Dosage compensation

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

Female-biased expression on the X chromosome as a key step in sex chromosome evolution in threespine sticklebacks

Abstract: Given that the genome of males and females are almost identical with the exception of genes on the Y (or W) chromosome or sex-determining alleles (in organisms without sex chromosomes), it is likely that many downstream processes resulting in sexual dimorphism are produced by changes in regulation. In early stages of sex chromosome evolution, as the Y-chromosome degenerates, gene expression should be significantly impacted for genes residing on the sex chromosome pair as regulatory mutations accumulate. However, this has rarely been examined because most model organisms have clearly diverged sex chromosomes. Fish provide a unique opportunity to examine the evolution of sex chromosomes because genetic sex determination has evolved quite recently in some groups of fish. We compared sex-specific transcription in threespine stickleback (Gasterosteus aculeatus) liver tissue using a long-oligo microarray. Of the 1,268 genes that were differentially expressed between sexes, a highly significant proportion (23%) was concentrated on chromosome 19, corresponding to the recently described nascent sex chromosomes. The sex-biased genes are enriched for different functional categories in males and females, although there is no specific functional enrichment on the sex chromosomes. Female-biased genes are concentrated at one end of the sex chromosome, corresponding to a deletion in the Y, suggesting a lack of global dosage compensation. Prior research on threespine sticklebacks has demonstrated various degrees of dissimilarity in upstream regions of genes on the Y providing a potential mechanism for the observed patterns of female-biased expression. We hypothesize that degeneration of the Y chromosome results in regulatory mutations that create a sex-specific expression pattern and that this physical concentration of sex-biased expression on the nascent sex chromosome may be a key feature characterizing intermediate phases of sex chromosome evolution.

A synaptobrevin-like gene in the Xq28 pseudoautosomal region undergoes X inactivation.

Abstract: The X and Y chromosomes that maintain human dimorphism are thought to have descended from a single progenitor, with the Y chromosome becoming largely depleted of genes1. A number of genes, however, retain copies on both X and Y chromosomes and escape the inactivation that affects most X-linked genes in somatic cells2. Many of those genes are present in two pseudoautosomal regions (PARs) at the termini of the short (p)3 and long (q)4,5 arms of the sex chromosomes. For both PARs, pairing facilitates the .exchange of information, ensuring the homogeni-sation of X and Y chromosomal material in these regions6–10. We report here a strikingly different regulation of expression of a gene in Xq PAR. Unlike all Xp PAR genes studied so far, a synaptobrevin-like gene, tentatively named SYBL1, undergoes X inactivation. In addition, it is also inactive on the Y chromosome, thereby maintaining dosage compensation in an unprecedented way.

The deficit of male-biased genes on the D. melanogaster X chromosome is expression-dependent: a consequence of dosage compensation?

Abstract: In Drosophila, there is a consistent deficit of male-biased genes on the X chromosome. It has been suggested that male-biased genes may evolve from initially unbiased genes as a result of increased expression levels in males. If transcription rates are limited, a large increase in expression in the testis may be harder to achieve for single-copy X-linked genes than for autosomal genes, because they are already hypertranscribed due to dosage compensation. This hypothesis predicts that the larger the increase in expression required to make a male-biased gene, the lower the chance of this being achievable if it is located on the X chromosome. Consequently, highly expressed male-biased genes should be located on the X chromosome less often than lowly expressed male-biased genes. This pattern is observed in our analysis of publicly available data, where microarray data or EST data are used to detect male-biased genes in D. melanogaster and to measure their expression levels. This is consistent with the idea that limitations in transcription rates may prevent male-biased genes from accumulating on the X chromosome.

The Phenotype of mes-2, mes-3, mes-4 and mes-6, Maternal-Effect Genes Required for Survival of the Germline in Caenorhabditis elegans, Is Sensitive to Chromosome Dosage

Abstract: Mutations in mes-2, mes-3, mes-4, and mes-6 result in maternal-effect sterility: hermaphrodite offspring of mes/mes mothers are sterile because of underproliferation and death of the germ cells, as well as an absence of gametes. Mutant germ cells do not undergo programmed cell death, but instead undergo a necrotic-type death, and their general poor health apparently prevents surviving germ cells from forming gametes. Male offspring of mes mothers display a significantly less severe germline phenotype than their hermaphrodite siblings, and males are often fertile. This differential response of hermaphrodite and male offspring to the absence of mes+ product is a result of their different X chromosome compositions; regardless of their sexual phenotype, XX worms display a more severe germline phenotype than XO worms, and XXX worms display the most severe phenotype. The sensitivity of the mutant phenotype to chromosome dosage, along with the similarity of two MES proteins to chromatin-associated regulators of gene expression in Drosophila, suggest that the essential role of the mes genes is in control of gene expression in the germline. An additional, nonessential role of the mes genes in the soma is suggested by the surprising finding that mutations in the mes genes, like mutations in dosage compensation genes, feminize animals whose male sexual identity is somewhat ambiguous. We hypothesize that the mes genes encode maternally supplied regulators of chromatin structure and gene expression in the germline and perhaps in somatic cells of the early embryo, and that at least some of their targets are on the X chromosomes.

Repeat E anchors Xist RNA to the inactive X chromosomal compartment through CDKN1A-interacting protein (CIZ1).

Abstract: 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.