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Journal articles on the topic 'Genetic Dosage Compensation'
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Veitia, Reiner A., Samuel Bottani, and James A. Birchler. "Gene dosage effects: nonlinearities, genetic interactions, and dosage compensation." Trends in Genetics 29, no. 7 (July 2013): 385–93. http://dx.doi.org/10.1016/j.tig.2013.04.004.
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Cowley, David E., William R. Atchley, and J. J. Rutledge. "QUANTITATIVE GENETICS OF DROSOPHILA MELANOGASTER. I. SEXUAL DIMORPHISM IN GENETIC PARAMETERS FOR WING TRAITS." Genetics 114, no. 2 (October 1, 1986): 549–66. http://dx.doi.org/10.1093/genetics/114.2.549.
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ABSTRACT Sexual dimorphism in genetic parameters is examined for wing dimensions of Drosophila melanogaster. Data are fit to a quantitative genetic model where phenotypic variance is a linear function of additive genetic autosomal variance (common to both sexes), additive genetic X-linked variances distinct for each sex, variance due to common rearing environment of families, residual environmental variance, random error variance due to replication, and variance due to measurement error and developmental asymmetry (left vs. right sides). Polygenic dosage compensation and its effect on genetic variances and covariances between sexes is discussed. Variance estimates for wing length and other wing dimensions highly correlated with length support the hypothesis that the Drosophila system of dosage compensation will cause male X-linked genetic variance to be substantially larger than female X-linked variance. Results for various wing dimensions differ, suggesting that the level of dosage compensation may differ for different traits. Genetic correlations between sexes for the same trait are presented. Total additive genetic correlations are near unity for most wing traits; this indicates that selection in the same direction in both sexes would have a minor effect on changing the magnitude of difference between sexes. Additive X-linked correlations suggest some genotype × sex interactions for X-linked effects.
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Meneely, Philip M., and William B. Wood. "Genetic Analysis of X-Chromosome Dosage Compensation in Caenorhabditis elegans." Genetics 117, no. 1 (September 1, 1987): 25–41. http://dx.doi.org/10.1093/genetics/117.1.25.
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ABSTRACT We have shown that the phenotypes resulting from hypomorphic mutations (causing reduction but not complete loss of function) in two X-linked genes can be used as a genetic assay for X-chromosome dosage compensation in Caenorhabditis elegans between males (XO) and hermaphrodites (XX). In addition we show that recessive mutations in two autosomal genes, dpy-21 V and dpy-26 IV, suppress the phenotypes resulting from the X-linked hypomorphic mutations, but not the phenotypes resulting from comparable autosomal hypomorphic mutations. This result strongly suggests that the dpy-21 and dpy-26 mutations cause increased X expression, implying that the normal function of these genes may be to lower the expression of X-linked genes. Recessive mutations in two other dpy genes, dpy-22 X and dpy-23 X, increase the severity of phenotypes resulting from some X-linked hypomorphic mutations, although dpy-23 may affect the phenotypes resulting from the autosomal hypomorphs as well. The mutations in all four of the dpy genes show their effects in both XO and XX animals, although to different degrees. Mutations in 18 other dpy genes do not show these effects.
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Plenefisch, J. D., L. DeLong, and B. J. Meyer. "Genes that implement the hermaphrodite mode of dosage compensation in Caenorhabditis elegans." Genetics 121, no. 1 (January 1, 1989): 57–76. http://dx.doi.org/10.1093/genetics/121.1.57.
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Abstract We report a genetic characterization of several essential components of the dosage compensation process in Caenorhabditis elegans. Mutations in the genes dpy-26, dpy-27, dpy-28, and the newly identified gene dpy-29 disrupt dosage compensation, resulting in elevated X-linked gene expression in XX animals and an incompletely penetrant maternal-effect XX-specific lethality. These dpy mutations appear to cause XX animals to express each set of X-linked genes at a level appropriate for XO animals. XO dpy animals are essentially wild type. Both the viability and the level of X-linked gene expression in XX animals carrying mutations in two or more dpy genes are the same as in animals carrying only a single mutation, consistent with the view that these genes act together in a single process (dosage compensation). To define a potential time of action for the gene dpd-28 we performed reciprocal temperature-shift experiments with a heat sensitive allele. The temperature-sensitive period for lethality begins 5 hr after fertilization at the 300-cell stage and extends to about 9 hr, a point well beyond the end of cell proliferation. This temperature-sensitive period suggests that dosage compensation is functioning in XX animals by mid-embryogenesis, when many zygotically transcribed genes are active. While mutations in the dpy genes have no effect on the sexual phenotype of otherwise wild-type XX or XO animals, they do have a slight feminizing effect on animals whose sex-determination process is already genetically perturbed. The opposite directions of the feminizing effects on sex determination and the masculinizing effects on dosage compensation caused by the dpy mutations are inconsistent with the wild-type dpy genes acting to coordinately control both processes. Instead, the feminizing effects are most likely an indirect consequence of disruptions in dosage compensation caused by the dpy mutations. Based on the cumulative evidence, the likely mechanism of dosage compensation in C. elegans involves reducing X-linked gene expression in XX animals to equal that in XO animals via the action of the dpy genes.
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Hsu, D. R., and B. J. Meyer. "The dpy-30 gene encodes an essential component of the Caenorhabditis elegans dosage compensation machinery." Genetics 137, no. 4 (August 1, 1994): 999–1018. http://dx.doi.org/10.1093/genetics/137.4.999.
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Abstract The need to regulate X chromosome expression in Caenorhabditis elegans arises as a consequence of the primary sex-determining signal, the X/A ratio (the ratio of X chromosomes to sets of autosomes), which directs 1X@A animals to develop as males and 2X/2A animals to develop as hermaphrodites. C. elegans possesses a dosage compensation mechanism that equalizes X chromosome expression between the two sexes despite their disparity in X chromosome dosage. Previous genetic analysis led to the identification of four autosomal genes, dpy-21, dpy-26, dpy-27 and dpy-28, whose products are essential in XX animals for proper dosage compensation, but not for sex determination. We report the identification and characterization of dpy-30, an essential component of the dosage compensation machinery. Putative null mutations in dpy-30 disrupt dosage compensation and cause a severe maternal-effect, XX-specific lethality. Rare survivors of the dpy-30 lethality are dumpy and express their X-linked genes at higher than wild-type levels. These dpy-30 mutant phenotypes superficially resemble those caused by mutations in dpy-26, dpy-27 and dpy-28; however, detailed phenotypic analysis reveals important differences that distinguish dpy-30 from these genes. In contrast to the XX-specific lethality caused by mutations in the other dpy genes, the XX-specific lethality caused by dpy-30 mutations is completely penetrant and temperature sensitive. In addition, unlike the other genes, dpy-30 is required for the normal development of XO animals. Although dpy-30 mutations do not significantly affect the viability of XO animals, they do cause them to be developmentally delayed and to possess numerous morphological and behavioral abnormalities. Finally, dpy-30 mutations can dramatically influence the choice of sexual fate in animals with an ambiguous sexual identity, despite having no apparent effect on the sexual phenotype of otherwise wild-type animals. Paradoxically, depending on the genetic background, dpy-30 mutations cause either masculinization or feminization, thus revealing the complex regulatory relationship between the sex determination and dosage compensation processes. The novel phenotypes caused by dpy-30 mutations suggest that in addition to acting in the dosage compensation process, dpy-30 may play a more general role in the development of both XX and XO animals.
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Cooper, M. K., M. J. Hamblen-Coyle, X. Liu, J. E. Rutila, and J. C. Hall. "Dosage compensation of the period gene in Drosophila melanogaster." Genetics 138, no. 3 (November 1, 1994): 721–32. http://dx.doi.org/10.1093/genetics/138.3.721.
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Abstract The period (per) gene is located on the X chromosome of Drosophila melanogaster. Its expression influences biological clocks in this fruit fly, including the one that subserves circadian rhythms of locomotor activity. Like most X-linked genes in Drosophila, per is under the regulatory control of gene dosage compensation. In this study, we assessed the activity of altered or augmented per+ DNA fragments in transformants. Relative expression levels in male and female adults were inferred from periodicities associated with locomotor behavioral rhythms, and by histochemically assessing beta-galactosidase levels in transgenics carrying different kinds of per-lacZ fusion genes. The results suggest that per contains multipartite regulatory information for dosage compensation within the large first intron and also within the 3' half of this genetic locus.
