Dosage compensation

About: Dosage compensation is a research topic. Over the lifetime, 1920 publications have been published within this topic receiving 124589 citations.

The relationship between position and expression of genes on the kangaroo X chromosome suggests a tissue-specific spread of inactivation from a single control site.

Abstract: In marsupials, X chromosome inactivation is paternal and incomplete. The tissue-specific pattern of inactivation of X-linked loci (G6PD, PGK, GLA) has been attributed to a piecemeal inactivation of different regions of the X. We here propose an alternative hypothesis, in which inactivation of the marsupial X is a chromosome-wide event, but is differentially regulated in different tissues. This hypothesis was suggested by the relationship between the positions and activity of genes on the kangaroo paternal X. In the absence of an HPRT polymorphism, we have used somatic cell hybridization to assess the activity of the paternal HPRT allele in lymphocytes and fibroblasts. The absence of the paternal X, and of the paternal forms of G6PD or PGK, from 33 cell hybrids made by fusing HPRT-deficient rodent cells with lymphocytes or fibroblasts of heterozygous females, suggests that the HPRT gene on the paternal X is inactive in both tissues and therefore not selectable. Since HPRT is located medially on the Xq near GLA, which shares the same characteristics of activity, we suggest that the locus-specific and tissue-specific patterns of activity result from a differential spread of inactivation from a single control locus, located near HPRT and GLA, outwards in both directions to G6PD and PGK. The nucleolus organizer region on the short arm does not seem to be part of the inactivated unit.

Sex differences in the human brain transcriptome of cases with schizophrenia

Abstract: While schizophrenia differs between males and females in age of onset, symptomatology and the course of the disease, the molecular mechanisms underlying these differences remain uncharacterized. In order to address questions about the sex-specific effects of schizophrenia, we performed a large-scale transcriptome analysis of RNA-seq data from 437 controls and 341 cases from two distinct cohorts from the CommonMind Consortium. Analysis across the cohorts identifies a reproducible gene expression signature of schizophrenia that is highly concordant with previous work. Differential expression across sex is reproducible across cohorts and identifies X- and Y-linked genes, as well as those involved in dosage compensation. Intriguingly, the sex expression signature is also enriched for genes involved in neurexin family protein binding and synaptic organization. Differential expression analysis testing a sex-by-diagnosis interaction effect did not identify any genome-wide signature after multiple testing corrections. Gene coexpression network analysis was performed to reduce dimensionality and elucidate interactions among genes. We found enrichment of co-expression modules for sex-by-diagnosis differential expression signatures, which were highly reproducible across the two cohorts and involve a number of diverse pathways, including neural nucleus development, neuron projection morphogenesis, and regulation of neural precursor cell proliferation. Overall, our results indicate that the effect size of sex differences in schizophrenia gene expression signatures is small and underscore the challenge of identifying robust sex-by-diagnosis signatures, which will require future analyses in larger cohorts.

Frequency of reactivation and variability in expression of X-linked enzyme loci.

Abstract: A mouse-human cell hybrid clone retaining an inactive human X chromosome was treated with 5-azacytidine. Following treatment, expression of the X-linked enzyme markers, hypoxanthine-guanine phosphoribosyltransferase (HPRT), glucose-6-phosphate dehydrogenase (G6PD), phosphoglycerate kinase (PGK), and alpha-galactosidase A (GLA) was examined. Results presented here show that 45 of the 62 clones positive for human HPRT expressed human GLA, while only four of 68 clones negative for human HPRT expressed human GLA. These results strongly suggest that there is coordinate reactivation of GLA and HPRT. Reactivated expression of G6PD was studied in detail. The studies show that 5-azacytidine can induce heritable changes in the inactive human X chromosome resulting in the expression of G6PD activity at a level lower than that from an active human X chromosome.

Chromosomal basis of dosage compensation in Drosophila. II. The DNA replication patterns of the male X-chromosome in an autosome--X insertion in D. melanogaster.

Abstract: The functional morphology and the replication pattern of the male X -chromosome in an autosome- X insertion stock ( T (1;3) 05) of Drosophila melanogaster have been examined. In larval salivary glands carrying this insertion neither the enlargement and pale staining of the single male X , nor the characteristic early completion of replication cycle, as revealed by 3 H-TdR autoradiography is in any way changed. The normal properties of the inserted autosomal segment are also unaltered. The results appear to support a ‘piecemeal’ type of dosage compensation mechanism in Drosophila operating through the male.

Application of the gene dosage balance hypothesis to auxin-related ribosomal mutants in Arabidopsis.

Abstract: Several proteomic studies in Arabidopsis have shown the presence of heterogeneous ribosomal populations in different tissues. However, the phenotypic consequences of the imbalance of those ribosomal populations, and the regulatory mechanisms activated to control specific ratios between them, have yet to be evaluated. In our previous report, the phenotypic characterization of the Arabidopsis ribosomal L4 (RPL4) family suggests that the maintenance of proper auxin-regulated developmental responses requires the simultaneous presence of RPL4A- and RPL4D-containing ribosomes. Based on the analysis of the compensatory mechanisms within the RPL4 family proteins in the rpl4a and rpl4d backgrounds, we propose the Gene Dosage Balance Hypothesis (GDBH) as a regulatory mechanism for ribosomal complexes in Arabidopsis. By using the concepts of dosage compensation and hierarchy, GDBH is able to explain the severity and specificity of different ribosomal mutant phenotypes associated with the same ribosomal complex.