Showing papers on "X chromosome published in 2007"
TL;DR: Using a high-resolution screen for DNA copy-number alterations in Wilms tumor, somatic deletions targeting a previously uncharacterized gene on the X chromosome are identified and called WTX, which is inactivated in approximately one-third of Wilms tumors.
Abstract: Wilms tumor is a pediatric kidney cancer associated with inactivation of the WT1 tumor-suppressor gene in 5 to 10% of cases. Using a high-resolution screen for DNA copy-number alterations in Wilms tumor, we identified somatic deletions targeting a previously uncharacterized gene on the X chromosome. This gene, which we call WTX, is inactivated in approximately one-third of Wilms tumors (15 of 51 tumors). Tumors with mutations in WTX lack WT1 mutations, and both genes share a restricted temporal and spatial expression pattern in normal renal precursors. In contrast to biallelic inactivation of autosomal tumor-suppressor genes, WTX is inactivated by a monoallelic "single-hit" event targeting the single X chromosome in tumors from males and the active X chromosome in tumors from females.
327 citations
TL;DR: It is found that recessive hybrid incompatibilities outnumber dominant ones and that hybrid male steriles outnumber all other types of incompatibility, consistent with the dominance and faster-male theories of Haldane's rule.
Abstract: Postzygotic reproductive isolation is characterized by two striking empirical patterns. The first is Haldane's rule—the preferential inviability or sterility of species hybrids of the heterogametic (XY) sex. The second is the so-called large X effect—substitution of one species's X chromosome for another's has a disproportionately large effect on hybrid fitness compared to similar substitution of an autosome. Although the first rule has been well-established, the second rule remains controversial. Here, we dissect the genetic causes of these two rules using a genome-wide introgression analysis of Drosophila mauritiana chromosome segments in an otherwise D. sechellia genetic background. We find that recessive hybrid incompatibilities outnumber dominant ones and that hybrid male steriles outnumber all other types of incompatibility, consistent with the dominance and faster-male theories of Haldane's rule, respectively. We also find that, although X-linked and autosomal introgressions are of similar size, most X-linked introgressions cause hybrid male sterility (60%) whereas few autosomal introgressions do (18%). Our results thus confirm the large X effect and identify its proximate cause: incompatibilities causing hybrid male sterility have a higher density on the X chromosome than on the autosomes. We evaluate several hypotheses for the evolutionary cause of this excess of X-linked hybrid male sterility.
284 citations
TL;DR: It is proposed that the Ctcf-Yy1-Tsix complex functions as a key component of the X chromosome binary switch, and Yy1 as a required cofactor for Ctcf.
248 citations
TL;DR: The results support a model in which MSL complex uses high-affinity sites to initially recognize the X chromosome and then associates with many of its targets through sequence-independent features of transcribed genes.
218 citations
TL;DR: It is concluded that the divergence value is saturated, confirming the cessation of X–Y recombination in the evolution of the sex chromosomes at ∼10–20 MYA.
Abstract: SILENE latifolia is a model system for the study of the evolution of plant sex chromosomes. The sex chromosomes of dioecious Silene species have several striking similarities with those of animals, including mammals (Guttman and Charlesworth 1998; Filatov 2005c; Nicolas et al. 2005), but they evolved independently and much more recently. The recent origin in a largely hermaphroditic plant genus, and the evidence of synteny of sex-linked genes and their orthologs in the hermaphroditic species S. vulgaris (Filatov 2005a), show clearly that, like mammalian sex chromosomes, those in S. latifolia evolved from a pair of ordinary chromosomes.
Due to its recent origin, the S. latifolia Y chromosome is probably in an early stage of degeneration. It is large in size, and it has been suggested that this reflects a large gene content (Negrutiu et al. 2001). However, this must be tested; an alternative is that the large size of the Y might reflect a highly repetitive DNA content, suggesting a stage in the degeneration process when repetitive sequences, including transposable elements, have probably accumulated, but before the stage in which most individual genes have lost function and can be deleted. The Y chromosome indeed appears to have accumulated chloroplast sequences (Kejnovsky et al. 2006), and there is also evidence of repetitive sequences and transposons in the S. latifolia genome (Pritham et al. 2003), but the extent of male-specific (Y-linked) sequence accumulation is not yet clear, although Y-specific sequences certainly exist (Donnison and Grant 1999). Similarly, the small Y chromosome-like region surrounding the sex-determining region in papaya (which may possibly have evolved more recently than the S. latifolia sex chromosomes) has a higher repetitive sequence content (and thus a lower gene density) than the genome as a whole (Liu et al. 2004).