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Juchniewicz, Patrycja, Ewa Piotrowska, Anna Kloska, Magdalena Podlacha, Jagoda Mantej, Grzegorz Węgrzyn, Stefan Tukaj, and Joanna Jakóbkiewicz-Banecka. "Dosage Compensation in Females with X-Linked Metabolic Disorders." International Journal of Molecular Sciences 22, no. 9 (April 26, 2021): 4514. http://dx.doi.org/10.3390/ijms22094514.
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Through the use of new genomic and metabolomic technologies, our comprehension of the molecular and biochemical etiologies of genetic disorders is rapidly expanding, and so are insights into their varying phenotypes. Dosage compensation (lyonization) is an epigenetic mechanism that balances the expression of genes on heteromorphic sex chromosomes. Many studies in the literature have suggested a profound influence of this phenomenon on the manifestation of X-linked disorders in females. In this review, we summarize the clinical and genetic findings in female heterozygotic carriers of a pathogenic variant in one of ten selected X-linked genes whose defects result in metabolic disorders.
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Papadopulos, Alexander S. T., Michael Chester, Kate Ridout, and Dmitry A. Filatov. "Rapid Y degeneration and dosage compensation in plant sex chromosomes." Proceedings of the National Academy of Sciences 112, no. 42 (October 5, 2015): 13021–26. http://dx.doi.org/10.1073/pnas.1508454112.
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The nonrecombining regions of animal Y chromosomes are known to undergo genetic degeneration, but previous work has failed to reveal large-scale gene degeneration on plant Y chromosomes. Here, we uncover rapid and extensive degeneration of Y-linked genes in a plant species, Silene latifolia, that evolved sex chromosomes de novo in the last 10 million years. Previous transcriptome-based studies of this species missed unexpressed, degenerate Y-linked genes. To identify sex-linked genes, regardless of their expression, we sequenced male and female genomes of S. latifolia and integrated the genomic contigs with a high-density genetic map. This revealed that 45% of Y-linked genes are not expressed, and 23% are interrupted by premature stop codons. This contrasts with X-linked genes, in which only 1.3% of genes contained stop codons and 4.3% of genes were not expressed in males. Loss of functional Y-linked genes is partly compensated for by gene-specific up-regulation of X-linked genes. Our results demonstrate that the rate of genetic degeneration of Y-linked genes in S. latifolia is as fast as in animals, and that the evolutionary trajectories of sex chromosomes are similar in the two kingdoms.
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Hirt, N., K. Eggermann, S. Hyrenbach, J. Lambeck, A. Busche, J. Fischer, S. Rudnik-Schoneborn, and H. Gaspar. "Genetic dosage compensation via co-occurrence of PMP22 duplication and PMP22 deletion." Neurology 84, no. 15 (March 20, 2015): 1605–6. http://dx.doi.org/10.1212/wnl.0000000000001470.
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Ishikawa, Koji, Koji Makanae, Shintaro Iwasaki, Nicholas T. Ingolia, and Hisao Moriya. "Post-Translational Dosage Compensation Buffers Genetic Perturbations to Stoichiometry of Protein Complexes." PLOS Genetics 13, no. 1 (January 25, 2017): e1006554. http://dx.doi.org/10.1371/journal.pgen.1006554.
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Wang, Peng, Si-Qi Xu, Bei-Qi Wang, Wing Kam Fung, and Ji-Yuan Zhou. "A robust and powerful test for case–control genetic association study on X chromosome." Statistical Methods in Medical Research 28, no. 10-11 (September 20, 2018): 3260–72. http://dx.doi.org/10.1177/0962280218799532.
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Hundreds of genome-wide association studies were conducted to map the disease genes on autosomes in human beings. It is known that many complex diseases are sex-determined and X chromosome is expected to play an important role. However, only a few single-nucleotide polymorphisms on X chromosome were found to be significantly associated with the diseases under study. On the other hand, to balance the genetic effect between two sexes, X chromosome inactivation occurs in most of X-linked genes by silencing one copy of two X chromosomes in females and dosage compensation is achieved. A few association studies on X chromosome incorporated the information on dosage compensation. However, some of them require the assumption of Hardy–Weinberg equilibrium and some need to specify the underlying genetic model. Therefore, in this article, we propose a novel method for association by taking account of different dosage compensation patterns. The proposed test is a robust approach because it requires neither specifying the underlying genetic models nor the assumption of Hardy–Weinberg equilibrium. Further, the proposed method allows for different deviations from Hardy–Weinberg equilibrium between cases and controls. Simulation results demonstrate that our proposed method generally outperforms the existing methods in terms of controlling the size and the test power. Finally, we apply the proposed test to the meta-analysis of the Graves' disease data for its practical use.
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Ishikawa, Koji, Akari Ishihara, and Hisao Moriya. "Exploring the Complexity of Protein-Level Dosage Compensation that Fine-Tunes Stoichiometry of Multiprotein Complexes." PLOS Genetics 16, no. 10 (October 28, 2020): e1009091. http://dx.doi.org/10.1371/journal.pgen.1009091.
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Proper control of gene expression levels upon various perturbations is a fundamental aspect of cellular robustness. Protein-level dosage compensation is one mechanism buffering perturbations to stoichiometry of multiprotein complexes through accelerated proteolysis of unassembled subunits. Although N-terminal acetylation- and ubiquitin-mediated proteasomal degradation by the Ac/N-end rule pathway enables selective compensation of excess subunits, it is unclear how widespread this pathway contributes to stoichiometry control. Here we report that dosage compensation depends only partially on the Ac/N-end rule pathway. Our analysis of genetic interactions between 18 subunits and 12 quality control factors in budding yeast demonstrated that multiple E3 ubiquitin ligases and N-acetyltransferases are involved in dosage compensation. We find that N-acetyltransferases-mediated compensation is not simply predictable from N-terminal sequence despite their sequence specificity for N-acetylation. We also find that the compensation of Pop3 and Bet4 is due in large part to a minor N-acetyltransferase NatD. Furthermore, canonical NatD substrates histone H2A/H4 were compensated even in its absence, suggesting N-acetylation-independent stoichiometry control. Our study reveals the complexity and robustness of the stoichiometry control system.
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Höök, Lars, Luis Leal, Venkat Talla, and Niclas Backström. "Multilayered Tuning of Dosage Compensation and Z-Chromosome Masculinization in the Wood White (Leptidea sinapis) Butterfly." Genome Biology and Evolution 11, no. 9 (August 10, 2019): 2633–52. http://dx.doi.org/10.1093/gbe/evz176.
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AbstractIn species with genetic sex determination, dosage compensation can evolve to equal expression levels of sex-linked and autosomal genes. Current knowledge about dosage compensation has mainly been derived from male-heterogametic (XX/XY) model organisms, whereas less is understood about the process in female-heterogametic systems (ZZ/ZW). In moths and butterflies, downregulation of Z-linked expression in males (ZZ) to match the expression level in females (ZW) is often observed. However, little is known about the underlying regulatory mechanisms, or if dosage compensation patterns vary across ontogenetic stages. In this study, we assessed dynamics of Z-linked and autosomal expression levels across developmental stages in the wood white (Leptidea sinapis). We found that although expression of Z-linked genes in general was reduced compared with autosomal genes, dosage compensation was actually complete for some categories of genes, in particular sex-biased genes, but equalization in females was constrained to a narrower gene set. We also observed a noticeable convergence in Z-linked expression between males and females after correcting for sex-biased genes. Sex-biased expression increased successively across developmental stages, and male-biased genes were enriched on the Z-chromosome. Finally, all five core genes associated with the ribonucleoprotein dosage compensation complex male-specific lethal were detected in adult females, in correspondence with a reduction in the expression difference between autosomes and the single Z-chromosome. We show that tuning of gene dosage is multilayered in Lepidoptera and argue that expression balance across chromosomal classes may predominantly be driven by enrichment of male-biased genes on the Z-chromosome and cooption of available dosage regulators.
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Menon, Debashish U., and Victoria H. Meller. "Imprinting of the Y Chromosome Influences Dosage Compensation in roX1 roX2 Drosophila melanogaster." Genetics 183, no. 3 (August 24, 2009): 811–20. http://dx.doi.org/10.1534/genetics.109.107219.
