Showing papers on "Dosage compensation published in 2007"
TL;DR: This work has established sex chromosome asynapsis as the primary trigger of MSCI, and it is now clear that it is maintained, although not completely, well beyond meiosis and into sperm development.
Abstract: X chromosome inactivation is most commonly studied in the context of female mammalian development, where it performs an essential role in dosage compensation. However, another form of X-inactivation takes place in the male, during spermatogenesis, as germ cells enter meiosis. This second form of X-inactivation, called meiotic sex chromosome inactivation (MSCI) has emerged as a novel paradigm for studying the epigenetic regulation of gene expression. New studies have revealed that MSCI is a special example of a more general mechanism called meiotic silencing of unsynapsed chromatin (MSUC), which silences chromosomes that fail to pair with their homologous partners and, in doing so, may protect against aneuploidy in subsequent generations. Furthermore, failure in MSCI is emerging as an important etiological factor in meiotic sterility.
617 citations
TL;DR: Unexpectedly widespread monoallelic expression suggests a mechanism that generates diversity in individual cells and their clonal descendants.
Abstract: Monoallelic expression with random choice between the maternal and paternal alleles defines an unusual class of genes comprising X-inactivated genes and a few autosomal gene families. Using a genome-wide approach, we assessed allele-specific transcription of about 4000 human genes in clonal cell lines and found that more than 300 were subject to random monoallelic expression. For a majority of monoallelic genes, we also observed some clonal lines displaying biallelic expression. Clonal cell lines reflect an independent choice to express the maternal, the paternal, or both alleles for each of these genes. This can lead to differences in expressed protein sequence and to differences in levels of gene expression. Unexpectedly widespread monoallelic expression suggests a mechanism that generates diversity in individual cells and their clonal descendants.
559 citations
TL;DR: 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, suggesting that some genomes can do without effective sex-specific sex-chromosome dosage compensation mechanisms.
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. Conclusions: 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.
316 citations
TL;DR: Using expression profiling and comparative sequence analysis, it is shown that selective gene extinction on the X chromosome, creation of new genes on autosomes and changed genomic location of existing genes contribute to the unusual X’chromosomes gene content.
Abstract: This issue includes a landmark collection of papers on the stalwart of the genetics lab, the Drosophila fruit fly. The centrepiece is the publication by the Drosophila 12 Genomes Consortium of the genomic sequence for ten Drosophila species. The paper compares the newly sequenced genomes (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi species), with the two previously known sequences for D. melanogaster and D. pseudoobscura. The resulting database of genetic variation will be invaluable for the study of the forces of evolutionary change. A second major collaboration has mined the dozen Drosophila genome sequences for conserved elements, and reports the relationship between conservation and function for many specific sequence motifs. A detailed regulatory network emerges, identifying protein-coding genes and exons, RNA genes, microRNAs and their targets. These papers are discussed in News and Views. Two further research papers use the new genomic data to study gene expression, first for genes with male-biased expression and those unique to each species and second, to track the evolution of gene dosage compensation on Drosophila sex chromosomes. Four new reviews focus on how the latest work on Drosophila is taking this genetically pliant lab model into exciting new fields. Pierre Leopold and Norbert Perrimon review advances in the study of endocrinology and homeostasis that are establishing Drosophila as a model for mammalian physiology. Drosophila has proved a powerful system in which to study the pathways controlling cell shape in growing tissue, as reported by Thomas Lecuit and Loic Le Goff. Leslie Vosshall reviews the remarkable work linking neural circuits and behaviour and John Lis reviews work on Drosophila that has rewritten the textbook view of gene transcription. The cover shows anaesthetized individuals of all twelve Drosophila species. The evolution of dosage compensation on Drosophila sex chromosomes is examined by using microarrays to determine relative gene expression of sex-linked genes in a number of fly species. How this expression changes over time is discussed, particularly in species with a neo-X chromosome, to determine why genes might have male-biased expression. X chromosomes evolve differently from autosomes, but general governing principles have not emerged1. For example, genes with male-biased expression are under-represented on the X chromosome of D. melanogaster2, but are randomly distributed in the genome of Anopheles gambiae3. In direct global profiling experiments using species-specific microarrays, we find a nearly identical paucity of genes with male-biased expression on D. melanogaster, D. simulans, D. yakuba, D. ananassae, D. virilis and D. mojavensis X chromosomes. We observe the same under-representation on the neo-X of D. pseudoobscura. It has been suggested that precocious meiotic silencing of the X chromosome accounts for reduced X chromosome male-biased expression in nematodes4, mammals5 and Drosophila6. We show that X chromosome genes with male-biased expression are under-represented in somatic cells and in mitotic male germ cells. These data are incompatible with simple X chromosome inactivation models. Using expression profiling and comparative sequence analysis, we show that selective gene extinction on the X chromosome, creation of new genes on autosomes and changed genomic location of existing genes contribute to the unusual X chromosome gene content.
