Dosage compensation

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

Skewed X-chromosome inactivation: cause or consequence?

Abstract: X-chromosome inactivation occurs early during female mammalian development to transcriptionally silence one of the two X chromosomes, thereby achieving dosage compensation with males who have only a single X chromosome and the sexdetermining Y chromosome (1). The choice of which X chromosome to inactivate is generally random in somatic tissue; however, once chosen, the inactivation is stably maintained, and the same chromosome is inactivated in all progeny cells. Therefore, females are mosaics of two populations of cells that differ in the X chromosome that is active. For more than three decades, researchers have used this mosaicism as a tool to examine the potential clonal origin of neoplasias in females (2), since, if the tumor(s) arose from a single cell after the time of Xchromosome inactivation, then it will have the same X chromosome active in all cells. This skewed (nonrandom) pattern of inactivation has been observed in a wide range of neoplastic tissues [see (3) for recent review] and can be considered a consequence of the monoclonal origin of the neoplasia. However in this issue of the Journal, Buller et al. (4) report the finding of an elevated incidence of nonrandom X-chromosome inactivation in the somatic tissue of females with invasive ovarian cancer and BRCA1 mutations. Buller et al. (4) make the interesting suggestion that the observed nonrandom inactivation may be indicative of a putative tumor suppressor gene on the X chromosome and that the combination of a germline mutation of this gene as well as nonrandom X-chromosome inactivation has eliminated wild-type activity of the gene and thus results in an elevated risk of developing cancer in these females. As males who inherit the mutation would also lack expression, either the gene functions in a female-specific tissue (such as the ovary) or the male carriers would also have an elevated predisposition to cancer. In this model, skewed X-chromosome inactivation would arise independently but would cause enhanced tumor susceptibility. The difficulty with such a model is that females with the germline mutation and random X-chromosome inactivation would still have approximately 50% of their cells that would be predisposed to tumor development, suggesting that they too would have significantly elevated predisposition to cancer. There are some demonstrated X-linked cancer predispositions [e.g., (5)], and loss of heterozygosity for regions of the X chromosome is seen in a number of cancers, including ovarian cancer [references in (4); (6,7)]; however, there are numerous causes of skewed Xchromosome inactivation (Table 1). Therefore, in addition to the skewed inactivation being a cause of tumor susceptibility, it may be that skewed inactivation and elevated cancer risk are both consequences of one event or are independent events. A large proportion of skewed inactivation patterns results from selection for or against alleles on the active X chromosome. Such selection can be variable among different tissues [e.g., see (8)], dependent on the expression of the gene, whether or not the gene product is cell diffusible (9), and interactions with other genes [reviewed in (10)]. Furthermore, depending on the fitness conferred by the variant, selection can be slow or fast, resulting in different extents of skewing. Because hematopoiesis continues throughout life, the greatest amount of skewing is often observed in blood (10). The proportion of individuals showing skewing of X-chromosome inactivation in blood [skewing defined, as in the study by Buller et al. (4) as one allele being on the active X chromosome in >75% of cells and demonstrated by a modified allelic cleavage ratio of 3.0] increases dramatically with age (11,12), rising from under 10% of neonates to more than 35% of women older than 60 years of age (11) and up to 45% of women older than 75 years of age (13). Therefore, in assessments of skewed inactivation (particularly those that examine blood; however, extensive surveys of other tissues have not been reported), the age of the individuals examined must be considered. While Buller et al. did some age comparisons (and also found similar patterns of skewing in some other tissues), it is anticipated that females presenting with cancer may include a high proportion of older individuals; therefore, increased age-related skewing of X-chromosome inactivation is a concern. In addition, relatively small selective advantages may lead to extensive skewing over time; therefore, it is possible that an X-linked gene is providing a growth advantage, causing skewing of inactivation as well as resulting in an increased predisposition to certain cancers. Skewed inactivation can result from a decrease in the size of

Genes that escape from X-chromosome inactivation: Potential contributors to Klinefelter syndrome.

Abstract: One of the two X chromosomes in females is epigenetically inactivated, thereby compensating for the dosage difference in X-linked genes between XX females and XY males. Not all X-linked genes are completely inactivated, however, with 12% of genes escaping X chromosome inactivation and another 15% of genes varying in their X chromosome inactivation status across individuals, tissues or cells. Expression of these genes from the second and otherwise inactive X chromosome may underlie sex differences between males and females, and feature in many of the symptoms of XXY Klinefelter males, who have both an inactive X and a Y chromosome. We review the approaches used to identify genes that escape from X-chromosome inactivation and discuss the nature of their sex-biased expression. These genes are enriched on the short arm of the X chromosome, and, in addition to genes in the pseudoautosomal regions, include genes with and without Y-chromosomal counterparts. We highlight candidate escape genes for some of the features of Klinefelter syndrome and discuss our current understanding of the mechanisms underlying silencing and escape on the X chromosome as well as additional differences between the X in males and females that may contribute to Klinefelter syndrome.

The Gene Sex-lethal of the Sciaridae Family (Order Diptera, Suborder Nematocera) and Its Phylogeny in Dipteran Insects

Abstract: This article reports the cloning and characterization of the gene homologous to Sex-lethal (Sxl) of Drosophila melanogaster from Sciara coprophila, Rhynchosciara americana, and Trichosia pubescens. This gene plays the key role in controlling sex determination and dosage compensation in D. melanogaster. The Sxl gene of the three species studied produces a single transcript encoding a single protein in both males and females. Comparison of the Sxl proteins of these Nematocera insects with those of the Brachycera showed their two RNA-binding domains (RBD) to be highly conserved, whereas significant variation was observed in both the N- and C-terminal domains. The great majority of nucleotide changes in the RBDs were synonymous, indicating that purifying selection is acting on them. In both sexes of the three Nematocera insects, the Sxl protein colocalized with transcription-active regions dependent on RNA polymerase II but not on RNA polymerase I. Together, these results indicate that Sxl does not appear to play a discriminatory role in the control of sex determination and dosage compensation in nematocerans. Thus, in the phylogenetic lineage that gave rise to the drosophilids, evolution coopted for the Sxl gene, modified it, and converted it into the key gene controlling sex determination and dosage compensation. At the same time, however, certain properties of the recruited ancestral Sxl gene were beneficial, and these are maintained in the evolved Sxl gene, allowing it to exert its sex-determining and dose compensation functions in Drosophila.