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Drosophila melanogaster males have a well-characterized regulatory system that increases X-linked gene expression. This essential process restores the balance between X-linked and autosomal gene products in males. A complex composed of the male-specific lethal (MSL) proteins and RNA is recruited to the body of transcribed X-linked genes where it modifies chromatin to increase expression. The RNA components of this complex, roX1 and roX2 (RNA on the X1, RNA on the X2), are functionally redundant. Males mutated for both roX genes have dramatically reduced survival. We show that reversal of sex chromosome inheritance suppresses lethality in roX1 roX2 males. Genetic tests indicate that the effect on male survival depends upon the presence and source of the Y chromosome, revealing a germ line imprint that influences dosage compensation. Conventional paternal transmission of the Y chromosome enhances roX1 roX2 lethality, while maternal transmission of the Y chromosome suppresses lethality. roX1 roX2 males with both maternal and paternal Y chromosomes have very low survival, indicating dominance of the paternal imprint. In an otherwise wild-type male, the Y chromosome does not appreciably affect dosage compensation. The influence of the Y chromosome, clearly apparent in roX1 roX2 mutants, thus requires a sensitized genetic background. We believe that the Y chromosome is likely to act through modulation of a process that is defective in roX1 roX2 mutants: X chromosome recognition or chromatin modification by the MSL complex.
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DeLong, Leslie, Lawrence P. Casson, and Barbara J. Meyer. "Assessment of X Chromosome Dosage Compensation in Caenorhabditis elegans by Phenotypic Analysis of lin-14." Genetics 117, no. 4 (December 1, 1987): 657–70. http://dx.doi.org/10.1093/genetics/117.4.657.
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ABSTRACT Caenorhabditis elegans compensates for the difference in X chromosome gene dose between males (XO) and hermaphrodites (XX) through a mechanism that equalizes the levels of X-specific mRNA transcripts between the two sexes. We have devised a sensitive and quantitative genetic assay to measure perturbations in X chromosome gene expression caused by mutations that affect this process of dosage compensation. The assay is based on quantitating the precocious alae phenotype caused by a mutation that reduces but does not eliminate the function of the X-linked gene lin-14. We demonstrate that in diploid animals the lin-14 gene is dosage compensated between XO and XX animals. In XXX diploid animals, however, lin-14 expression is not compensated, implying that the normal dosage compensation mechanism in C. elegans lacks the capacity to compensate completely for the additional X chromosome in triplex animals. Using the lin-14 assay we compare the effects of mutations in the genes dpy-21, dpy-26, dpy-27, dpy-28, and dpy-22 on X-linked gene expression. Additionally, in the case of dpy-21 we correlate the change in phenotypic expression of lin-14 with a corresponding change in the lin-14 mRNA transcript level.
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Villeneuve, A. M., and B. J. Meyer. "The role of sdc-1 in the sex determination and dosage compensation decisions in Caenorhabditis elegans." Genetics 124, no. 1 (January 1, 1990): 91–114. http://dx.doi.org/10.1093/genetics/124.1.91.
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Abstract Our previous work demonstrated that mutations in the X-linked gene sdc-1 disrupt both sex determination and dosage compensation in Caenorhabditis elegans XX animals, suggesting that sdc-1 acts at a step that is shared by the sex determination and dosage compensation pathways prior to their divergence. In this report, we extend our understanding of early events in C. elegans sex determination and dosage compensation and the role played by sdc-1 in these processes. First, our analysis of 14 new sdc-1 alleles suggests that the phenotypes resulting from the lack of sdc-1 function are (1) an incompletely penetrant sexual transformation of XX animals toward the male fate, and (2) increased levels of X-linked gene transcripts in XX animals, correlated with XX-specific morphological defects but not significant XX-specific lethality. Further, all alleles exhibit strong maternal rescue for all phenotypes assayed. Second, temperature-shift experiments suggest that sdc-1 acts during the first half of embryogenesis in determining somatic sexual phenotype, long before sexual differentiation actually takes place, and consistent with our previous proposal that sdc-1 acts at an early step in the regulatory hierarchy controlling the choice of sexual fate. Other temperature-shift experiments suggest that sdc-1 may be involved in establishing but not maintaining the XX mode of dosage compensation. Third, a genetic mosaic analysis of sdc-1 produced an unusual result: the genotypic mosaics failed to display the sdc-1 sexual transformation phenotypes. This result suggests several possible interpretations: (1) sdc-1 is expressed immediately, in the one- or two-celled embryo; (2) sdc-1 acts non-cell-autonomously, such that expression of the gene in either the AB or P1 lineage can supply sdc-1(+) function to cells of the other lineage; (3) the X/A ratio is assessed immediately, in the one- or two-celled embryo; or (4) the X/A signal directs the choice of sexual fate in a non-cell-autonomous fashion. Finally, examination of the classes of sexual phenotypes produced in sdc-1 mutant strains suggests that different cells in the organism may not choose their sexual fates independently.
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Rice, William R. "Genetic Hitchhiking and the Evolution of Reduced Genetic Activity of the Y Sex Chromosome." Genetics 116, no. 1 (May 1, 1987): 161–67. http://dx.doi.org/10.1093/genetics/116.1.161.
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ABSTRACT A new model for the evolution of reduced genetic activity of the Y sex chromosome is described. The model is based on the process of genetic hitchhiking. It is shown that the Y chromosome can gradually lose its genetic activity due to the fixation of deleterious mutations that are linked with other beneficial genes. Fixation of deleterious Y-linked mutations generates locus-specific selection for dosage tolerance and/or compensation. The hitchhiking effect is most pronounced when operating in combination with an alternative model, Muller's ratchet. It is shown, however, that the genetic hitchhiking mechanism can operate under conditions where Muller's ratchet is ineffective.
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Alkalay, Avishai A., Tingwei Guo, Cristina Montagna, M. Cristina Digilio, Bruno Dallapiccola, Bruno Marino, and Bernice Morrow. "Genetic dosage compensation in a family with velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome." American Journal of Medical Genetics Part A 155, no. 3 (February 18, 2011): 548–54. http://dx.doi.org/10.1002/ajmg.a.33861.
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Griffin, Robert M., Holger Schielzeth, and Urban Friberg. "Autosomal and X-Linked Additive Genetic Variation for Lifespan and Aging: Comparisons Within and Between the Sexes in Drosophila melanogaster." G3 Genes|Genomes|Genetics 6, no. 12 (December 1, 2016): 3903–11. http://dx.doi.org/10.1534/g3.116.028308.
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Abstract Theory makes several predictions concerning differences in genetic variation between the X chromosome and the autosomes due to male X hemizygosity. The X chromosome should: (i) typically show relatively less standing genetic variation than the autosomes, (ii) exhibit more variation in males compared to females because of dosage compensation, and (iii) potentially be enriched with sex-specific genetic variation. Here, we address each of these predictions for lifespan and aging in Drosophila melanogaster. To achieve unbiased estimates of X and autosomal additive genetic variance, we use 80 chromosome substitution lines; 40 for the X chromosome and 40 combining the two major autosomes, which we assay for sex-specific and cross-sex genetic (co)variation. We find significant X and autosomal additive genetic variance for both traits in both sexes (with reservation for X-linked variation of aging in females), but no conclusive evidence for depletion of X-linked variation (measured through females). Males display more X-linked variation for lifespan than females, but it is unclear if this is due to dosage compensation since also autosomal variation is larger in males. Finally, our results suggest that the X chromosome is enriched for sex-specific genetic variation in lifespan but results were less conclusive for aging overall. Collectively, these results suggest that the X chromosome has reduced capacity to respond to sexually concordant selection on lifespan from standing genetic variation, while its ability to respond to sexually antagonistic selection may be augmented.
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Inoue, Y. H., T. Taira, and M. T. Yamamoto. "Genetics of an unstable white mutant in Drosophila simulans: reversion, suppression and somatic instability." Genetics 119, no. 4 (August 1, 1988): 903–12. http://dx.doi.org/10.1093/genetics/119.4.903.
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Abstract A spontaneous white mutation, white-milky (wmky) of Drosophila simulans is moderately unstable and is associated with a 16-kb long DNA insertion into the white gene. wmky, which is an unstable mutation found in D. simulans, has been genetically analyzed. Among nine spontaneous, partial reversions toward wild type, five were white locus mutations. They are phenotypically different from each other and three show eye color sexual dimorphism indicating a failure of the dosage compensation mechanism. Two w locus mutations whose eye color appeared identical between males and females were also isolated. Of the other back-mutants, three were associated with a recessive suppressor of wmky and one was a semidominant suppressor. These suppressor loci are located on the third chromosome at map positions about 90 and 120, respectively. The suppressor mutations demonstrate specific effects on w locus mutations derived from wmky which lack in the gene dosage compensation. Somatic instability was detected at the frequency of 5.6 X 10(-4) in wmky flies heterozygous for the recessive suppressor and the frequency was increased 10-fold when the suppressor mutation was placed in a different genetic background.
