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Dosage compensation

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


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TL;DR: The Meyer laboratory has shown that both her-1 repression and dosage compensation are mediated through direct assembly of the same complex of proteins, referred to as the dosage compensation complex, which makes it possible to inhibit genes in an extraordinarily wide variety of biological contexts.
Abstract: In recent years, it has become apparent that eukaryotic transcriptional repression mechanisms are remarkably varied in their modes of action and effects. Repression can be established by proteins that act over a short range, or at a long distance (Mannervik et al. 1999). Some mechanisms of repression are readily reversible, but others establish a heritable state of long-term silencing (Moazed 2001). Many transcriptional repressors alter chromatin structure through histone deacetylation or methylation, and thereby affect nucleosome positioning and accessibility of the DNA to positively acting factors (Kornberg and Lorch 1999; Zhang and Reinberg 2001). Multiple steps in transcriptional initiation are also sensitive to obstruction by repressors (Maldonado et al. 1999), and individual repressors such as Ssn6–Tup1 target both chromatin and the RNA Pol II complex (Smith and Johnson 2000). The Caenorhabditis elegans germ line transcriptional repressor PIE-1 is a predicted RNAbinding protein that appears to act after initiation (Batchelder et al. 1999; Tenenhaus et al. 2001). This array of mechanisms makes it possible to inhibit genes in an extraordinarily wide variety of biological contexts. We understand less about how repression might be tailored to achieve particular levels of inhibition. This is a seemingly simple matter if the goal is for a gene to be in an “off” state, although whether the repressed state is to be rapidly reversible could add a further level of complexity. But what if having an on/off switch is not enough, and instead a partial suppression of transcription is required, to attain a particular level of expression? Furthermore, what if the biological program in which this partial repression is needed also requires that other genes be inhibited more completely? Can the same or overlapping repression mechanisms be customized to have different effects at different loci, a scheme that would provide the simplest solution to the problem? Can these same mechanisms be used both to inhibit individual genes and establish a global repression over a large region? Precisely the above situation is presented during establishment of the hermaphrodite fate in C. elegans. In these nematodes, whether an individual becomes a hermaphrodite (XX) or male (XO) is determined by the number of sex chromosomes present (Meyer 2000). In hermaphrodites, transcription of nearly all genes on both X chromosomes must be reduced by half, to bring their expression in line with levels that arise from a single X chromosome in males. This process is called dosage compensation, a term that refers to the various mechanisms by which species alter expression of sex chromosome genes in one sex, to compensate for the difference in chromosome number between the two sexes (Marin et al. 2000). Dosage compensation mechanisms are considerably diverse: for example, in Drosophila, transcription of X chromosome genes is doubled in males, but in mammals one of the two X chromosomes is inactivated in females. In C. elegans, in addition to a twofold global reduction in X chromosome transcription, the hermaphrodite fate also depends on specific repression of the autosomal male sex-determination gene her-1 (Meyer 2000). In contrast to dosage compensation, this specific repression of her-1 involves a more than 20-fold reduction in transcription. Evidence that these two distinct repression processes require some of the same proteins (Meyer 2000), has suggested that they may share some targeting or effector mechanisms. In a recent study, the Meyer laboratory has shown that both her-1 repression and dosage compensation are mediated through direct assembly of the same complex of proteins, referred to as the dosage compensation complex (Fig. 1; Chu et al. 2002). How can this protein complex establish such dramatically variant levels of specific and chromosome-wide repression? The dosage compensation complex also represses to different degrees when it is bound to different individual her-1 DNA regulatory elements. Surprisingly, these repression levels do not appear to correlate with the affinity of DNA binding, suggesting that the dosage compensation complex can have significantly different effects within when it is recruited within different contexts. An important strength of these experiments is that they were performed in vivo, and have thereby provided a window into what is actually happening at these target loci. They have defined a fascinating question for further study: How does the milieu in which the dosage compensation complex is recruited influence its function?

4 citations

Journal ArticleDOI
TL;DR: The i(12p)-positive cells displayed global hypomethylation of gene-poor regions on 12p, a footprint previously associated with constitutional and acquired gains of whole chromosomes as well as with X-chromosome inactivation in females, and it is hypothesized that this non-genic hypometHylation is associated with chromatin processing that facilitates cellular adaptation to excess genetic material.
Abstract: To ascertain the epigenomic features, i.e., the methylation, non-coding RNA, and gene expression patterns, associated with gain of i(12p) in Pallister-Killian syndrome (PKS), we investigated single cell clones, harboring either disomy 12 or tetrasomy 12p, from a patient with PKS. The i(12p)-positive cells displayed a characteristic expression and methylation signature. Of all the genes on 12p, 13% were overexpressed, including the ATN1, COPS7A, and NECAP1 genes in 12p13.31, a region previously implicated in PKS. However, the median expression fold change (1.3) on 12p was lower than expected by tetrasomy 12p. Thus, partial dosage compensation occurs in cells with i(12p). The majority (89%) of the significantly deregulated genes were not situated on 12p, indicating that global perturbation of gene expression is a key pathogenetic event in PKS. Three genes-ATP6V1G1 in 9q32, GMPS in 3q25.31, and TBX5 in 12q24.21-exhibited concomitant hypermethylation and decreased expression. The i(12p)-positive cells displayed global hypomethylation of gene-poor regions on 12p, a footprint previously associated with constitutional and acquired gains of whole chromosomes as well as with X-chromosome inactivation in females. We hypothesize that this non-genic hypomethylation is associated with chromatin processing that facilitates cellular adaptation to excess genetic material.