To make progress in understanding sex chromosome evolution and organization in plants, and to test for genetic degeneration of Y chromosomes, sex-linked genetic markers are required. Several kinds of Y-linked genetic markers have been developed in S. latifolia, including anonymous markers such as AFLPs and RAPDs (Di Stilio et al. 1998; Nakao et al. 2002; Obara et al. 2002). Although it is straightforward to develop such anonymous markers, which are useful for obtaining genetic maps of the sex chromosomes (Lebel-Hardenack et al. 2002; Moore et al. 2003; Zluvova et al. 2005; Scotti and Delph 2006), these markers provide no information about the age of the sex chromosome system or the times since recombination between the X and Y stopped in different regions of these chromosomes, nor about whether the Y chromosome is genetically degenerated or degenerating. Genic markers are thus potentially much more valuable than anonymous ones. Such markers provide access to the gene coding sequences, containing synonymous and nonsynonymous sites that are subject to different selective constraints in functional copies (Gillespie 1991; Ohta 1995), so that it becomes possible to estimate the divergence time between the X and Y copies and to test for genetic degeneration of Y-linked copies (Guttman and Charlesworth 1998; Nicolas et al. 2005). Such studies are progressing rapidly for the neo-Y chromosome of Drosophila miranda (Bachtrog 2003; Bachtrog 2004).
Only seven genes on the Y chromosome of S. latifolia have been described after almost a decade of work (Guttman and Charlesworth 1998; Delichere et al. 1999; Atanassov et al. 2001; Matsunaga et al. 2003; Moore et al. 2003; Filatov 2005c; Nicolas et al. 2005). One of these has no X counterpart, being duplicated from an autosomal gene (Matsunaga et al. 2003), and only one is degenerated (Guttman and Charlesworth 1998). The five X-linked genes so far mapped are arranged along a gradient of X–Y synonymous divergence (Filatov 2005a), increasing with distance from the pseudoautosomal region (Filatov 2005a; Nicolas et al. 2005), although neither family allowed mapping all these genes. These findings suggest progressive steps in the cessation of recombination between the X and Y chromosomes, thus creating “evolutionary strata” on the sex chromosomes, similar to those described in mammalian X and Y chromosomes (Lahn and Page 1999). In the S. latifolia sex chromosomes, three divergence levels have been suggested. The two genes, SlX3/Y3 and SlX4/Y4, with the highest divergence have synonymous site divergence (Ks) >15%, while, for the least diverged pair, SlX1/Y1, Ks is only 3.6% (and intron divergence ∼2%), and two gene pairs, DD44X/DD44Y and SlSSX/SlSSY, have intermediate divergence (Ks ∼7–8%). With only five loci, discrete groupings of Ks values cannot be statistically significant, and the number is too low to formally test the ordering along the X chromosome of genes with different X–Y divergence in “evolutionary strata.”
To answer these questions, and to help understand the evolution of sex chromosomes, we use straightforward genetic approaches to identify sex-linked genes in S. latifolia, based on cDNA sequences obtained from this species. By using segregation analysis of ISVS and single nucleotide polymorphisms (SNPs), we identify four new Y-linked loci with homologs on the X chromosome. Comparison of silent site divergence between pairs of X/Y homologs, together with genetic mapping of the X-linked copies, confirm the existence of a gradient in divergence (evolutionary strata) of genes in this sex chromosome system, which is much younger than the sex chromosomes of mammals or birds.
214 citations
TL;DR: Compared the responses of the signal target, the female-specific SxlPe promoter of the switch gene Sex-lethal, in haploid, diploid, and triploid embryos, it is concluded that the X:A ratio predicts sexual fate, but does not actively specify it.