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Sun, Dan, Iksoo Huh, Wendy M. Zinzow-Kramer, Donna L. Maney, and Soojin V. Yi. "Rapid regulatory evolution of a nonrecombining autosome linked to divergent behavioral phenotypes." Proceedings of the National Academy of Sciences 115, no. 11 (February 26, 2018): 2794–99. http://dx.doi.org/10.1073/pnas.1717721115.
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In the white-throated sparrow (Zonotrichia albicollis), the second chromosome bears a striking resemblance to sex chromosomes. First, within each breeding pair of birds, one bird is homozygous for the standard arrangement of the chromosome (ZAL2/ZAL2) and its mate is heterozygous for a different version (ZAL2/ZAL2m). Second, recombination is profoundly suppressed between the two versions, leading to genetic differentiation between them. Third, the ZAL2mversion is linked with phenotypic traits, such as bright plumage, high aggression, and low parental behavior, which are usually associated with males. These similarities to sex chromosomes suggest that the evolutionary mechanisms that shape sex chromosomes, in particular genetic degeneration of the heterogametic version due to the suppression of recombination, are likely important in this system as well. Here, we investigated patterns of protein sequence evolution and gene expression evolution between the ZAL2 and ZAL2mchromosomes by whole-genome sequencing and transcriptome analyses. Patterns of protein evolution exhibited only weak signals of genetic degeneration, and few genes harbored signatures of positive selection. We found substantial evidence of transcriptome evolution, such as significant expression divergence between ZAL2 and ZAL2malleles and signatures of dosage compensation for highly expressed genes. These results suggest that, early in the evolution of heteromorphic chromosomes, gene expression divergence and dosage compensation can prevail before large-scale genetic degeneration. Our results show further that suppression of recombination between heteromorphic chromosomes can lead to the evolution of alternative (sex-like) behavioral phenotypes before substantial genetic degeneration.
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Barbash, Daniel A. "Genetic Testing of the Hypothesis That Hybrid Male Lethality Results From a Failure in Dosage Compensation: TABLE 1." Genetics 184, no. 1 (October 19, 2009): 313–16. http://dx.doi.org/10.1534/genetics.109.108100.
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Birchler, James A. "Parallel Universes for Models of X Chromosome Dosage Compensation in Drosophila: A Review." Cytogenetic and Genome Research 148, no. 1 (2016): 52–67. http://dx.doi.org/10.1159/000445924.
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Dosage compensation in Drosophila involves an approximately 2-fold increase in expression of the single X chromosome in males compared to the per gene expression in females with 2 X chromosomes. Two models have been considered for an explanation. One proposes that the male-specific lethal (MSL) complex that is associated with the male X chromosome brings histone modifiers to the sex chromosome to increase its expression. The other proposes that the inverse effect which results from genomic imbalance would tend to upregulate the genome approximately 2-fold, but the MSL complex sequesters histone modifiers from the autosomes to the X to mute this autosomal male-biased expression. On the X, the MSL complex must override the high level of resulting histone modifications to prevent overcompensation of the X chromosome. Each model is evaluated in terms of fitting classical genetic and recent molecular data. Potential paths toward resolving the models are suggested.
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Whittle, Carrie A., Arpita Kulkarni, and Cassandra G. Extavour. "Absence of a Faster-X Effect in Beetles (Tribolium, Coleoptera)." G3: Genes|Genomes|Genetics 10, no. 3 (January 27, 2020): 1125–36. http://dx.doi.org/10.1534/g3.120.401074.
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The faster-X effect, namely the rapid evolution of protein-coding genes on the X chromosome, has been widely reported in metazoans. However, the prevalence of this phenomenon across diverse systems and its potential causes remain largely unresolved. Analysis of sex-biased genes may elucidate its possible mechanisms: for example, in systems with X/Y males a more pronounced faster-X effect in male-biased genes than in female-biased or unbiased genes may suggest fixation of recessive beneficial mutations rather than genetic drift. Further, theory predicts that the faster-X effect should be promoted by X chromosome dosage compensation. Here, we asked whether we could detect a faster-X effect in genes of the beetle Tribolium castaneum (and T. freemani orthologs), which has X/Y sex-determination and heterogametic males. Our comparison of protein sequence divergence (dN/dS) on the X chromosome vs. autosomes indicated a rarely observed absence of a faster-X effect in this organism. Further, analyses of sex-biased gene expression revealed that the X chromosome was particularly highly enriched for ovary-biased genes, which evolved slowly. In addition, an evaluation of male X chromosome dosage compensation in the gonads and in non-gonadal somatic tissues indicated a striking lack of compensation in the testis. This under-expression in testis may limit fixation of recessive beneficial X-linked mutations in genes transcribed in these male sex organs. Taken together, these beetles provide an example of the absence of a faster-X effect on protein evolution in a metazoan, that may result from two plausible factors, strong constraint on abundant X-linked ovary-biased genes and a lack of gonadal dosage compensation.
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Oliver, B., N. Perrimon, and A. P. Mahowald. "Genetic evidence that the sans fille locus is involved in Drosophila sex determination." Genetics 120, no. 1 (September 1, 1988): 159–71. http://dx.doi.org/10.1093/genetics/120.1.159.
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Abstract Females homozygous for sans fille1621 (= fs(1)1621) have an abnormal germ line. Instead of producing eggs, the germ-line cells proliferate forming ovarian tumors or excessive numbers of nurse cells. The Sex-lethal gene product(s) regulate the branch point of the dosage compensation and sex determination pathways in the soma. The role of Sex-lethal in the germ line is not clear but the germ line of females homozygous for female sterile Sex-lethal alleles or germ-line clones of loss-of-function alleles are characterized by ovarian tumors. Females heterozygous for sans fille1621 or Sex-lethal are phenotypically wild type with respect to viability and fertility but females trans-heterozygous for sans fille1621 and Sex-lethal show ovarian tumors, somatic sexual transformations, and greatly reduced viability.
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Pultz, M. A., and B. S. Baker. "The dual role of hermaphrodite in the Drosophila sex determination regulatory hierarchy." Development 121, no. 1 (January 1, 1995): 99–111. http://dx.doi.org/10.1242/dev.121.1.99.
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The hermaphrodite (her) locus has both maternal and zygotic functions required for normal female development in Drosophila. Maternal her function is needed for the viability of female offspring, while zygotic her function is needed for female sexual differentiation. Here we focus on understanding how her fits into the sex determination regulatory hierarchy. Maternal her function is needed early in the hierarchy: genetic interactions of her with the sisterless genes (sis-a and sis-b), with function-specific Sex-lethal (Sxl) alleles and with the constitutive allele SxlM#1 suggest that maternal her function is needed for Sxl initiation. When mothers are defective for her function, their daughters fail to activate a reporter gene for the Sxl early promoter and are deficient in Sxl protein expression. Dosage compensation is misregulated in the moribund daughters: some salivary gland cells show binding of the maleless (mle) dosage compensation regulatory protein to the X chromosome, a binding pattern normally seen only in males. Thus maternal her function is needed early in the hierarchy as a positive regulator of Sxl, and the maternal effects of her on female viability probably reflect Sxl's role in regulating dosage compensation. In contrast to her's maternal function, her's zygotic function in sex determination acts at the end of the hierarchy. This zygotic effect is not rescued by constitutive Sxl expression, nor by constitutive transformer (tra) expression. Moreover, the expression of doublesex (dsx) transcripts appears normal in her mutant females. We conclude that the maternal and zygotic functions of her are needed at two distinctly different levels of the sex determination regulatory hierarchy.
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Ren, Li, Xiaojing Yan, Liu Cao, Jiaming Li, Xueyin Zhang, Xin Gao, Jia Liu, Jialin Cui, and Shaojun Liu. "Combined effects of dosage compensation and incomplete dominance on gene expression in triploid cyprinids." DNA Research 26, no. 6 (December 1, 2019): 485–94. http://dx.doi.org/10.1093/dnares/dsz026.
