Showing papers on "X chromosome published in 2014"

Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators

Abstract: The human X and Y chromosomes evolved from an ordinary pair of autosomes, but millions of years ago genetic decay ravaged the Y chromosome, and only three per cent of its ancestral genes survived. We reconstructed the evolution of the Y chromosome across eight mammals to identify biases in gene content and the selective pressures that preserved the surviving ancestral genes. Our findings indicate that survival was nonrandom, and in two cases, convergent across placental and marsupial mammals. We conclude that the gene content of the Y chromosome became specialized through selection to maintain the ancestral dosage of homologous X-Y gene pairs that function as broadly expressed regulators of transcription, translation and protein stability. We propose that beyond its roles in testis determination and spermatogenesis, the Y chromosome is essential for male viability, and has unappreciated roles in Turner's syndrome and in phenotypic differences between the sexes in health and disease.

X chromosome regulation: diverse patterns in development, tissues and disease

Abstract: Genes on the mammalian X chromosome are present in one copy in males and two copies in females. The complex mechanisms that regulate the X chromosome lead to evolutionary and physiological variability in gene expression between species, the sexes, individuals, developmental stages, tissues and cell types. In early development, delayed and incomplete X chromosome inactivation (XCI) in some species causes variability in gene expression. Additional diversity stems from escape from XCI and from mosaicism or XCI skewing in females. This causes sex-specific differences that manifest as differential gene expression and associated phenotypes. Furthermore, the complexity and diversity of X dosage regulation affect the severity of diseases caused by X-linked mutations.

Noncoding RNAs and Epigenetic Mechanisms During X-Chromosome Inactivation

Abstract: In mammals, the process of X-chromosome inactivation ensures equivalent levels of X-linked gene expression between males and females through the silencing of one of the two X chromosomes in female cells. The process is established early in development and is initiated by a unique locus, which produces a long noncoding RNA, Xist. The Xist transcript triggers gene silencing in cis by coating the future inactive X chromosome. It also induces a cascade of chromatin changes, including posttranslational histone modifications and DNA methylation, and leads to the stable repression of all X-linked genes throughout development and adult life. We review here recent progress in our understanding of the molecular mechanisms involved in the initiation of Xist expression, the propagation of the Xist RNA along the chromosome, and the cis-elements and trans-acting factors involved in the maintenance of the repressed state. We also describe the diverse strategies used by nonplacental mammals for X-chromosome dosage compensation and highlight the common features and differences between eutherians and metatherians, in particular regarding the involvement of long noncoding RNAs.

Turner syndrome revisited: review of new data supports the hypothesis that all viable 45,X cases are cryptic mosaics with a rescue cell line, implying an origin by mitotic loss

Abstract: We review the data pertinent to the hypothesis we proposed three decades ago, that all embryos that survive gestation as women with Turner syndrome and have an ostensibly non-mosaic 45,X karyotype, actually are cryptic mosaics for a “rescue line” that includes a viable karyotype. Reanalysis of the prevalence and frequency of 45,X in available data on spontaneous abortuses, and livebirths, confirms prior estimates that 1 % to 1.5 % of all recognizable pregnancies start as an apparent non-mosaic 45,X but about 99 % do not survive gestation. From the rates of 45,X in early embryos, which are notably higher than the inferred rate of gametes hypohaploid for a sex chromosome, as well as the negative maternal age association with 45,X of maternal origin we deduce, in agreement with but on independent grounds from Hall et al. (2006), that a very large proportion of 45,X embryos acquired their 45,X line after fertilization. Results of a search for mosaic cell lines in patients with “Turner syndrome” in several reports indicate that not only does the detection rate of a mosaic line depend upon the number and sensitivity of the markers used, and the number of different tissues examined, but also upon the severity of the phenotype of those cases studied, and the number of cells karyotyped initially. Such factors may explain variation in the extent of detected “cryptic” mosaicism in 45,X individuals (currently at least 50 %). We note a report by Urbach and Benvenitsy (2009) of a gene necessary for placental function, PSF2RA, which lies in the pseudoautosomal-one region of the X and Y chromosomes. Deletion of such a gene could account for the high embryonic lethality in 45,X conceptions, and a rescue line in the placenta could account for embryonic and fetal survival of those cases in which a cryptic mosaic line cannot be found in the usual studies of blood and other tissues from affected individuals. Our primary conclusions are 1) all 45,X individuals with Turner syndrome are cryptic mosaics, 2) absence of the X chromosome in 45,X embryos is caused primarily by mitotic factors, and 3) the placenta is a strong candidate for the location of the rescue line in apparently non-mosaic 45,X individuals.