4 citations

Journal ArticleDOI
01 Jan 2012-Fly
TL;DR: Key developmental genes which could create developmental havoc if their levels were unbalanced show more exquisite regulation, suggesting nature distinguishes them and ensures their expression is kept in the desirable range.
Abstract: Equalizing sex chromosome expression between the sexes when they have largely differing gene content appears to be necessary, and across species, is accomplished in a variety of ways. Even in birds, where the process is less than complete,1 a mechanism to reduce the difference in gene dose between the sexes exists. In early development, while the dosage difference is unregulated and still in flux, it is frequently exploited by sex determination mechanisms. The Drosophila female sex determination process is one clear example, determining the sexes based on X chromosome dose. Recent data show that in Drosophila, the female sex not only reads this gene balance difference, but at the same time usurps the moment. Taking advantage of the transient default state of male dosage compensation, the sex determination master-switch Sex-lethal which resides on the X, has its expression levels enhanced before it works to correct the gene imbalance.2 Intriguingly, key developmental genes which could create developmental havoc if their levels were unbalanced show more exquisite regulation,3 suggesting nature distinguishes them and ensures their expression is kept in the desirable range.

4 citations

Posted ContentDOI
14 Oct 2021-bioRxiv
TL;DR: In this paper, the authors described a powerful and cost-effective "chromosomics" approach, combining probes generated from the microdissected sex chromosomes with transcriptome sequencing to explore this diversity in non-model Australian reptiles with heteromorphic or cryptic sex chromosomes.
Abstract: Reptile sex determination is attracting much attention because the great diversity of sex-determination and dosage compensation mechanisms permits us to approach fundamental questions about sex chromosome turnover and evolution. However, reptile sex chromosome variation remains largely uncharacterized and no reptile master sex determination genes have yet been identified. Here we describe a powerful and cost-effective “chromosomics” approach, combining probes generated from the microdissected sex chromosomes with transcriptome sequencing to explore this diversity in non-model Australian reptiles with heteromorphic or cryptic sex chromosomes. We tested the pipeline on a turtle, a gecko, and a worm-lizard, and we also identified sequences located on sex chromosomes in a monitor lizard using linked-read sequencing. Genes identified on sex chromosomes were compared to the chicken genome to identify homologous regions among the four species. We identified candidate sex determining genes within these regions, including conserved vertebrate sex-determining genes pdgfa, pdgfra amh and wt1, and demonstrated their testis or ovary-specific expression. All four species showed gene-by-gene rather than chromosome-wide dosage compensation. Our results imply that reptile sex chromosomes originated by independent acquisition of sex-determining genes on different autosomes, as well as translocations between different ancestral macro- and micro-chromosomes. We discuss the evolutionary drivers of the slow differentiation, but rapid turnover, of reptile sex chromosomes.