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Abstract Hybridization and polyploidy are pervasive evolutionary features of flowering plants and frequent among some animal groups, such as fish. These processes always lead to novel genotypes and various phenotypes, including growth heterosis. However, its genetic basis in lower vertebrate is still poorly understood. Here, we conducted transcriptome-level analyses of the allopolyploid complex of Carassius auratus red var. (R) (♀) × Cyprinus carpio L. (C) (♂), including the allodiploid and allotetraploid with symmetric subgenomes, and the two allotriploids with asymmetric subgenomes. The gradual changes of gene silencing and novel gene expression suggested the weakening of the constraint of polymorphic expression in genotypic changes. Then, analyses of the direction and magnitude of homoeolog expression exhibited various asymmetric expression patterns, which supported that R incomplete dominance and dosage compensation were co-regulated in the two triploids. Under these effects, various magnitudes of R-homoeolog expression bias were observed in growth-regulated genes, suggesting that they might contribute to growth heterosis in the two triploids. The determination of R incomplete dominance and dosage compensation, which might be led by asymmetric subgenomes and multiple sets of homologous chromosomes, explained why various expression patterns were shaped and their potential contribution to growth heterosis in the two triploids.
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Cowley, D. E., and W. R. Atchley. "Quantitative Genetics of Drosophila Melanogaster. II. Heritabilities and Genetic Correlations between Sexes for Head and Thorax Traits." Genetics 119, no. 2 (June 1, 1988): 421–33. http://dx.doi.org/10.1093/genetics/119.2.421.
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Abstract A quantitative genetic analysis is reported for traits on the head and thorax of adult fruit flies, Drosophila melanogaster. Females are larger than males, and the magnitude of sexual dimorphism is similar for traits derived from the same imaginal disc, but the level of sexual dimorphism varies widely across discs. The greatest difference between males and females occurs for the dimensions of the sclerotized mouthparts of the proboscis. Most of the traits studied are highly heritable with heritabilities ranging from 0.26 to 0.84 for males and 0.27 to 0.81 for females. In general, heritabilities are slightly higher for males, possibly reflecting the effect of dosage compensation on X-linked variance. The X chromosome contributes substantially to variance for many of these traits, and including results reported elsewhere, the variance for over two-thirds of the traits studied includes X-linked variance. The genetic correlations between sexes for the same trait are generally high and close to unity. Coupled with the small differences in the traits between sexes for heritabilities and phenotypic variances, these results suggest that selection would be very slow to change the level of sexual dimorphism in size of various body parts.
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Steinemann, Sigrid, and Manfred Steinemann. "The Amylase Gene Cluster on the Evolving Sex Chromosomes of Drosophila miranda." Genetics 151, no. 1 (January 1, 1999): 151–61. http://dx.doi.org/10.1093/genetics/151.1.151.
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Abstract On the basis of chromosomal homology, the Amylase gene cluster in Drosophila miranda must be located on the secondary sex chromosome pair, neo-X (X2) and neo-Y, but is autosomally inherited in all other Drosophila species. Genetic evidence indicates no active amylase on the neo-Y chromosome and the X2-chromosomal locus already shows dosage compensation. Several lines of evidence strongly suggest that the Amy gene cluster has been lost already from the evolving neo-Y chromosome. This finding shows that a relatively new neo-Y chromosome can start to lose genes and hence gradually lose homology with the neo-X. The X2-chromosomal Amy1 is intact and Amy2 contains a complete coding sequence, but has a deletion in the 3′-flanking region. Amy3 is structurally eroded and hampered by missing regulatory motifs. Functional analysis of the X2-chromosomal Amy1 and Amy2 regions from D. miranda in transgenic D. melanogaster flies reveals ectopic AMY1 expression. AMY1 shows the same electrophoretic mobility as the single amylase band in D. miranda, while ectopic AMY2 expression is characterized by a different mobility. Therefore, only the Amy1 gene of the resident Amy cluster remains functional and hence Amy1 is the dosage compensated gene.
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Pérez-Enciso, Miguel, Alex Clop, Josep M. Folch, Armand Sánchez, Maria A. Oliver, Cristina Óvilo, C. Barragán, Luis Varona, and José L. Noguera. "Exploring Alternative Models for Sex-Linked Quantitative Trait Loci in Outbred Populations: Application to an Iberian × Landrace Pig Intercross." Genetics 161, no. 4 (August 1, 2002): 1625–32. http://dx.doi.org/10.1093/genetics/161.4.1625.
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Abstract We present a very flexible method that allows us to analyze X-linked quantitative trait loci (QTL) in crosses between outbred lines. The dosage compensation phenomenon is modeled explicitly in an identity-by-descent approach. A variety of models can be fitted, ranging from considering alternative fixed alleles within the founder breeds to a model where the only genetic variation is within breeds, as well as mixed models. Different genetic variances within each founder breed can be estimated. We illustrate the method with data from an F2 cross between Iberian × Landrace pigs for intramuscular fat content and meat color component a*. The Iberian allele exhibited a strong overdominant effect for intramuscular fat in females. There was also limited evidence of one or more regions affecting color component a*. The analysis suggested that the QTL alleles were fixed in the Iberian founders, whereas there was some evidence of segregation in Landrace for the QTL affecting a* color component.
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Monfort, Asun, and Anton Wutz. "Progress in understanding the molecular mechanism of Xist RNA function through genetics." Philosophical Transactions of the Royal Society B: Biological Sciences 372, no. 1733 (September 25, 2017): 20160368. http://dx.doi.org/10.1098/rstb.2016.0368.
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The Xist gene produces a long noncoding RNA that initiates chromosome-wide gene repression on the inactive X chromosome in female mammals. Recent progress has advanced the understanding of Xist function at the molecular level. This review provides an overview of insights from genetic approaches and puts the new data in the context of an emerging mechanistic model as well as the existing literature. Some consideration is given on how independent biochemical studies on X inactivation help to advance on the wider question of chromatin regulation in the mammalian dosage compensation system. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.
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Jowhar, Ziad, Sigal Shachar, Prabhakar R. Gudla, Darawalee Wangsa, Erin Torres, Jill L. Russ, Gianluca Pegoraro, Thomas Ried, Armin Raznahan, and Tom Misteli. "Effects of human sex chromosome dosage on spatial chromosome organization." Molecular Biology of the Cell 29, no. 20 (October 2018): 2458–69. http://dx.doi.org/10.1091/mbc.e18-06-0359.
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Sex chromosome aneuploidies (SCAs) are common genetic syndromes characterized by the presence of an aberrant number of X and Y chromosomes due to meiotic defects. These conditions impact the structure and function of diverse tissues, but the proximal effects of SCAs on genome organization are unknown. Here, to determine the consequences of SCAs on global genome organization, we have analyzed multiple architectural features of chromosome organization in a comprehensive set of primary cells from SCA patients with various ratios of X and Y chromosomes by use of imaging-based high-throughput chromosome territory mapping (HiCTMap). We find that X chromosome supernumeracy does not affect the size, volume, or nuclear position of the Y chromosome or an autosomal chromosome. In contrast, the active X chromosome undergoes architectural changes as a function of increasing X copy number as measured by a decrease in size and an increase in circularity, which is indicative of chromatin compaction. In Y chromosome supernumeracy, Y chromosome size is reduced suggesting higher chromatin condensation. The radial positioning of chromosomes is unaffected in SCA karyotypes. Taken together, these observations document changes in genome architecture in response to alterations in sex chromosome numbers and point to trans-effects of dosage compensation on chromosome organization.
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Zhuang, Qinwei Kim-Wee, Jose Hector Galvez, Qian Xiao, Najla AlOgayil, Jeffrey Hyacinthe, Teruko Taketo, Guillaume Bourque, and Anna K. Naumova. "Sex Chromosomes and Sex Phenotype Contribute to Biased DNA Methylation in Mouse Liver." Cells 9, no. 6 (June 9, 2020): 1436. http://dx.doi.org/10.3390/cells9061436.
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Sex biases in the genome-wide distribution of DNA methylation and gene expression levels are some of the manifestations of sexual dimorphism in mammals. To advance our understanding of the mechanisms that contribute to sex biases in DNA methylation and gene expression, we conducted whole genome bisulfite sequencing (WGBS) as well as RNA-seq on liver samples from mice with different combinations of sex phenotype and sex-chromosome complement. We compared groups of animals with different sex phenotypes, but the same genetic sexes, and vice versa, same sex phenotypes, but different sex-chromosome complements. We also compared sex-biased DNA methylation in mouse and human livers. Our data show that sex phenotype, X-chromosome dosage, and the presence of Y chromosome shape the differences in DNA methylation between males and females. We also demonstrate that sex bias in autosomal methylation is associated with sex bias in gene expression, whereas X-chromosome dosage-dependent methylation differences are not, as expected for a dosage-compensation mechanism. Furthermore, we find partial conservation between the repertoires of mouse and human genes that are associated with sex-biased methylation, an indication that gene function is likely to be an important factor in this phenomenon.