243 citations
TL;DR: This report demonstrates the first example of an organism with a lack of global dosage compensation, providing an unexpected case of a viable system with large-scale imbalance in gene expression between sexes.
Abstract: The contrasting dose of sex chromosomes in males and females potentially introduces a large-scale imbalance in levels of gene expression between sexes, and between sex chromosomes and autosomes. In many organisms, dosage compensation has thus evolved to equalize sex-linked gene expression in males and females. In mammals this is achieved by X chromosome inactivation and in flies and worms by up- or down-regulation of X-linked expression, respectively. While otherwise widespread in systems with heteromorphic sex chromosomes, the case of dosage compensation in birds (males ZZ, females ZW) remains an unsolved enigma.
229 citations
TL;DR: The results support a model in which MSL complex uses high-affinity sites to initially recognize the X chromosome and then associates with many of its targets through sequence-independent features of transcribed genes.
218 citations
TL;DR: The genomes of higher eukaryotes are carefully balanced systems of gene expression that compensate for the different numbers of sex chromosomes in the two sexes by adjusting gene expression levels.
Abstract: The genomes of higher eukaryotes are carefully balanced systems of gene expression that compensate for the different numbers of sex chromosomes in the two sexes by adjusting gene expression levels. Different strategies for sex chromosome dosage compensation have evolved, which all involve modulating chromatin structure as a means to fine-tune transcription levels. As data accumulate, previous over-simplifications are being revised, and novel features of the compensation processes are gaining attention, many of which are of sufficient global validity to influence our view on gene expression beyond the realm of dosage compensation itself.
217 citations
TL;DR: It is proposed that homologous associations driven by this novel X-pairing region (Xpr) of the Xic enable a cell to sense that more than one X chromosome is present and coordinate reciprocal Xist/Tsix expression.
Abstract: Mammalian dosage compensation involves silencing of one of the two X chromosomes in females and is controlled by the X-inactivation center (Xic). The Xic, which includes Xist and its antisense transcription unit Tsix/Xite, somehow senses the number of X chromosomes and triggers Xist up-regulation from one of the two X chromosomes in females. We found that a segment of the mouse Xic lying several hundred kilobases upstream of Xist brings the two Xics together before the onset of X inactivation. This region can autonomously drive Xic trans-interactions even as an ectopic single-copy transgene. Its introduction into male embryonic stem cells is strongly selected against, consistent with a possible role in trans-activating Xist. We propose that homologous associations driven by this novel X-pairing region (Xpr) of the Xic enable a cell to sense that more than one X chromosome is present and coordinate reciprocal Xist/Tsix expression.
191 citations
TL;DR: The understanding of dosage compensation in placental mammals is critically reviewed and these findings are placed in the context of other cellular processes that intersect with mammalian dosage compensation.
Abstract: X inactivation is the mechanism by which mammals adjust the genetic imbalance that arises from the different numbers of gene-rich X-chromosomes between the sexes. The dosage difference between XX females and XY males is functionally equalized by silencing one of the two X chromosomes in females. This dosage-compensation mechanism seems to have arisen concurrently with early mammalian evolution and is based on the long functional Xist RNA, which is unique to placental mammals. It is likely that previously existing mechanisms for other cellular functions have been recruited and adapted for the evolution of X inactivation. Here, we critically review our understanding of dosage compensation in placental mammals and place these findings in the context of other cellular processes that intersect with mammalian dosage compensation.
177 citations
TL;DR: The sex chromosome system is being exploited in economically important species and special strains have been devised for mass rearing of male-only broods in the silkworm for higher silk production and in pest species for the release of sterile males in pest management programs.