Abstract: In the textbook view, the ratio of X chromosomes to autosome sets, X:A, is the primary signal specifying sexual fate in Drosophila. An alternative idea is that X chromosome number signals sex through the direct actions of several X-encoded signal element (XSE) proteins. In this alternative, the influence of autosome dose on X chromosome counting is largely indirect. Haploids (1X;1A), which possess the male number of X chromosomes but the female X:A of 1.0, and triploid intersexes (XX;AAA), which possess a female dose of two X chromosomes and the ambiguous X:A ratio of 0.67, represent critical tests of these hypotheses. To directly address the effects of ploidy in primary sex determination, we compared the responses of the signal target, the female-specific SxlPe promoter of the switch gene Sex-lethal, in haploid, diploid, and triploid embryos. We found that haploids activate SxlPe because an extra precellular nuclear division elevates total X chromosome numbers and XSE levels beyond those in diploid males. Conversely, triploid embryos cellularize one cycle earlier than diploids, causing premature cessation of SxlPe expression. This prevents XX;AAA embryos from fully engaging the autoregulatory mechanism that maintains subsequent Sxl expression, causing them to develop as sexual mosaics. We conclude that the X:A ratio predicts sexual fate, but does not actively specify it. Instead, the instructive X chromosome signal is more appropriately seen as collective XSE dose in the early embryo. Our findings reiterate that correlations between X:A ratios and cell fates in other organisms need not implicate the value of the ratio as an active signal.
204 citations
TL;DR: It is demonstrated that a 117-kb genomic DNA fragment that carries DMY is able to induce testis differentiation and subsequent male development in XX (genetically female) medaka and suggested that the functional difference between the X and Y chromosomes in medaka is a single gene.
Abstract: Although the sex-determining gene SRY/Sry has been identified in mammals, homologues and genes that have a similar function have yet to be identified in nonmammalian vertebrates. Recently, DMY (the DM-domain gene on the Y chromosome) was cloned from the sex-determining region on the Y chromosome of the teleost fish medaka (Oryzias latipes). DMY has been shown to be required for the normal development of male individuals. In this study, we show that a 117-kb genomic DNA fragment that carries DMY is able to induce testis differentiation and subsequent male development in XX (genetically female) medaka. In addition, overexpression of DMY cDNA under the control of the CMV promoter also caused XX sex reversal. These results demonstrate that DMY is sufficient for male development in medaka and suggest that the functional difference between the X and Y chromosomes in medaka is a single gene. Our data indicate that DMY is an additional sex-determining gene in vertebrates.
194 citations
TL;DR: It is proposed that homologous associations driven by this novel X-pairing region (Xpr) of the Xic enable a cell to sense that more than one X chromosome is present and coordinate reciprocal Xist/Tsix expression.
Abstract: Mammalian dosage compensation involves silencing of one of the two X chromosomes in females and is controlled by the X-inactivation center (Xic). The Xic, which includes Xist and its antisense transcription unit Tsix/Xite, somehow senses the number of X chromosomes and triggers Xist up-regulation from one of the two X chromosomes in females. We found that a segment of the mouse Xic lying several hundred kilobases upstream of Xist brings the two Xics together before the onset of X inactivation. This region can autonomously drive Xic trans-interactions even as an ectopic single-copy transgene. Its introduction into male embryonic stem cells is strongly selected against, consistent with a possible role in trans-activating Xist. We propose that homologous associations driven by this novel X-pairing region (Xpr) of the Xic enable a cell to sense that more than one X chromosome is present and coordinate reciprocal Xist/Tsix expression.
191 citations
TL;DR: The understanding of dosage compensation in placental mammals is critically reviewed and these findings are placed in the context of other cellular processes that intersect with mammalian dosage compensation.
Abstract: X inactivation is the mechanism by which mammals adjust the genetic imbalance that arises from the different numbers of gene-rich X-chromosomes between the sexes. The dosage difference between XX females and XY males is functionally equalized by silencing one of the two X chromosomes in females. This dosage-compensation mechanism seems to have arisen concurrently with early mammalian evolution and is based on the long functional Xist RNA, which is unique to placental mammals. It is likely that previously existing mechanisms for other cellular functions have been recruited and adapted for the evolution of X inactivation. Here, we critically review our understanding of dosage compensation in placental mammals and place these findings in the context of other cellular processes that intersect with mammalian dosage compensation.
