Dosage compensation

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

Molecular cytological differentiation of active from inactive X domains in interphase: implications for X chromosome inactivation.

Abstract: A fluorescence in situ hybridization method using a biotinylated DNA probe specific for the centromeric region of the human X chromosome was used to differentiate the genetically active from the inactive X in interphase cells. With this technique, we were able to interpret both the relative position and the degree of condensation of the X chromosomes within the nucleus. We first established the specificity of fluorescence labelling of the hybridized probe by comparing its location and appearance (either dense or diffuse) when associated with a sex chromatin body (SCB) in early passage normal human female fibroblasts. In these cells, where the presence of inactive X chromatin was verified by identification of a 4',6-diamidino-2-phenyl indole (DAPI)-positive SCB in 85% of the cells examined, the X chromatin fluorescence was always associated with the SCB. The signal was dense in structure in 98% and peripheral in location in 80% of the nuclei. A second type of signal, diffuse in form, was observed in 85% of the nuclei and presumably represents the location of the active X chromosome. It was located peripherally or centrally with equal frequency and was not associated with any identifiable nuclear component. This diffuse signal was the major type associated with human male fibroblasts. In rodent x human hybrid cells containing a human inactive X, the fluorescent signal was associated with an SCB-like structure in only 13% of the nuclei; it was dense in 66% of the nuclei and equally peripheral or central in location. This indicates an alteration in the interphase structure of the human inactive X chromosome in hybrid cells which may explain its known instability with respect to genetic activity in such systems.

Getting a Full Dose? Reconsidering Sex Chromosome Dosage Compensation in the Silkworm, Bombyx mori

Abstract: Dosage compensation--equalizing gene expression levels in response to differences in gene dose or copy number--is classically considered to play a critical role in the evolution of heteromorphic sex chromosomes. As the X and Y diverge through degradation and gene loss on the Y (or the W in female-heterogametic ZW taxa), it is expected that dosage compensation will evolve to correct for sex-specific differences in gene dose. Although this is observed in some organisms, recent genome-wide expression studies in other taxa have revealed striking exceptions. In particular, reports that both birds and the silkworm moth (Bombyx mori) lack dosage compensation have spurred speculation that this is the rule for all female-heterogametic taxa. Here, we revisit the issue of dosage compensation in silkworm by replicating and extending the previous analysis. Contrary to previous reports, our efforts reveal a pattern typically associated with dosage compensated taxa: the global male:female expression ratio does not differ between the Z and autosomes. We believe the previous report of unequal male:female ratios on the Z reflects artifacts of microarray normalization in conjunction with not testing a major assumption that the male:female global expression ratio was unbiased for autosomal loci. However, we also find that the global Z chromosome expression is significantly reduced relative to autosomes, a pattern not expected in dosage compensated taxa. This combination of male:female parity with an overall reduction in expression for sex-linked loci is not consistent with the prevailing evolutionary theory of sex chromosome evolution and dosage compensation.

Characterization of the bovine pseudoautosomal boundary: Documenting the evolutionary history of mammalian sex chromosomes