Abstract: The speciose insect order Lepidoptera (moths and butterflies) and their closest relatives, Trichoptera (caddis flies), share a female-heterogametic sex chromosome system. Originally a Z/ZZ (female/male) system, it evolved by chromosome rearrangement to a WZ/ZZ (female/male) system in the most species-rich branch of Lepidoptera, a monophyletic group consisting of Ditrysia and Tischeriina, which together comprise more than 98% of all species. Further sporadic rearrangements created multi-sex chromosome systems; sporadic losses of the W changed the system formally back to Z/ZZ in some species. Primary sex determination depends on a Z-counting mechanism in Z/ZZ species, but on a female-determining gene, Fem, in the W chromosome of the silkworm. The molecular mechanism is unknown in both cases. The silkworm shares the last step, dsx, of the hierarchical sex-determining pathway with Drosophila and other insects investigated, but probably not the intermediate steps between the primary signal and dsx. The W chromosome is heterochromatic in most species. It contains few genes and is flooded with interspersed repetitive elements. In interphase nuclei of females it is readily discernible as a heterochromatic body which grows with increasing degree of polyploidy in somatic cells. It is used as a marker for the genetic sex in studies of intersexes and Wolbachia infections. The sex chromosome system is being exploited in economically important species. Special strains have been devised for mass rearing of male-only broods in the silkworm for higher silk production and in pest species for the release of sterile males in pest management programs.
163 citations
TL;DR: Random inactivation of one of the two female X chromosomes establishes dosage compensation between XY males and XX females in placental mammals and is implicated in the mechanism of random choice.
TL;DR: It is proposed that X-linked genes are silenced in female ES cells by spreading of Xist RNA through the X chromosome territory as the cells differentiate, with silencing times for individual genes dependent on their proximity to the Xist locus.
Abstract: Dosage compensation in mammals involves silencing of one X chromosome in XX females and requires expression, in cis, of Xist RNA. The X to be inactivated is randomly chosen in cells of the inner cell mass (ICM) at the blastocyst stage of development. Embryonic stem (ES) cells derived from the ICM of female mice have two active X chromosomes, one of which is inactivated as the cells differentiate in culture, providing a powerful model system to study the dynamics of X inactivation. Using microarrays to assay expression of X-linked genes in undifferentiated female and male mouse ES cells, we detect global up-regulation of expression (1.4- to 1.6-fold) from the active X chromosomes, relative to autosomes. We show a similar up-regulation in ICM from male blastocysts grown in culture. In male ES cells, up-regulation reaches 2-fold after 2–3 weeks of differentiation, thereby balancing expression between the single X and the diploid autosomes. We show that silencing of X-linked genes in female ES cells occurs on a gene-by-gene basis throughout differentiation, with some genes inactivating early, others late, and some escaping altogether. Surprisingly, by allele-specific analysis in hybrid ES cells, we also identified a subgroup of genes that are silenced in undifferentiated cells. We propose that X-linked genes are silenced in female ES cells by spreading of Xist RNA through the X chromosome territory as the cells differentiate, with silencing times for individual genes dependent on their proximity to the Xist locus.
TL;DR: Genetic biology should be considered for any disease or phenotype that occurs in one sex more than the other, because the disease mechanism may be influenced directly by an X-linked gene or indirectly through the consequences of X inactivation.
TL;DR: Because of X‐inactivation, females heterozygous for X‐linked genes are mixtures of two types of cells and show a variable phenotype, which can depart from equality due to cell selection either at the tissue or whole organism level.
Abstract: The inactivation of one X-chromosome in females in early development is the process by which the effective dosage of X-linked genes is equalized between XX females and XY males. The mechanism that brings this about is thesubject of intense research. The X-linked gene Xist is a key player, which is necessary but not sufficient for the initiation of X-inactivation. It codes for an untranslated RNA that coats the inactive X-chromosome, which takes on properties characteristic of heterochromatin, but how this change in chromatin is brought about remains unknown. Because of X-inactivation, females heterozygous for X-linked genes are mixtures of two types of cells and show a variable phenotype. The proportions of the two types of cells can depart from equality due to cell selection either at the tissue or whole organism level. In rare cases, changes in the Xist gene can cause skewing of X-inactivation. A few genes escape from X-inactivation either wholly or partially. Conclusion: X-chromosome inactivation is a physiological mechanism that equalizes gene-dosage effects on the sex chromosomes. The occurrence of this normal process affects the phenotype seen in females carrying X-linked mutant genes or chromosome anomalies.