177 citations
TL;DR: It is postulated that recurrent bouts of sex-ratio meiotic drive and its subsequent suppression might underlie several common features observed in the heterogametic sex, including meiotic sex chromosome inactivation and achiasmy.
Abstract: The evolution of heteromorphic sex chromosomes creates a genetic condition favoring the invasion of sex-ratio meiotic drive elements, resulting in the biased transmission of one sex chromosome over the other, in violation of Mendel's first law. The molecular mechanisms of sex-ratio meiotic drive may therefore help us to understand the evolutionary forces shaping the meiotic behavior of the sex chromosomes. Here we characterize a sex-ratio distorter on the X chromosome (Dox) in Drosophila simulans by genetic and molecular means. Intriguingly, Dox has very limited coding capacity. It evolved from another X-linked gene, which also evolved de nova. Through retrotransposition, Dox also gave rise to an autosomal suppressor, not much yang (Nmy). An RNA interference mechanism seems to be involved in the suppression of the Dox distorter by the Nmy suppressor. Double mutant males of the genotype dox; nmy are normal for both sex-ratio and spermatogenesis. We postulate that recurrent bouts of sex-ratio meiotic drive and its subsequent suppression might underlie several common features observed in the heterogametic sex, including meiotic sex chromosome inactivation and achiasmy.
172 citations
TL;DR: A graphic representation is produced that provides a minimum baseline age-related rate of X chromosome loss that should assist diagnostic cytogenetics laboratories to determine the significance of 45,X cell lines detected in women of all ages.
Abstract: The detection of a low level 45,X cell line during routine cytogenetic analysis in an adult female can be difficult to interpret. In the absence of recent information regarding loss of the X chromosom
TL;DR: Random inactivation of one of the two female X chromosomes establishes dosage compensation between XY males and XX females in placental mammals and is implicated in the mechanism of random choice.
TL;DR: It is proposed that X-linked genes are silenced in female ES cells by spreading of Xist RNA through the X chromosome territory as the cells differentiate, with silencing times for individual genes dependent on their proximity to the Xist locus.
Abstract: Dosage compensation in mammals involves silencing of one X chromosome in XX females and requires expression, in cis, of Xist RNA. The X to be inactivated is randomly chosen in cells of the inner cell mass (ICM) at the blastocyst stage of development. Embryonic stem (ES) cells derived from the ICM of female mice have two active X chromosomes, one of which is inactivated as the cells differentiate in culture, providing a powerful model system to study the dynamics of X inactivation. Using microarrays to assay expression of X-linked genes in undifferentiated female and male mouse ES cells, we detect global up-regulation of expression (1.4- to 1.6-fold) from the active X chromosomes, relative to autosomes. We show a similar up-regulation in ICM from male blastocysts grown in culture. In male ES cells, up-regulation reaches 2-fold after 2–3 weeks of differentiation, thereby balancing expression between the single X and the diploid autosomes. We show that silencing of X-linked genes in female ES cells occurs on a gene-by-gene basis throughout differentiation, with some genes inactivating early, others late, and some escaping altogether. Surprisingly, by allele-specific analysis in hybrid ES cells, we also identified a subgroup of genes that are silenced in undifferentiated cells. We propose that X-linked genes are silenced in female ES cells by spreading of Xist RNA through the X chromosome territory as the cells differentiate, with silencing times for individual genes dependent on their proximity to the Xist locus.
TL;DR: This work used mice in which sex chromosome complement and gonadal sex were independent, and found that XX mice showed faster food-reinforced instrumental habit formation than XY mice, regardless of gonadal phenotype.
Abstract: Sex differences in brain function and behavior are regularly attributed to gonadal hormones. Some brain sexual dimorphisms, however, are direct actions of sex chromosome genes that are not mediated by gonadal hormones. We used mice in which sex chromosome complement (XX versus XY) and gonadal sex (ovaries versus testes) were independent, and found that XX mice showed faster food-reinforced instrumental habit formation than XY mice, regardless of gonadal phenotype.