Abstract: Maleness in placental mammals and marsupials is determined by the SRY gene located on the Y chromosome. This major sex determinant arose ∼166 million years ago (Mya) on an ancestral autosome as an allele of the SOX3 gene (Veyrunes et al. 2008). As is commonly observed for chromosomes carrying sex-determining genes (Ohno 1967), the Y has since undergone progressive degeneration, being reduced in present-day man to a mere 25 Mb of euchromatin harboring no more than 27 distinct protein-coding genes or gene families, appended with an approximately equal amount of dispensable heterochromatin (Skaletsky et al. 2003). These numbers are to be compared with the ∼155 Mb and 1100 genes of its ancestral partner, the X chromosome (Ross et al. 2005). The decay of the Y is thought to result from the successive selection of male-beneficial/female-deleterious alleles embedded in haplotypes that lost the ability to recombine with the X and are hence confined to males (Charlesworth 1991). Absence of recombination causes rapid degeneration by mutation, deletion, and transposon invasion accumulating as a result of a higher mutation rate in the male versus the female germline (due to the larger number of cell divisions required to produce male vs. female gametes), inefficient repair (e.g., Muller’s ratchet), and inefficient selection (e.g., shielding of deleterious recessives and Hill–Robertson interference) (e.g., Charlesworth et al. 2005; Bachtrog 2006; Graves 2006). The most commonly invoked recombination-blocking mechanism is chromosomal inversion. The observation of a stepwise increase in sequence similarity between genes ordered on the human X with their gametologs on the Y (“evolutionary strata”) suggests that five such recombination-blocking inversions have occurred in the human lineage (Lahn and Page 1999; Ross et al. 2005). These have isolated an increasing proportion of the Y from its X partner, progressively reducing the region of X–Y homology to the ∼2.7 Mb pseudoautosomal region 1 (PAR1). The five inversions in the human lineage were initially dated to 240–320 Mya, 130–170 Mya, 80–130 Mya, 38–44 Mya, and 29–32 Mya, respectively, yet recent reexamination of the age of the therian sex chromosomes (Veyrunes et al. 2008) forces reevaluation of these estimates. Loss of genes from the Y causes male hemizygosity and thus a different gonosome-to-autosome balance in the two sexes. This is thought to drive progression of dosage compensation involving (in mammals) doubling of expression levels from the X (Nguyen and Disteche 2006) and compensatory XIST-dependent inactivation of one X chromosome in females (Lyon 1961; Heard and Disteche 2006). Notably, while virtually all genes located in the older strata undergo X inactivation, their proportion decreases in the younger layers (Carrel and Willard 2005). Concomitantly, the enrichment in L1 interspersed repeats, which may operate as way stations spreading the inactivation process (Lyon 1998; Carrel et al. 2006), increases with stratum age (Ross et al. 2005). The generalization of dosage compensation across most of the X chromosome is thought to underlie its “frozen” gene content in mammals (Ohno 1967). The human and dog X chromosome sequences, for instance, are essentially colinear, while the human and mouse X chromosomes are nearly perfectly syntenic despite multiple intrachromosomal rearrangements (Ross et al. 2005). Figure 1A illustrates the equally remarkable conservation of gene content and order between the human and bovine X chromosomes. Figure 1. (A) Graphical representation of unique BLAST hits (E-value < 10−2) between the human and bovine X chromosomes. Sequences mapping to human PAR1-2 or strata 1–5 are color-labeled as indicated. (B) Schematic representation of distal ... Despite the largely frozen gene content of the X, the evolution of mammalian sex chromosomes has been punctuated by interchromosomal exchanges. An autosome to proto-gonosome translocation occurring after placental mammals diverged from marsupials has increased the size of the eutherian neo-gonosome by addition of the “X added region” (XAR) (Graves 2006). Autosome to Y transposition has augmented the content of the Y chromosome in male-beneficial genes, including retrotransposition of CDY before the divergence of marsupials and eutherians (Lahn and Page 1999; Skaletsky et al. 2003), transposition of DAZ during primate evolution (Saxena et al. 1996), and transposition of FLJ36031 prior to carnivore radiation and TETY1 following the divergence of cat and dog lineages (Murphy et al. 2006). Moreover, the human Y euchromosome has acquired an X transposed region (XTR) after its divergence from chimpanzees (Skaletsky et al. 2003). In addition, X-linked genes have generated pseudogenes by retrotransposition to autosomes, presumably to compensate for their silencing during male meiotic sex chromosome inactivation (MSCI) (e.g., Potrzebowski et al. 2008).

The right dose for every sex

Abstract: Sex chromosomes in different organisms are studied as model systems for chromatin regulation of transcription and epigenetics. Similar to the female X in mammals, the male X chromosome in Drosophila is involved in the process of dosage compensation. However, in contrast to one of the mammalian female X chromosomes undergoing inactivation, the Drosophila male X is transcriptionally upregulated by approximately twofold. The Drosophila male X is a remarkable example for a specialized, transcriptionally hyperactive chromatin domain that facilitates the study of chromatin regulation in the context of transcription, nuclear architecture, and chromatin remodeling. In addition, the rich phenomenology of dosage compensation in Drosophila provides an opportunity to explore the complexities of gene regulation through epigenetic chromatin configurations, histone modifications, and noncoding RNAs. Male-specific lethal (MSL) factors constitute the MSL complex or dosage compensation complex and are important for transcription regulation of X-linked genes. Recent biochemical studies have identified a number of interesting factors that associate with the MSL complex including components of the nuclear pore complex and exosome subunits. Furthermore, global analysis of MSL complex binding showed that MSL complexes are enriched on genes with preferential binding to 3' end of genes. Taken together, these findings suggest a role of the MSL complex in transcription elongation, RNA processing, and/or nuclear organization.