TL;DR: The binding location of the condensin homolog DPY-27 and the zinc finger protein SDC-3, two components of the C. elegans dosage compensation complex (DCC), is mapped to aid in understanding how proteins involved in higher-order chromosome dynamics can regulate transcription at individual loci.
Abstract: Among organisms with chromosome-based mechanisms of sex determination, failure to equalize expression of X-linked genes between the sexes is typically lethal. In C. elegans, XX hermaphrodites halve transcription from each X chromosome to match the output of XO males1. Here, we mapped the binding location of the condensin homolog DPY-27 and the zinc finger protein SDC-3, two components of the C. elegans dosage compensation complex (DCC)2,3. We observed strong foci of DCC binding on X, surrounded by broader regions of localization. Binding foci, but not adjacent regions of localization, were distinguished by clusters of a 10-bp DNA motif, suggesting a recruitment-and-spreading mechanism for X recognition. The DCC was preferentially bound upstream of genes, suggesting modulation of transcriptional initiation and polymerase-coupled spreading. Stronger DCC binding upstream of genes with high transcriptional activity indicated a mechanism for tuning DCC activity at specific loci. These data aid in understanding how proteins involved in higher-order chromosome dynamics can regulate transcription at individual loci.
TL;DR: The aggregation of dosage compensated genes near theMHM locus may reflect a local sex- and chromosome-specific mechanism of dosage compensation, perhaps mediated by the MHM non-coding RNA.
Abstract: 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.
TL;DR: It is argued that the sex benefit of females during the host response is associated with polymorphism of X- linked genes and cellular mosaicism for X-linked parental alleles, which represents a more adaptive and balanced cellular machinery that is advantageous during the innate immune response.
Abstract: Females as compared with males display better general health status, longevity, and improved clinical course after injury and infection. It is generally believed that the female advantage is associated with the effects of sex hormones. This review argues that the sex benefit of females during the host response is associated with polymorphism of X-linked genes and cellular mosaicism for X-linked parental alleles. Cells from females carry both parental X chromosomes (maternal, Xm; or paternal, Xp), whereas males carry only one (Xm). Because of dosage compensation and random X inactivation, half of the cells from females express either Xm or Xp. Therefore, females are cellular mosaics for their X-linked polymorphic genes. This cellular mosaicism in females represents a more adaptive and balanced cellular machinery that is advantageous during the innate immune response. Several genes encoding key metabolic and regulatory proteins reside on the X chromosome, including members of the apoptotic cascade, hormone homeostasis, glucose metabolic enzymes, superoxide-producing machinery, and the toll-like receptor/nuclear factor kappaB/c-Jun N-terminal kinase signaling pathway. Polymorphic forms of these X-linked proteins are likely to manifest in phenotypic differences in the mosaic cell populations in females and may contribute to sex-related differences in the host response to injury and infection. The unique inheritance pattern of X-linked polymorphisms and their potential confounding effects in clinical trials are also discussed; furthermore, we present potential biomarkers for studying mosaic cell populations of innate immunity.
TL;DR: The region homologous to the human and mouse X-inactivation centre expanded in early mammals, and this unstable region was disrupted independently in marsupial and monotreme lineages, confirming the conclusion that non-eutherian mammals lack XIST.
Abstract: Marsupial, as well as eutherian, mammals are subject to X chromosome inactivation in the somatic cells of females, although the phenotype and the molecular mechanism differ in important respects. Monotreme mammals appear to subscribe at least to a form of dosage compensation of X-borne genes. An important question is whether inactivation in these non-eutherian mammals involves co-ordination by a control locus homologous to the XIST gene and neighbouring genes, which play a key regulatory role in human and mouse X inactivation. We mapped BACs containing several orthologues of protein-coding genes that flank human and mouse XIST and genes that lie in the homologous region in chicken and frog. We found that these genes map to two distant locations on the opossum X, and also to different locations on a platypus autosome. We failed to find any trace of an XIST orthologue in any marsupial or monotreme or on any flanking BAC, confirming the conclusion from recent work that non-eutherian mammals lack XIST. We propose the region homologous to the human and mouse X-inactivation centre expanded in early mammals, and this unstable region was disrupted independently in marsupial and monotreme lineages. In the eutherian lineage, inserted and existing sequences provided the starting material for the non-translated RNAs of the X-inactivation centre, including XIST.