TL;DR: The organization and evolution of the sex chromosomes across a broad range of mammals is discussed, and how the Y chromosome, and SRY, evolved is speculated on.
TL;DR: It is found that X linkage inhibits the activity of a testis-specific promoter, consistent with global inactivation of the X chromosome in the male germline and support a selective explanation for X chromosome avoidance of genes with beneficial effects late in spermatogenesis.
Abstract: Genes with male- and testis-enriched expression are under-represented on the Drosophila melanogaster X chromosome. There is also an excess of retrotransposed genes, many of which are expressed in testis, that have “escaped” the X chromosome and moved to the autosomes. It has been proposed that inactivation of the X chromosome during spermatogenesis contributes to these patterns: genes with a beneficial function late in spermatogenesis should be selectively favored to be autosomal in order to avoid inactivation. However, conclusive evidence for X inactivation in the male germline has been lacking. To test for such inactivation, we used a transgenic construct in which expression of a lacZ reporter gene was driven by the promoter sequence of the autosomal, testis-specific ocnus gene. Autosomal insertions of this transgene showed the expected pattern of male- and testis-specific expression. X-linked insertions, in contrast, showed only very low levels of reporter gene expression. Thus, we find that X linkage inhibits the activity of a testis-specific promoter. We obtained the same result using a vector in which the transgene was flanked by chromosomal insulator sequences. These results are consistent with global inactivation of the X chromosome in the male germline and support a selective explanation for X chromosome avoidance of genes with beneficial effects late in spermatogenesis.
TL;DR: This work suggests that chromosome territory reorganisation can be an important step in the gene silencing process and two model systems have emphasized the role of this level of nuclear organization within the nucleus during development.
TL;DR: Genetic biology should be considered for any disease or phenotype that occurs in one sex more than the other, because the disease mechanism may be influenced directly by an X-linked gene or indirectly through the consequences of X inactivation.
TL;DR: A comparative study of platypus and echidna by chromosome painting and comparative gene mapping shows that monotremes have a unique XY sex chromosome system that shares some homology with the avian Z.
Abstract: Background
Sex-determining systems have evolved independently in vertebrates. Placental mammals and marsupials have an XY system, birds have a ZW system. Reptiles and amphibians have different systems, including temperature-dependent sex determination, and XY and ZW systems that differ in origin from birds and placental mammals. Monotremes diverged early in mammalian evolution, just after the mammalian clade diverged from the sauropsid clade. Our previous studies showed that male platypus has five X and five Y chromosomes, no SRY, and DMRT1 on an X chromosome. In order to investigate monotreme sex chromosome evolution, we performed a comparative study of platypus and echidna by chromosome painting and comparative gene mapping.
TL;DR: The XD chromosome in D. recens appears to be in chromosome-wide linkage disequilibrium and in the early stages of mutational degradation, which makes the XD chromosome susceptible to the accumulation of deleterious mutations.
Abstract: Adaptation by natural selection proceeds most efficiently when alleles compete solely on the basis of their effects on the survival and reproduction of their carriers. A major condition for this is equal Mendelian segregation, but meiotic drive can short-circuit this process. The evolution of drive often involves multiple, interacting genetic components, together with enhancers and suppressors of drive. Chromosomal inversions that suppress crossing over are also frequently associated with drive systems. This study investigates the effects of these processes on patterns of molecular evolution in the fly Drosophila recens, which is polymorphic for a driving X chromosome (XD). Whereas standard wild-type chromosomes exhibit high levels of polymorphism at multiple loci, all of the XD chromosomes effectively carry a single multilocus haplotype that spans at least 130 cM. The XD is associated with a complex set of inversions that completely suppresses recombination between the standard wild-type chromosome and XD in heterozygous females, which maintain nonrandom associations among loci that presumably interact epistatically for the expression of drive. The long-term costs of foregoing recombination may be substantial; in combination with its low equilibrium frequency, this makes the XD chromosome susceptible to the accumulation of deleterious mutations. Consistent with this, XD chromosomes are apparently fixed for a recessive mutation that causes female sterility. Thus, the XD in D. recens appears to be in chromosome-wide linkage disequilibrium and in the early stages of mutational degradation.