4 citations

Journal ArticleDOI
TL;DR: The report by Lee et al. makes a unique contribution by extending the study of the impact of supernumerary sex chromosomes to include rare cases of children with four or five sex chromosomes, with intriguing differences between those with an extra X or Y.
Abstract: Most people have 23 pairs of chromosomes; one set from the mother and one from the father. However, nondisjunction errors during meiosis can lead to a case of trisomy, where there are three rather than two chromosomes. Although such events are not uncommon, they are usually lethal, and account for a high proportion of spontaneous abortions. The most common trisomy compatible with survival to birth involves chromosome 21, one of the smallest chromosomes. This is associated with serious developmental abnormalities affecting a range of organs (Down syndrome). In comparison, the effects of a sex chromosome trisomy are relatively mild. Most children with XXX, XXY or XYY constitutions attend regular school and, apart from a tendency to be somewhat taller than average, appear physically normal. The reason for this can be found in the peculiar nature of the sex chromosomes. The Y chromosome is very small and is thought to contain fewer than 100 genes, compared with over 1000 on the X chromosome. All else being equal, females should have considerably more gene product than males. However, in normal XX females, most of one X-chromosome is inactivated. A process of methylation causes the DNA to be packed in a tight ball, preventing gene expression. This process of ‘dosage compensation’ has the effect of reducing the difference between males and females in amount of gene product. X-inactivation is not complete; there are regions on the tips of the sex chromosomes that remain active and behave just like autosomes; these are referred to as the pseudoautosomal region. In addition, there are areas of the X-chromosome outside the pseudoautosomal region that escape inactivation, where both copies of a gene are expressed. There appears to be quite substantial individual variation in the number and location of genes that escape inactivation. If we put these pieces of information together, we start to see why the impact of an additional sex chromosome is relatively mild. For boys with XYY constitution, the additional Y chromosome contains relatively few genes. For girls or boys with an extra X, only one X chromosome is completely activated, and so a minority of X-linked genes are expressed in extra dose. Nevertheless, there are cognitive impacts of an extra sex chromosome, as discussed in the article by Lee et al. (2012), with intriguing differences between those with an extra X or Y. There is surprisingly little research on sex chromosome trisomies: The explanation is largely due to the mild impact of the trisomy, which means that many people who have a sex chromosome trisomy would not be aware of their status. Most of the information we have about prevalence and consequences of sex chromosome trisomies comes from a set of studies carried out in the 1960–1970s in which newborn babies underwent chromosome screening. Such studies are unlikely to be repeated now for two reasons. First, they are highly labour-intensive: given that, for instance, XXX chromosome constitution is found in around 1 in 1,000 girls, this means we would have to screen 10,000 cases to get a sample of just 10 affected cases. Research is also limited by ethical concerns. The studies done in the 1960s proved problematic as the researchers started to realise that telling parents that their newborn child had a sex chromosome trisomy was bound to cause anxiety and distress, especially since information about its likely impact was so uncertain. Findings from the newborn screening studies were summarized in a systematic review by Leggett, Jacobs, Nation, Scerif, and Bishop (2010), who noted a reduction in IQ in XXX, XXY and XYY groups, with both groups of males showing evidence of disproportionate verbal impairments. Such deficits are assumed to be caused by the excess proteins that arise from supernumerary X- or Y-linked genes that escape inactivation. The report by Lee et al. makes a unique contribution by extending the study of the impact of supernumerary sex chromosomes to include rare cases of children with four or five sex chromosomes. They demonstrate a clear ‘dosage’ effect, whereby the more chromosomes, the greater the negative impact on IQ and development. Each additional X- or Y-chromosome was associated with a decrease in IQ of around 1 SD. Intriguingly, they also found that additional X chromosomes had a greater effect on structural language skills, whereas additional Y chromosomes had disproportionate effect on pragmatic problems and autistic features. It should be noted, however, that those with extra X chromosomes included both girls and boys, whereas the extra-Y chromosome group were all male. Bishop et al. (2011) considered boys and girls separately and found that XXY and XYY boys had similar communication profiles, whereas XXX girls had less evidence of pragmatic impairments. Findings of autistic features in XYY males is of particular interest. When XYY was first described in the 1960s there was intense media interest in the idea that these were ‘supermales’ with unusual levels of aggression and criminality. An early study by Witkin et al. (1976) put these ideas into perspective. Witkin et al. capitalised on the excellent medical, military and criminal public records available in Denmark, as well as the willingness of a high proportion of the population to cooperate by providing DNA samples to the researchers. By restricting their study to tall men, they were able to identify 12 cases of XYY and 16 cases of XXY in a population of over 4,000 males. They confirmed a higher rate of criminality among XYY males than either XY or XXY males, but noted that the crimes mostly involved property rather than aggressive assaults, and could at least partly be explained in terms of the lower IQ of XYY males relative to XY males. The findings on autistic features by Lee et al. (2012) cast the XYY phenotype in a new light, suggesting that a tendency to get in trouble with the law may be related to deficits in social communication and interpersonal skills, rather than unnatural levels of aggression. Difficult ethical choices still surround the topic of supernumerary sex chromosomes. In many countries, when an abnormal number of sex chromosomes is identified on prenatal testing, the parents are offered a termination of the pregnancy. The study by Lee et al. (2012) therefore has important clinical implications, as well as theoretical importance, because parental choices can be influenced by what they are told about the likely outcome of the child. As the authors note, we must be cautious in interpreting findings based on cases where an unusual karyotype only comes to light when a child is investigated for behaviour problems. Nevertheless, all recent studies have found evidence of an increase in autistic features in boys with XYY identified prenatally, where ascertainment bias is unlikely to account for associations with developmental difficulties. It is, however, important to emphasise that although there is an increased risk of both structural language problems and autistic features in children with additional sex chromosomes, there is wide individual variation. Some children with trisomies do not have any difficulties, and only a minority merit a diagnosis of autistic disorder (Bishop et al., 2011; Ross et al., 2012).

4 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202330
202272
202183
202051
201980
201870