TL;DR: It is reported here that ERL2 is haploinsufficient for maintaining female fertility in the absence of ER and ERL1, and genetic interaction of the ER family and the WOX-family gene, PFS2, reveals their contribution to integument development through interrelated mechanisms.
Abstract: The Arabidopsis genome contains three ERECTA-family genes, ERECTA (ER), ERECTA-LIKE 1 (ERL1) and ERL2 that encode leucine-rich repeat receptor-like kinases. This gene family acts synergistically to coordinate cell proliferation and growth during above-ground organogenesis with the major player, ER, masking the loss-of-function phenotypes of the other two members. To uncover the specific developmental consequence and minimum threshold requirement for signaling, ER-family gene function was successively eliminated. We report here that ERL2 is haploinsufficient for maintaining female fertility in the absence of ER and ERL1. Ovules of the haploinsufficient er-105 erl1-2 erl2-1/+ mutant exhibit abnormal development with reduced cell proliferation in the integuments and gametophyte abortion. Our analysis indicates that progression of integument growth requires ER-family signaling in a dosage-dependent manner and that transcriptional compensation among ER-family members occurs to maintain the required signaling threshold. The specific misregulation of cyclin A genes in the er-105 erl1-2 erl2-1/+ mutant suggests that downstream targets of the ER-signaling pathway might include these core cell-cycle regulators. Finally, genetic interaction of the ER family and the WOX-family gene, PFS2, reveals their contribution to integument development through interrelated mechanisms.
TL;DR: It is demonstrated that MSCI and PMSC occur in the opossum, and the idea that male germ-line silencing may have provided an ancestral form of mammalian dosage compensation is supported.
Abstract: In marsupials, dosage compensation involves silencing of the father's X-chromosome. Because no XIST orthologue has been found, how imprinted X-inactivation occurs is unknown. In eutherians, the X is subject to meiotic sex chromosome inactivation (MSCI) in the paternal germ line and persists thereafter as postmeiotic sex chromatin (PMSC). One hypothesis proposes that the paternal X is inherited by the eutherian zygote as a preinactive X and raises the possibility of a similar process in the marsupial germ line. Here we demonstrate that MSCI and PMSC occur in the opossum. Surprisingly, silencing occurs before X-Y association. After MSCI, the X and Y fuse through a dense plate without obvious synapsis. Significantly, sex chromosome silencing continues after meiosis, with the opossum PMSC sharing features of eutherian PMSC. These results reveal a common gametogenic program in two diverse clades of mammals and support the idea that male germ-line silencing may have provided an ancestral form of mammalian dosage compensation.
TL;DR: Using DNA methylation of promoter sequences to assess whether genes are silenced in females the authors report the inactivation status of seven X-linked genes in humans and mice as well as two additional eutherians, the mole and the cow, providing evidence that escape from inactivation is common among Eutheria.
TL;DR: This review emphasizes the opportunity that Xist provides to functionally define epigenetic transitions in development, to understand cell identity, pluripotency and stem cell differentiation.
TL;DR: A statistical mechanics model of XCI is proposed and how a "blocking factor" complex is self-assembled and why only one is formed out of many diffusible molecules, resulting in a spontaneous symmetry breaking in the binding to two identical chromosomes is described.
Abstract: In mammals, dosage compensation of X linked genes in female cells is achieved by inactivation of one of their two X chromosomes which is randomly chosen. The earliest steps in X-chromosome inactivation (XCI), namely, the mechanism whereby cells count their X chromosomes and choose between two equivalent X chromosomes, remain mysterious. Starting from the recent discovery of X chromosome colocalization at the onset of X-chromosome inactivation, we propose a statistical mechanics model of XCI, which is investigated by computer simulations and checked against experimental data. Our model describes how a "blocking factor" complex is self-assembled and why only one is formed out of many diffusible molecules, resulting in a spontaneous symmetry breaking in the binding to two identical chromosomes. These results are used to derive a scenario of biological implications.