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Deshmukh, Saniya, VK Chaithanya Ponnaluri, Nan Dai, Sriharsa Pradhan, and Deepti Deobagkar. "Levels of DNA cytosine methylation in theDrosophilagenome." PeerJ 6 (July 2, 2018): e5119. http://dx.doi.org/10.7717/peerj.5119.
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Insects provide an accessible system to study the contribution of DNA methylation to complex epigenetic phenotypes created to regulate gene expression, chromatin states, imprinting and dosage compensation. The members of genusDrosophilahave been used as a model system to study aspects of biology like development, behaviour and genetics. Despite the popularity ofDrosophila melanogasteras a genetic and epigenetic model organism, DNA methylation studies are limited due to low levels of genomic 5-methylcytosine. Our study employs a sensitive liquid chromatography-mass spectrometry (LCMS) based method to quantify the levels of 5-methylcytosine from the genomic DNA in different members of the genusDrosophila. Our results reveal that, despite being phylogenetically related, there is a marked variation in the levels of 5-methylcytosine between the genomes of the members of genusDrosophila. Also, there is a change in the genomic levels of 5-methylcytosine through each life cycle stage of holometabolous development inD. melanogaster.
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Hilfiker, A., H. Amrein, A. Dubendorfer, R. Schneiter, and R. Nothiger. "The gene virilizer is required for female-specific splicing controlled by Sxl, the master gene for sexual development in Drosophila." Development 121, no. 12 (December 1, 1995): 4017–26. http://dx.doi.org/10.1242/dev.121.12.4017.
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The gene virilizer (vir) is needed for dosage compensation and sex determination in females and for an unknown vital function in both sexes. In genetic mosaics, XX somatic cells mutant for vir differentiate male structures. One allele, vir2f, is lethal for XX, but not for XY animals. This female-specific lethality can be rescued by constitutive expression of Sxl or by mutations in msl (male-specific lethal) genes. Rescued animals develop as strongly masculinized intersexes or pseudomales. They have male-specifically spliced mRNA of tra, and when rescued by msl, also of Sxl. Our data indicate that vir is a positive regulator of female-specific splicing of Sxl and of tra pre-mRNA.
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Kuwabara, P. E. "A novel regulatory mutation in the C. elegans sex determination gene tra-2 defines a candidate ligand/receptor interaction site." Development 122, no. 7 (July 1, 1996): 2089–98. http://dx.doi.org/10.1242/dev.122.7.2089.
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Sex determination in the nematode C. elegans is dependent on cell-to-cell communication, which appears to be mediated by the predicted membrane protein TRA-2A and the secreted protein HER-1. In XO males, HER-1 is hypothesised to function as a repressive ligand that inactivates the TRA-2A receptor. In XX animals, HER-1 is absent and TRA-2A promotes hermaphrodite development by negatively regulating the FEM proteins. This paper describes the molecular and genetic characterisation of a novel class of feminising mutations called tra-2(eg), for enhanced gain-of-function. In XX animals, mutant tra-2(eg) activity promotes entirely normal hermaphrodite development. However, the tra-2(eg) mutations generate an XO-specific gain-of-function phenotype, because they transform XO mutants from male into hermaphrodite. Therefore, the tra-2(eg) mutations identify a major regulatory site, which may be the TRA-2A/HER-1 interaction site. All ten tra-2(eg) mutations encode identical missense changes in a predicted extracellular domain of TRA-2A, named the EG site. It is proposed that the tra-2(eg) mutation encodes a TRA-2A protein that functions constitutively in XO animals, because it is defective in HER-1 binding. Phenotypic characterisation of sexually transformed XO tra-2(eg) hermaphrodites reveals that their fertility is strongly affected by dosage compensation mutations, suggesting that dosage compensation plays a role in normal gametogenesis.
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Cline, Thomas W. "A FEMALE-SPECIFIC LETHAL LESION IN AN X-LINKED POSITIVE REGULATOR OF THE DROSOPHILA SEX DETERMINATION GENE, SEX-LETHAL." Genetics 113, no. 3 (July 1, 1986): 641–63. http://dx.doi.org/10.1093/genetics/113.3.641.
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ABSTRACT Characterization of a partial-loss-of-function, female-specific lethal mutation has identified an X-linked genetic element (1-34.3; 10B4) that functions as a positive regulator of Sxl, a central gene controlling sex determination in Drosophila melanogaster. The name, sisterless-a, was chosen both to suggest functional similarities that exist between this gene and another positive regulator of Sxl, the maternally acting gene daughterless (da), and also to highlight an important difference; namely, that in contrast to da, it is the zygotic rather than maternal functioning of sis-a that is involved in its interaction with Sxl. As with da, the female-specific lethal phenotype of sis-a is suppressed both by SxlM #1, a gain-of-function mutant allele of the target gene, and, to a lesser extent, by a duplication of Sxl +. Mutations at sis-a, da and Sxl display female-specific dominant synergism, each enhancing the others' lethal effects. The allele specificity with respect to Sxl of these dominant interactions indicates that sis-a and da affect the same aspect of Sxl regulation. As with previous studies of da and Sxl, the masculinizing effects of loss of sis-a function are generally obscured by lethal effects, presumably related to upsets in dosage compensation. The masculinizing effects can be dissociated from lethal effects by analysis of triploid intersexes (XX AAA) or by analysis of diploid females who are also mutant for autosomal genes known to be required for the transcriptional hyperactivation associated with dosage compensation in males. Analysis of foreleg development shows that intersexuality generated by sis-a is of the mosaic type: At the level of individual cells, only male or female development is observed, never an intermediate sexual phenotype characteristic of true intersexes. Sexual development of diplo-X germline and somatic clones of sis-a tissue generated by mitotic recombination during larval stages is normal, as is the sexual phenotype of homozygous sis-a escapers. Considered in their totality, these results indicate that sis-a functions early in development to help establish the activity state of Sxl and thereby initiate the sexual pathway commitment, rather than functioning later in the processes by which Sxl maintains and expresses the sex determination decision.
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Loos, Friedemann, Cheryl Maduro, Agnese Loda, Johannes Lehmann, Gert-Jan Kremers, Derk ten Berge, J. Anton Grootegoed, and Joost Gribnau. "XistandTsixTranscription Dynamics Is Regulated by the X-to-Autosome Ratio and Semistable Transcriptional States." Molecular and Cellular Biology 36, no. 21 (August 15, 2016): 2656–67. http://dx.doi.org/10.1128/mcb.00183-16.
Full textAbstract:
In female mammals, X chromosome inactivation (XCI) is a key process in the control of gene dosage compensation between X-linked genes and autosomes.XistandTsix, two overlapping antisense-transcribed noncoding genes, are central elements of the X inactivation center (Xic) regulating XCI.Xistupregulation results in the coating of the entire X chromosome by Xist RNA incis, whereasTsixtranscription acts as a negative regulator ofXist. Here, we generatedXistandTsixreporter mouse embryonic stem (ES) cell lines to study the genetic and dynamic regulation of these genes upon differentiation. Our results revealed mutually antagonistic roles forTsixonXistand vice versa and indicate the presence of semistable transcriptional states of theXiclocus predicting the outcome of XCI. These transcriptional states are instructed by the X-to-autosome ratio, directed by regulators of XCI, and can be modulated by tissue culture conditions.
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Hou, Jie, Xiaowen Shi, Chen Chen, Md Soliman Islam, Adam F. Johnson, Tatsuo Kanno, Bruno Huettel, et al. "Global impacts of chromosomal imbalance on gene expression in Arabidopsis and other taxa." Proceedings of the National Academy of Sciences 115, no. 48 (November 14, 2018): E11321—E11330. http://dx.doi.org/10.1073/pnas.1807796115.