TL;DR: The binding location of the condensin homolog DPY-27 and the zinc finger protein SDC-3, two components of the C. elegans dosage compensation complex (DCC), is mapped to aid in understanding how proteins involved in higher-order chromosome dynamics can regulate transcription at individual loci.
Abstract: Among organisms with chromosome-based mechanisms of sex determination, failure to equalize expression of X-linked genes between the sexes is typically lethal. In C. elegans, XX hermaphrodites halve transcription from each X chromosome to match the output of XO males1. Here, we mapped the binding location of the condensin homolog DPY-27 and the zinc finger protein SDC-3, two components of the C. elegans dosage compensation complex (DCC)2,3. We observed strong foci of DCC binding on X, surrounded by broader regions of localization. Binding foci, but not adjacent regions of localization, were distinguished by clusters of a 10-bp DNA motif, suggesting a recruitment-and-spreading mechanism for X recognition. The DCC was preferentially bound upstream of genes, suggesting modulation of transcriptional initiation and polymerase-coupled spreading. Stronger DCC binding upstream of genes with high transcriptional activity indicated a mechanism for tuning DCC activity at specific loci. These data aid in understanding how proteins involved in higher-order chromosome dynamics can regulate transcription at individual loci.
TL;DR: The finding that the X chromosome loss is preferential suggests the critical involvement of X chromosome gene products in the female predisposition to PBC and emphasizes the need to determine the parental origin of the maintained chromosome to investigate the role of imprinting.
TL;DR: It is suggested that heterochromatic instability is a common but largely unexplored mechanism, leading to widespread genomic misregulation and the evolution of some cancers.
Abstract: Interest has recently reawakened in whether loss of the heterochromatic X chromosome (Barr body) is prevalent in certain breast and ovarian cancers, and new insights into the mechanisms involved have emerged. Mitotic segregation errors commonly explain the loss of the inactive X chromosome (Xi), but compromise of Xi heterochromatin in some cancers may signal broader deficits of nuclear heterochromatin. The debated link between BRCA1 and Xi might reflect a general relationship between BRCA1 and heterochromatin, which could connect BRCA1 to both epigenetic and genetic instability. We suggest that heterochromatic instability is a common but largely unexplored mechanism, leading to widespread genomic misregulation and the evolution of some cancers.
TL;DR: The EuroMRX effort is the first attempt to unravel the molecular basis of cognitive dysfunction by large‐scale approaches in a large patient cohort and shows that it is now possible to identify 42% of the genetic defects in non‐syndromic and syndromic XLMR families with obligate female carriers.
Abstract: The EuroMRX family cohort consists of about 400 families with non-syndromic and 200 families with syndromic X-linked mental retardation (XLMR). After exclusion of Fragile X (Fra X) syndrome, probands from these families were tested for mutations in the coding sequence of 90 known and candidate XLMR genes. In total, 73 causative mutations were identified in 21 genes. For 42% of the families with obligate female carriers, the mental retardation phenotype could be explained by a mutation. There was no difference between families with (lod score >2) or without (lod score <2) significant linkage to the X chromosome. For families with two to five affected brothers (brother pair=BP families) only 17% of the MR could be explained. This is significantly lower (P=0.0067) than in families with obligate carrier females and indicates that the MR in about 40% (17/42) of the BP families is due to a single genetic defect on the X chromosome. The mutation frequency of XLMR genes in BP families is lower than can be expected on basis of the male to female ratio of patients with MR or observed recurrence risks. This might be explained by genetic risk factors on the X chromosome, resulting in a more complex etiology in a substantial portion of XLMR patients. The EuroMRX effort is the first attempt to unravel the molecular basis of cognitive dysfunction by large-scale approaches in a large patient cohort. Our results show that it is now possible to identify 42% of the genetic defects in non-syndromic and syndromic XLMR families with obligate female carriers.
TL;DR: It is argued that the sex benefit of females during the host response is associated with polymorphism of X- linked genes and cellular mosaicism for X-linked parental alleles, which represents a more adaptive and balanced cellular machinery that is advantageous during the innate immune response.