TL;DR: It is shown that POF binding is dependent on heterochromatin and that P OF and HP1 bind interdependently to the 4th chromosome, and a balancing mechanism involving POF andHP1 is proposed that provides a feedback system for fine‐tuning expression status of genes on the 4 fourth chromosome.
Abstract: Drosophila melanogaster exhibits two expression-regulating systems that target whole, specific chromosomes: the dosage compensation system whereby the male-specific lethal complex doubles transcription of genes on the male X-chromosome and the chromosome 4-specific protein Painting of fourth, POF. POF is the first example of an autosome-specific protein and its presence raises the question of the universality of chromosome-specific regulation. Here we show that POF and heterochromatin protein 1 (HP1) are involved in the global regulation of the 4th chromosome. Contrary to previous conclusions, Pof is not essential for survival of diplo-4th karyotype flies. However, Pof is essential for survival of haplo-4th individuals and expression of chromosome 4 genes in diplo-4th individuals is decreased in the absence of Pof. Mapping of POF using chromatin immunoprecipitation suggested that it binds within genes. Furthermore, we show that POF binding is dependent on heterochromatin and that POF and HP1 bind interdependently to the 4th chromosome. We propose a balancing mechanism involving POF and HP1 that provides a feedback system for fine-tuning expression status of genes on the 4th chromosome.
TL;DR: It is shown that MSL complex recruitment requires the genes to be in a transcriptionally active state and targeting cues are found toward the 3' end of the gene and depend on the passage of the transcription machinery through the gene, whereby the type of promoter and the direction of transcription are dispensable.
Abstract: Dosage compensation is a process required to balance the expression of X-linked genes between males and females. In Drosophila this is achieved by targeting the dosage compensation complex or the male-specific lethal (MSL) complex to the male X chromosome. In order to study the mechanism of targeting, we have studied two X-chromosomal genes, mof and CG3016, using chromatin immunoprecipitation as well as immuno-FISH analysis on transgenic flies. We show that MSL complex recruitment requires the genes to be in a transcriptionally active state. MSL complex recruitment is reversible because blocking transcription severely reduces MSL binding to its target genes. Furthermore, targeting cues are found toward the 3' end of the gene and depend on the passage of the transcription machinery through the gene, whereby the type of promoter and the direction of transcription are dispensable. We propose a model of dynamic MSL complex binding to active genes based on exposed DNA target elements.
TL;DR: The failure to find XIST/TSIX in M. domestica may suggest that the ancestral XIC is too divergent to allow for detection by current methods, and argues that marsupial XCI does not require XIST and opens the search for alternative mechanisms of dosage compensation.
Abstract: X-chromosome inactivation (XCI) evolved in mammals to deal with X-chromosome dosage imbalance between the XX female and the XY male. In eutherian mammals, random XCI of the soma requires a master regulatory locus known as the ‘X-inactivation center’(XIC/Xic), wherein lies the noncoding XIST/Xist silencer RNA and its regulatory antisense Tsix gene. By contrast, marsupial XCI is imprinted to occur on the paternal X chromosome. To determine whether marsupials and eutherians share the XIC-driven mechanism, we search for the sequence equivalents in the genome of the South American opossum, Monodelphis domestica. Positional cloning and bioinformatic analysis reveal several interesting findings. First, protein-coding genes that flank the eutherian XIC are well-conserved in M. domestica, as well as in chicken, frog, and pufferfish. However, in M. domestica we fail to identify any recognizable XIST or TSIX equivalents. Moreover, cytogenetic mapping shows a surprising break in synteny with eutherian mammals and other vertebrates. Therefore, during the evolution of the marsupial X chromosome, one or more rearrangements broke up an otherwise evolutionarily conserved block of vertebrate genes. The failure to find XIST/TSIX in M. domestica may suggest that the ancestral XIC is too divergent to allow for detection by current methods. Alternatively, the XIC may have arisen relatively late in mammalian evolution, possibly in eutherians with the emergence of random XCI. The latter argues that marsupial XCI does not require XIST and opens the search for alternative mechanisms of dosage compensation.
TL;DR: It is concluded that BEAF function affects chromatin structure or dynamics, and Maternal or zygotic BEAF is sufficient to obtain adults, although having only maternal BEAF impairs female fertility.