Full textAbstract:
Changes in dosage of part of the genome (aneuploidy) have long been known to produce much more severe phenotypic consequences than changes in the number of whole genomes (ploidy). To examine the basis of these differences, global gene expression in mature leaf tissue for all five trisomies and in diploids, triploids, and tetraploids of Arabidopsis thaliana was studied. The trisomies displayed a greater spread of expression modulation than the ploidy series. In general, expression of genes on the varied chromosome ranged from compensation to dosage effect, whereas genes from the remainder of the genome ranged from no effect to reduced expression approaching the inverse level of chromosomal imbalance (2/3). Genome-wide DNA methylation was examined in each genotype and found to shift most prominently with trisomy 4 but otherwise exhibited little change, indicating that genetic imbalance is generally mechanistically unrelated to DNA methylation. Independent analysis of gene functional classes demonstrated that ribosomal, proteasomal, and gene body methylated genes were less modulated compared with all classes of genes, whereas transcription factors, signal transduction components, and organelle-targeted protein genes were more tightly inversely affected. Comparing transcription factors and their targets in the trisomies and in expression networks revealed considerable discordance, illustrating that altered regulatory stoichiometry is a major contributor to genetic imbalance. Reanalysis of published data on gene expression in disomic yeast and trisomic mouse cells detected similar stoichiometric effects across broad phylogenetic taxa, and indicated that these effects reflect normal gene regulatory processes.
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Yi, Soojin, Doris Bachtrog, and Brian Charlesworth. "A Survey of Chromosomal and Nucleotide Sequence Variation inDrosophila miranda." Genetics 164, no. 4 (August 1, 2003): 1369–81. http://dx.doi.org/10.1093/genetics/164.4.1369.
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AbstractThere have recently been several studies of the evolution of Y chromosome degeneration and dosage compensation using the neo-sex chromosomes of Drosophila miranda as a model system. To understand these evolutionary processes more fully, it is necessary to document the general pattern of genetic variation in this species. Here we report a survey of chromosomal variation, as well as polymorphism and divergence data, for 12 nuclear genes of D. miranda. These genes exhibit varying levels of DNA sequence polymorphism. Compared to its well-studied sibling species D. pseudoobscura, D. miranda has much less nucleotide sequence variation, and the effective population size of this species is inferred to be several-fold lower. Nevertheless, it harbors a few inversion polymorphisms, one of which involves the neo-X chromosome. There is no convincing evidence for a recent population expansion in D. miranda, in contrast to D. pseudoobscura. The pattern of population subdivision previously observed for the X-linked gene period is not seen for the other loci, suggesting that there is no general population subdivision in D. miranda. However, data on an additional region of period confirm population subdivision for this gene, suggesting that local selection is operating at or near period to promote differentiation between populations.
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Granadino, B., M. Torres, D. Bachiller, E. Torroja, J. L. Barbero, and L. Sánchez. "Genetic and molecular analysis of new female-specific lethal mutations at the gene Sxl of Drosophila melanogaster." Genetics 129, no. 2 (October 1, 1991): 371–83. http://dx.doi.org/10.1093/genetics/129.2.371.
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Abstract We have isolated three female-specific lethal mutations at the gene Sex-lethal (Sxl): Sxlfb, Sxlfc and Sxlfd. We have carried out the complementation analysis between these mutations and other previously reported Sxlf mutations. It is possible to classify the alleles tested in this report into two complementation groups: the bc group defined by Sxlfb, and Sxlfc, and the LS group defined by SxlfLS. The other alleles tested affect both complementation groups albeit with different degrees. Contrary to what happens with mutations at the LS group, mutations at the bc group do not affect sex determination, nor late dosage compensation nor oogenesis. Both Sxlfb and Sxlfc present a DNA insertion of at least 5 kb between position -10 and -11 on the molecular map, within the fourth intron. On the contrary, Sxlfd, a strong mutation affecting all Sxl functions, is not associated to any detectable DNA alteration in Southern blots, so that it seems to be a "point" mutation. In agreement with their phenotypes, both Sxlfc/SxlfLS and Sxlfc homozygous female larvae express only the late Sxl transcripts characteristic of females, while females homozygous for SxlfLS express only the late Sxl transcripts characteristic of males. Moreover, Sxlfc presents a lethal synergistic interaction with mutations at either da or the X:A ratio, two signals that define the initial activity state of Sxl, while SxlfLS do not. These data suggest that the two complementation groups are related to the two sets of early and late Sxl transcripts, which are responsible for the early and late Sxl functions, respectively: Sxlfb and Sxlfc would affect the early functions and SxlfLS would affect the late Sxl functions.
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Birchler, J. A., J. C. Hiebert, and K. Paigen. "Analysis of autosomal dosage compensation involving the alcohol dehydrogenase locus in Drosophila melanogaster." Genetics 124, no. 3 (March 1, 1990): 677–86. http://dx.doi.org/10.1093/genetics/124.3.677.
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Abstract An example of autosomal dosage compensation involving the expression of the alcohol dehydrogenase (Adh) locus is described. Flies trisomic for a quarter of the length of the left arm of chromosome two, including Adh, have diploid levels of enzyme activity and alcohol dehydrogenase messenger RNA. Subdivision of the compensating trisomic into smaller ones revealed a region that exerts an inverse regulatory effect on alcohol dehydrogenase activity and messenger RNA levels and a smaller region surrounding the structural gene that exhibits a direct gene dosage response. The two opposing effects are of sufficient magnitude that they cancel when simultaneously present resulting in the observed compensation in the larger aneuploid. An Adh promoter-white structural gene fusion construct is affected by the inverse regulatory region indicating that the effect is mediated through the Adh promoter sequences. The role of autosomal dosage compensation in understanding aneuploid syndromes and karyotype evolution in Drosophila species is discussed.
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Hwang, Sunyoung, Paola Cavaliere, Rui Li, Lihua Julie Zhu, Noah Dephoure, and Eduardo M. Torres. "Consequences of aneuploidy in human fibroblasts with trisomy 21." Proceedings of the National Academy of Sciences 118, no. 6 (February 1, 2021): e2014723118. http://dx.doi.org/10.1073/pnas.2014723118.
Full textAbstract:
An extra copy of chromosome 21 causes Down syndrome, the most common genetic disease in humans. The mechanisms contributing to aneuploidy-related pathologies in this syndrome, independent of the identity of the triplicated genes, are not well defined. To characterize aneuploidy-driven phenotypes in trisomy 21 cells, we performed global transcriptome, proteome, and phenotypic analyses of primary human fibroblasts from individuals with Patau (trisomy 13), Edwards (trisomy 18), or Down syndromes. On average, mRNA and protein levels were increased by 1.5-fold in all trisomies, with a subset of proteins enriched for subunits of macromolecular complexes showing signs of posttranscriptional regulation. These results support the lack of evidence for widespread dosage compensation or dysregulation of chromosomal domains in human autosomes. Furthermore, we show that several aneuploidy-associated phenotypes are present in trisomy 21 cells, including lower viability and increased dependency on serine-driven lipid synthesis. Our studies establish a critical role of aneuploidy, independent of triplicated gene identity, in driving cellular defects associated with trisomy 21.
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Baker, B. S., K. Burtis, T. Goralski, W. Mattox, and R. Nagoshi. "Molecular genetic aspects of sex determination in Drosophila melanogaster." Genome 31, no. 2 (January 15, 1989): 638–45. http://dx.doi.org/10.1139/g89-117.
Full textAbstract:
The molecular analyses of three of the regulatory genes (transformer (tra), doublesex (dsx), and transformer-2 (tra-2)) controlling sexual differentiation in Drosophila have demonstrated that the control of RNA processing has a major role in regulating somatic sexual differentiation. The activities of both the tra and dsx genes are controlled at the level of RNA processing. In the case of tra the use of different splice acceptor sites results in a functional transcript being produced only in females, whereas at dsx the use of different splice acceptor sites in the two sexes results in the production of transcripts that encode different proteins in males and females. The tra-2 gene has been shown to be necessary for the processing of the dsx pre-mRNA in females and the conceptual translation of a tra-2 cDNA shows that it encodes a protein with similarity to a family of RNA-binding proteins which includes known splicesome components. We previously suggested that the pattern of sexual differentiation and dosage compensation characteristic of a male was a default regulatory state. The findings reviewed here provide a molecular basis for this default expression in males as well as an insight into how females differ from males in control of the expression of these genes. For both the tra and dsx genes the molecular basis of their male (default) state of expression appears to be the processing of their transcripts by the housekeeping RNA splicing machinery. In females the specification of the alternative pattern of splicing at both tra and dsx is by the sex determination regulatory genes that function upstream of them in this regulatory cascade. It seems likely that the activities of these sex determination regulatory genes in females do not provide all of the information that is necessary for proper splicing of the transcripts of the genes downstream of them. Rather we imagine that the products of the Sxl, tra, and tra-2 genes are acting to impose a specificity on the basic cellular splicing machinery.Key words: Drosophila melanogaster, sex determination, sexual differentiation.