Abstract: Females as compared with males display better general health status, longevity, and improved clinical course after injury and infection. It is generally believed that the female advantage is associated with the effects of sex hormones. This review argues that the sex benefit of females during the host response is associated with polymorphism of X-linked genes and cellular mosaicism for X-linked parental alleles. Cells from females carry both parental X chromosomes (maternal, Xm; or paternal, Xp), whereas males carry only one (Xm). Because of dosage compensation and random X inactivation, half of the cells from females express either Xm or Xp. Therefore, females are cellular mosaics for their X-linked polymorphic genes. This cellular mosaicism in females represents a more adaptive and balanced cellular machinery that is advantageous during the innate immune response. Several genes encoding key metabolic and regulatory proteins reside on the X chromosome, including members of the apoptotic cascade, hormone homeostasis, glucose metabolic enzymes, superoxide-producing machinery, and the toll-like receptor/nuclear factor kappaB/c-Jun N-terminal kinase signaling pathway. Polymorphic forms of these X-linked proteins are likely to manifest in phenotypic differences in the mosaic cell populations in females and may contribute to sex-related differences in the host response to injury and infection. The unique inheritance pattern of X-linked polymorphisms and their potential confounding effects in clinical trials are also discussed; furthermore, we present potential biomarkers for studying mosaic cell populations of innate immunity.
TL;DR: Performance of several approaches for testing association on the X chromosome are compared, and how departure from Hardy‐Weinberg equilibrium would affect type I error and power of these association tests using X‐linked SNPs is examined.
Abstract: Test statistics for association between markers on autosomal chromosomes and a disease have been extensively studied. No research has been reported on performance of such test statistics for association on the X chromosome. With 100,000 or more single-nucleotide polymorphisms (SNPs) available for genome-wide association studies, thousands of them come from the X chromosome. The X chromosome contains rich information about population history and linkage disequilibrium. To identify X-linked marker susceptibility to a disease, it is important to study properties of various statistics that can be used to test for association on the X chromosome. In this article, we compare performance of several approaches for testing association on the X chromosome, and examine how departure from Hardy-Weinberg equilibrium would affect type I error and power of these association tests using X-linked SNPs. The results are applied to the X chromosome of Klein et al. [2005], a genome-wide association study with 100K SNPs for age-related macular degeneration. We found that a SNP (rs10521496) covered by DIAPH2, known to cause premature ovarian failure (POF) in females, is associated with age-related macular degeneration. Genet. Epidemiol. 2007. Published 2007 Wiley-Liss, Inc.
TL;DR: The region homologous to the human and mouse X-inactivation centre expanded in early mammals, and this unstable region was disrupted independently in marsupial and monotreme lineages, confirming the conclusion that non-eutherian mammals lack XIST.
Abstract: Marsupial, as well as eutherian, mammals are subject to X chromosome inactivation in the somatic cells of females, although the phenotype and the molecular mechanism differ in important respects. Monotreme mammals appear to subscribe at least to a form of dosage compensation of X-borne genes. An important question is whether inactivation in these non-eutherian mammals involves co-ordination by a control locus homologous to the XIST gene and neighbouring genes, which play a key regulatory role in human and mouse X inactivation. We mapped BACs containing several orthologues of protein-coding genes that flank human and mouse XIST and genes that lie in the homologous region in chicken and frog. We found that these genes map to two distant locations on the opossum X, and also to different locations on a platypus autosome. We failed to find any trace of an XIST orthologue in any marsupial or monotreme or on any flanking BAC, confirming the conclusion from recent work that non-eutherian mammals lack XIST. We propose the region homologous to the human and mouse X-inactivation centre expanded in early mammals, and this unstable region was disrupted independently in marsupial and monotreme lineages. In the eutherian lineage, inserted and existing sequences provided the starting material for the non-translated RNAs of the X-inactivation centre, including XIST.
TL;DR: Evidence is presented that the epigenetic reprogramming of the inactive X-chromosome is initiated earlier than was previously thought, around the time that primordial germ cells (PGCs) migrate through the hindgut.