Abstract: The Drosophila BEAF-32A and BEAF-32B proteins bind to the scs′ insulator and to hundreds of other sites on Drosophila chromosomes. These two proteins are encoded by the same gene. We used ends-in homologous recombination to generate the null BEAFAB-KO allele and also isolated the BEAFA-KO allele that eliminates production of only the BEAF-32A protein. We find that the BEAF proteins together are essential, but BEAF-32B alone is sufficient to obtain viable flies. Our results show that BEAF is important for both oogenesis and development. Maternal or zygotic BEAF is sufficient to obtain adults, although having only maternal BEAF impairs female fertility. In the absence of all BEAF, a few fertile but sickly males are obtained. Using both a chromosomal position-effect assay and an enhancer-blocking assay, we find that BEAF is necessary for scs′ insulator function. Lack of BEAF causes a disruption of male X polytene chromosome morphology. However, we did not find evidence that dosage compensation was affected. Position-effect variegation of the wm4h allele and different variegating y transgenes was enhanced by the knockout mutation. Combined with the effects on male X polytene chromosomes, we conclude that BEAF function affects chromatin structure or dynamics.
TL;DR: Findings suggest a role of the MSL complex in transcription elongation, RNA processing, and/or nuclear organization of the male X chromosome in Drosophila.
Abstract: Sex chromosomes in different organisms are studied as model systems for chromatin regulation of transcription and epigenetics. Similar to the female X in mammals, the male X chromosome in Drosophila is involved in the process of dosage compensation. However, in contrast to one of the mammalian female X chromosomes undergoing inactivation, the Drosophila male X is transcriptionally upregulated by approximately twofold. The Drosophila male X is a remarkable example for a specialized, transcriptionally hyperactive chromatin domain that facilitates the study of chromatin regulation in the context of transcription, nuclear architecture, and chromatin remodeling. In addition, the rich phenomenology of dosage compensation in Drosophila provides an opportunity to explore the complexities of gene regulation through epigenetic chromatin configurations, histone modifications, and noncoding RNAs. Male-specific lethal (MSL) factors constitute the MSL complex or dosage compensation complex and are important for transcription regulation of X-linked genes. Recent biochemical studies have identified a number of interesting factors that associate with the MSL complex including components of the nuclear pore complex and exosome subunits. Furthermore, global analysis of MSL complex binding showed that MSL complexes are enriched on genes with preferential binding to 3' end of genes. Taken together, these findings suggest a role of the MSL complex in transcription elongation, RNA processing, and/or nuclear organization.
TL;DR: Mechanisms to compensate for dosage differences of genes on sex chromosomes are widespread in animals, but in birds, compensation is inefficient, implying that for many genes dosage compensation is not critical.
Abstract: Mechanisms to compensate for dosage differences of genes on sex chromosomes are widespread in animals and have been thought to be critical for viability. However, in birds, compensation is inefficient, implying that for many genes dosage compensation is not critical, and for some genes, dosage differences have even been selected for.
TL;DR: This highly asymmetric, rapid evolution of the MSL genes further suggests that misregulated dosage compensation may represent one of the underlying causes of male hybrid inviability in Drosophila, wherein the fate of hybrid males depends on which species' X chromosome is inherited.
Abstract: In many taxa, males and females have unequal ratios of sex chromosomes to autosomes, which has resulted in the invention of diverse mechanisms to equilibrate gene expression between the sexes (dosage compensation). Failure to compensate for sex chromosome dosage results in male lethality in Drosophila. In Drosophila, a male-specific lethal (MSL) complex of proteins and noncoding RNAs binds to hundreds of sites on the single male X chromosome and up-regulates gene expression. Here we use population genetics of two closely related Drosophila species to show that adaptive evolution has occurred in all five protein-coding genes of the MSL complex. This positive selection is asymmetric between closely related species, with a very strong signature apparent in Drosophila melanogaster but not in Drosophila simulans. In particular, the MSL1 and MSL2 proteins have undergone dramatic positive selection in D. melanogaster, in domains previously shown to be responsible for their specific targeting to the X chromosome. This signature of positive selection at an essential protein-DNA interface of the complex is unexpected and suggests that X chromosomal MSL-binding DNA segments may themselves be changing rapidly. This highly asymmetric, rapid evolution of the MSL genes further suggests that misregulated dosage compensation may represent one of the underlying causes of male hybrid inviability in Drosophila, wherein the fate of hybrid males depends on which species' X chromosome is inherited.