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Tan, Choon Ping, and Sara Nakielny. "Control of the DNA Methylation System Component MBD2 by Protein Arginine Methylation." Molecular and Cellular Biology 26, no. 19 (October 1, 2006): 7224–35. http://dx.doi.org/10.1128/mcb.00473-06.
Full textAbstract:
ABSTRACT DNA methylation is vital for proper chromatin structure and function in mammalian cells. Genetic removal of the enzymes that catalyze DNA methylation results in defective imprinting, transposon silencing, X chromosome dosage compensation, and genome stability. This epigenetic modification is interpreted by methyl-DNA binding domain (MBD) proteins. MBD proteins respond to methylated DNA by recruiting histone deacetylases (HDAC) and other transcription repression factors to the chromatin. The MBD2 protein is dispensable for animal viability, but it is implicated in the genesis of colon tumors. Here we report that the MBD2 protein is controlled by arginine methylation. We identify the protein arginine methyltransferase enzymes that catalyze this modification and show that arginine methylation inhibits the function of MBD2. Arginine methylation of MBD2 reduces MBD2-methyl-DNA complex formation, reduces MBD2-HDAC repression complex formation, and impairs the transcription repression function of MBD2 in cells. Our report provides a molecular description of a potential regulatory mechanism for an MBD protein family member. It is the first to demonstrate that protein arginine methyltransferases participate in the DNA methylation system of chromatin control.
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Qian, S., and V. Pirrotta. "Dosage compensation of the Drosophila white gene requires both the X chromosome environment and multiple intragenic elements." Genetics 139, no. 2 (February 1, 1995): 733–44. http://dx.doi.org/10.1093/genetics/139.2.733.
Full textAbstract:
Abstract The X-linked white gene when transposed to autosomes retains only partial dosage compensation. One copy of the gene in males expresses more than one copy but less than two copies in females. When inserted in ectopic X chromosome sites, the mini-white gene of the CaspeR vector can be fully dosage compensated and can even achieve hyperdosage compensation, meaning that one copy in males gives more expression than two copies in females. As sequences are removed gradually from the 5' end of the gene, we observe a progressive transition from hyperdosage compensation to full dosage compensation to partial dosage compensation. When the deletion reaches -17, the gene can no longer dosage compensate fully even on the X chromosome. A deletion reaching +173, 4 bp preceding the AUG initiation codon, further reduces dosage compensation both on the X chromosome and on autosomes. This truncated gene can still partially dosage compensate on autosomes, indicating the presence of dosage compensation determinants in the protein coding region. We conclude that full dosage compensation requires an X chromosome environment and that the white gene contains multiple dosage-compensation determinants, some near the promoter and some in the coding region.
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Sunwoo, Hongjae, David Colognori, John E. Froberg, Yesu Jeon, and Jeannie T. Lee. "Repeat E anchors Xist RNA to the inactive X chromosomal compartment through CDKN1A-interacting protein (CIZ1)." Proceedings of the National Academy of Sciences 114, no. 40 (September 18, 2017): 10654–59. http://dx.doi.org/10.1073/pnas.1711206114.
Full textAbstract:
X chromosome inactivation is an epigenetic dosage compensation mechanism in female mammals driven by the long noncoding RNA, Xist. Although recent genomic and proteomic approaches have provided a more global view of Xist’s function, how Xist RNA localizes to the inactive X chromosome (Xi) and spreads in cis remains unclear. Here, we report that the CDKN1-interacting zinc finger protein CIZ1 is critical for localization of Xist RNA to the Xi chromosome territory. Stochastic optical reconstruction microscopy (STORM) shows a tight association of CIZ1 with Xist RNA at the single-molecule level. CIZ1 interacts with a specific region within Xist exon 7–namely, the highly repetitive Repeat E motif. Using genetic analysis, we show that loss of CIZ1 or deletion of Repeat E in female cells phenocopies one another in causing Xist RNA to delocalize from the Xi and disperse into the nucleoplasm. Interestingly, this interaction is exquisitely sensitive to CIZ1 levels, as overexpression of CIZ1 likewise results in Xist delocalization. As a consequence, this delocalization is accompanied by a decrease in H3K27me3 on the Xi. Our data reveal that CIZ1 plays a major role in ensuring stable association of Xist RNA within the Xi territory.
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Pala, Irene, Manfred Schartl, Miguel Brito, Joana Malta Vacas, and Maria Manuela Coelho. "Gene expression regulation and lineage evolution: the North and South tale of the hybrid polyploid Squalius alburnoides complex." Proceedings of the Royal Society B: Biological Sciences 277, no. 1699 (June 16, 2010): 3519–25. http://dx.doi.org/10.1098/rspb.2010.1071.
Full textAbstract:
The evolution of hybrid polyploid vertebrates, their viability and their perpetuation over evolutionary time have always been questions of great interest. However, little is known about the impact of hybridization and polyploidization on the regulatory networks that guarantee the appropriate quantitative and qualitative gene expression programme. The Squalius alburnoides complex of hybrid fish is an attractive system to address these questions, as it includes a wide variety of diploid and polyploid forms, and intricate systems of genetic exchange. Through the study of genome-specific allele expression of seven housekeeping and tissue-specific genes, we found that a gene copy silencing mechanism of dosage compensation exists throughout the distribution range of the complex. Here we show that the allele-specific patterns of silencing vary within the complex, according to the geographical origin and the type of genome involved in the hybridization process. In southern populations, triploids of S. alburnoides show an overall tendency for silencing the allele from the minority genome, while northern population polyploids exhibit preferential biallelic gene expression patterns, irrespective of genomic composition. The present findings further suggest that gene copy silencing and variable expression of specific allele combinations may be important processes in vertebrate polyploid evolution.
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Boumil, Rebecca Maxfield, Yuya Ogawa, Bryan K. Sun, Khanh D. Huynh, and Jeannie T. Lee. "Differential Methylation of Xite and CTCF Sites in Tsix Mirrors the Pattern of X-Inactivation Choice in Mice." Molecular and Cellular Biology 26, no. 6 (March 15, 2006): 2109–17. http://dx.doi.org/10.1128/mcb.26.6.2109-2117.2006.
Full textAbstract:
ABSTRACT During mammalian dosage compensation, one of two X-chromosomes in female cells is inactivated. The choice of which X is silenced can be imprinted or stochastic. Although genetic loci influencing the choice decision have been identified, the primary marks for imprinting and random selection remain undefined. Here, we examined the role of DNA methylation, a mechanism known to regulate imprinting in autosomal loci, and sought to determine whether differential methylation on the two Xs might predict their fates. To identify differentially methylated domains (DMDs) at the X-inactivation center, we used bisulfite sequencing and methylation-sensitive restriction enzyme analyses. We found DMDs in Tsix and Xite, two genes previously shown to influence choice. Interestingly, the DMDs in Tsix lie within CTCF binding sites. Allelic methylation differences occur in gametes and are erased in embryonic stem cells carrying two active Xs. Because the pattern of DNA methylation mirrors events of X-inactivation, we propose that differential methylation of DMDs in Tsix and Xite constitute a primary mark for epigenetic regulation. The discovery of DMDs in CTCF sites draws further parallels between X-inactivation and autosomal imprinting.
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Hiebert, J. C., and J. A. Birchler. "Dosage compensation of the copia retrotransposon in Drosophila melanogaster." Genetics 130, no. 3 (March 1, 1992): 539–45. http://dx.doi.org/10.1093/genetics/130.3.539.
Full textAbstract:
Abstract Dosage compensation in Drosophila has been studied at the steady state RNA level for several single-copy genes; however, an important point is addressed by analyzing a repetitive, transposable element for dosage compensation. The two issues of gene-specific cis control and genomic position can be studied by determining the extent of dosage compensation of a transposable element at different chromosomal locations. To determine whether the multicopy copia transposable element can dosage compensate, we used the X-linked white-apricot (wa) mutation in which a copia element is present. The extent of dosage compensation was determined for the white and copia promoters in larvae and adults in two different genomic locations of the wa allele. We conclude that copia is able to dosage compensate, and that the white promoter and the copia promoter are not coordinate in their dosage compensation abilities when assayed under these various conditions. Thus, two transcriptional units, one within the other, both of which are able to dosage compensate, do so differently in response to developmental stage and genomic position.