically act to buffer out dose effects. Studies of autosomal monosomy are, in many ways, good proxies for sex chromosome dose. However, autosomal monosomy generally occurs in a single generation, in contrast to changes in sex chromosome dose, which often occur more gradually as Y and W gene content decays gradually. Despite this key difference, studies of autosomal monosomy indicate that, for many of those genes that do show dose effects, halving the gene dose does not necessarily result in a 50% reduction in expression levels, but rather somewhere in between 50% and 100% of the expression expected from two copies [6Guo M. et al.Dosage effects on gene expression in a maize ploidy series.Genetics. 1996; 142: 1349-1355PubMed Google Scholar, 7Malone J.H. et al.Mediation of Drosophila autosomal dosage effects and compensation by network interactions.Genome Biol. 2012; 13: R28Crossref PubMed Scopus (71) Google Scholar]. The variation in dose effects means that even in species with no active sex chromosome dosage compensation mechanism, some sex-linked genes will not differ in expression between the sexes, and most genes will not show a 50% reduction in expression due to halved gene dose in the heterogametic sex. Additionally, genes that lack dose effects, or lack the full 50% reduction in response to halving the gene dose, are not necessarily dosage compensated. Sex chromosome dosage compensation connotes an active transcriptional process, selected for in the heterogametic sex, that restores expression from the single X or Z chromosome to diploid levels [16Ohno S. Sex Chromosomes and Sex-linked Genes. Springer-Verlag, 1967Crossref Google Scholar]. Genes that lack dose effects cannot have been actively selected to increase expression because their expression did not fall with reduced gene dose. Rather, their expression levels are passively buffered by the transcriptional machinery or network interactions. This may seem a somewhat semantic argument; however, differentiating these two mechanisms, one direct and actively selected for and the other indirect and a consequence of other gene characteristics, is in fact important. In systems with incomplete sex chromosome dosage compensation, variation in dose effect can lead to some confusion. Specifically, it can be difficult to determine whether similar expression in males and females for any given sex-linked gene is due to direct dosage compensation [17Muyle A. et al.Rapid de novo evolution of X chromosome dosage compensation in Silene latifolia, a plant with young sex chromosomes.PLoS Biol. 2012; 10: e1001308Crossref PubMed Scopus (115) Google Scholar], where selection has acted to increase expression in the heterogametic sex, or is simply an indirect consequence of a locus that does not experience a dose effect. Moreover, sex chromosomes show unique patterns of masculinization and feminization of gene expression [18Vicoso B. Charlesworth B. Evolution on the X chromosome: unusual patterns and processes.Nat. Rev. Genet. 2006; 7: 645-653Crossref PubMed Scopus (353) Google Scholar], which can act against the evolution of dosage compensation [19Wright A.E. et al.Trade-off between selection for dosage compensation and masculinization of the avian Z chromosome.Genetics. 2012; 192: 1433-1445Crossref PubMed Scopus (56) Google Scholar] and further obscure the genetic and evolutionary forces shaping express" @default.
• W2047962502 created "2016-06-24" @default.
• W2047962502 creator A5065185968 @default.
• W2047962502 date "2013-12-01" @default.
• W2047962502 modified "2023-10-04" @default.
• W2047962502 title "Sex chromosome dosage compensation: definitely not for everyone" @default.
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