Abstract: Background. The inactive X chromosome characteristic of female somatic lineages is reactivated during development of the female germ celllineage. Inmouse,analysisofprotein products ofX-linked genes and/ortransgenes located ontheX chromosome has indicated that reactivation occurs after primordial germ cells reach the genital ridges. Principal Findings/Methodology. We present evidence that the epigenetic reprogramming of the inactive X-chromosome is initiated earlier than was previously thought, around the time that primordial germ cells (PGCs) migrate through the hindgut. Specifically, we find that Xist RNA expression, the primary signal for establishment of chromosome silencing, is extinguished in migrating PGCs. This is accompanied by displacement of Polycomb-group repressor proteinsEed and Suz(12), and loss of the inactive X associated histone modification, methylation of histone H3 lysine 27. Conclusions/Significance. We conclude that X reactivation in primordial germ cells occurs progressively, initiated by extinction of Xist RNA around the time that germ cells migrate through the hindgut to the genital ridges. The events thatweobserveare reminiscent ofX reactivationofthepaternal X chromosomein innercellmasscellsofmouse pre-implantation embryos and suggest a unified model in which execution of the pluripotency program represses Xist RNA thereby triggering progressive reversal of epigenetic silencing of the X chromosome.
TL;DR: These findings provide direct evidence on the MSUC acting at the mRNA level, and implicate that autosomal asynapsis in meiosis may cause male sterility by interfering with meiotic sex chromosome inactivation.
Abstract: Heterozygosity for certain mouse and human chromosomal rearrangements is characterized by the incomplete meiotic synapsis of rearranged chromosomes, by their colocalization with the XY body in primary spermatocytes, and by male-limited sterility. Previously, we argued that such X-autosomal associations could interfere with meiotic sex chromosome inactivation. Recently, supporting evidence has reported modifications of histones in rearranged chromosomes by a process called the meiotic silencing of unsynapsed chromatin (MSUC). Here, we report on the transcriptional down-regulation of genes within the unsynapsed region of the rearranged mouse chromosome 17, and on the subsequent disturbance of X chromosome inactivation. The partial transcriptional suppression of genes in the unsynapsed chromatin was most prominent prior to the mid-pachytene stage of primary spermatocytes. Later, during the mid-late pachytene, the rearranged autosomes colocalized with the XY body, and the X chromosome failed to undergo proper transcriptional silencing. Our findings provide direct evidence on the MSUC acting at the mRNA level, and implicate that autosomal asynapsis in meiosis may cause male sterility by interfering with meiotic sex chromosome inactivation.
TL;DR: It is concluded definitively that BRCA1 is not required for XIST RNA coating of the X chromosome, which correlates with chromosomal genetic abnormalities, including gains, losses, reduplications, and rearrangements of theX-chromosome.
Abstract: Identification among breast tumors of those arising in a hereditary BRCA1 context remains a medical challenge. Abnormalities in X chromosome copy number and in the epigenetic stability of the inactive X chromosome (Xi) have been proposed to characterize BRCA1 breast tumors. In particular, it has been proposed that loss of BRCA1 function can lead to loss of X inactive-specific transcript (XIST) RNA association with the Xi. However, few studies have addressed this issue in a sufficiently large series of BRCA1 primary tumors. Here we assess X-chromosome status using single-cell (RNA and DNA fluorescence in situ hybridization) and global genomic (array-comparative genomic hybridization and allelotyping) approaches on a series of 11 well-defined BRCA1 tumors. We show that many or most cells of the tumors contain one or more XIST RNA domains. Furthermore, the number of XIST RNA domains per cell varied considerably even within a single tumor. Frequent X-chromosome allelic and copy number aberrations were found, in agreement with aberrant XIST RNA domain numbers. In summary, by combining multiple approaches to assess the genetics and epigenetics of a large series of BRCA1 primary tumors, we can conclude definitively that BRCA1 is not required for XIST RNA coating of the X chromosome. The intratumoral and intertumoral variability in XIST RNA domain number in BRCA1 tumors correlates with chromosomal genetic abnormalities, including gains, losses, reduplications, and rearrangements of the X-chromosome. Finally, we also show the necessity for combined global and single-cell approaches in the assessment of tumors with such a high degree of heterogeneity.