An international study of intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic characterization and outcome

Abstract: Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). To date, fluorescence in situ hybridisation (FISH), with probes specific for the RUNX1 gene, provides the only reliable detection method (five or more RUNX1 signals per cell). Patients with iAMP21 are older (median age 9 years) with a low white cell count. Previously, we demonstrated a high relapse risk when these patients were treated as standard risk. Recent studies have shown improved outcome on intensive therapy. In view of these treatment implications, accurate identification is essential. Here we have studied the cytogenetics and outcome of 530 iAMP21 patients that highlighted the association of specific secondary chromosomal and genetic changes with iAMP21 to assist in diagnosis, including the gain of chromosome X, loss or deletion of chromosome 7, ETV6 and RB1 deletions. These iAMP21 patients when treated as high risk showed the same improved outcome as those in trial-based studies regardless of the backbone chemotherapy regimen given. This study reinforces the importance of intensified treatment to reduce the risk of relapse in iAMP21 patients. This now well-defined patient subgroup should be recognised by World Health Organisation (WHO) as a distinct entity of BCP-ALL.

Genetic degeneration of old and young Y chromosomes in the flowering plant Rumex hastatulus

Abstract: Heteromorphic sex chromosomes have originated independently in many species, and a common feature of their evolution is the degeneration of the Y chromosome, characterized by a loss of gene content and function. Despite being of broad significance to our understanding of sex chromosome evolution, the genetic changes that occur during the early stages of Y-chromosome degeneration are poorly understood, especially in plants. Here, we investigate sex chromosome evolution in the dioecious plant Rumex hastatulus, in which X and Y chromosomes have evolved relatively recently and occur in two distinct systems: an ancestral XX/XY system and a derived XX/XY1Y2 system. This polymorphism provides a unique opportunity to investigate the effect of sex chromosome age on patterns of divergence and gene degeneration within a species. Despite recent suppression of recombination and low X-Y divergence in both systems, we find evidence that Y-linked genes have started to undergo gene loss, causing ∼28% and ∼8% hemizygosity of the ancestral and derived X chromosomes, respectively. Furthermore, genes remaining on Y chromosomes have accumulated more amino acid replacements, contain more unpreferred changes in codon use, and exhibit significantly reduced gene expression compared with their X-linked alleles, with the magnitude of these effects being greatest for older sex-linked genes. Our results provide evidence for reduced selection efficiency and ongoing Y-chromosome degeneration in a flowering plant, and indicate that Y degeneration can occur soon after recombination suppression between sex chromosomes.

Anolis sex chromosomes are derived from a single ancestral pair.

Abstract: To explain the frequency and distribution of heteromorphic sex chromosomes in the lizard genus Anolis, we compared the relative roles of sex chromosome conservation versus turnover of sex-determining mechanisms. We used model-based comparative methods to reconstruct karyotype evolution and the presence of heteromorphic sex chromosomes onto a newly generated Anolis phylogeny. We found that heteromorphic sex chromosomes evolved multiple times in the genus. Fluorescent in situ hybridization (FISH) of repetitive DNA showed variable rates of Y chromosome degeneration among Anolis species and identified previously undetected, homomorphic sex chromosomes in two species. We confirmed homology of sex chromosomes in the genus by performing FISH of an X-linked bacterial artificial chromosome (BAC) and quantitative PCR of X-linked genes in multiple Anolis species sampled across the phylogeny. Taken together, these results are consistent with long-term conservation of sex chromosomes in the group. Our results pave the way to address additional questions related to Anolis sex chromosome evolution and describe a conceptual framework that can be used to evaluate the origins and evolution of heteromorphic sex chromosomes in other clades.

XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis

Abstract: Women are more susceptible to multiple sclerosis (MS) and have more robust immune responses than men. However, men with MS tend to demonstrate a more progressive disease course than women, suggesting a disconnect between the severity of an immune attack and the CNS response to a given immune attack. We have previously shown in an MS model, experimental autoimmune encephalomyelitis, that autoantigen-sensitized XX lymph node cells, compared with XY, are more encephalitogenic. These studies demonstrated an effect of sex chromosomes in the induction of immune responses, but did not address a potential role of sex chromosomes in the CNS response to immune-mediated injury. Here, we examined this possibility using XX versus XY bone marrow chimeras reconstituted with a common immune system of one sex chromosomal type. We found that experimental autoimmune encephalomyelitis mice with an XY sex chromosome complement in the CNS, compared with XX, demonstrated greater clinical disease severity with more neuropathology in the spinal cord, cerebellum, and cerebral cortex. A candidate gene on the X chromosome, toll-like receptor 7, was then examined. Toll-like receptor 7 expression in cortical neurons was higher in mice with XY compared with mice with XX CNS, consistent with the known neurodegenerative role for toll-like receptor 7 in neurons. These results suggest that sex chromosome effects on neurodegeneration in the CNS run counter to effects on immune responses, and may bear relevance to the clinical enigma of greater MS susceptibility in women but faster disability progression in men. This is a demonstration of a direct effect of sex chromosome complement on neurodegeneration in a neurological disease.

Accounting for eXentricities: analysis of the X chromosome in GWAS reveals X-linked genes implicated in autoimmune diseases.

Abstract: Many complex human diseases are highly sexually dimorphic, suggesting a potential contribution of the X chromosome to disease risk. However, the X chromosome has been neglected or incorrectly analyzed in most genome-wide association studies (GWAS). We present tailored analytical methods and software that facilitate X-wide association studies (XWAS), which we further applied to reanalyze data from 16 GWAS of different autoimmune and related diseases (AID). We associated several X-linked genes with disease risk, among which (1) ARHGEF6 is associated with Crohn's disease and replicated in a study of ulcerative colitis, another inflammatory bowel disease (IBD). Indeed, ARHGEF6 interacts with a gastric bacterium that has been implicated in IBD. (2) CENPI is associated with three different AID, which is compelling in light of known associations with AID of autosomal genes encoding centromere proteins, as well as established autosomal evidence of pleiotropy between autoimmune diseases. (3) We replicated a previous association of FOXP3, a transcription factor that regulates T-cell development and function, with vitiligo; and (4) we discovered that C1GALT1C1 exhibits sex-specific effect on disease risk in both IBDs. These and other X-linked genes that we associated with AID tend to be highly expressed in tissues related to immune response, participate in major immune pathways, and display differential gene expression between males and females. Combined, the results demonstrate the importance of the X chromosome in autoimmunity, reveal the potential of extensive XWAS, even based on existing data, and provide the tools and incentive to properly include the X chromosome in future studies.

Sex-Biased Gene Expression and Evolution of the X Chromosome in Nematodes

Abstract: Studies of X chromosome evolution in various organisms have indicated that sex-biased genes are nonrandomly distributed between the X and autosomes. Here, to extend these studies to nematodes, we annotated and analyzed X chromosome gene content in four Caenorhabditis species and in Pristionchus pacificus. Our gene expression analyses comparing young adult male and female mRNA-seq data indicate that, in general, nematode X chromosomes are enriched for genes with high female-biased expression and depleted of genes with high male-biased expression. Genes with low sex-biased expression do not show the same trend of X chromosome enrichment and depletion. Combined with the observation that highly sex-biased genes are primarily expressed in the gonad, differential distribution of sex-biased genes reflects differences in evolutionary pressures linked to tissue-specific regulation of X chromosome transcription. Our data also indicate that X dosage imbalance between males (XO) and females (XX) is influential in shaping both expression and gene content of the X chromosome. Predicted upregulation of the single male X to match autosomal transcription (Ohno’s hypothesis) is supported by our observation that overall transcript levels from the X and autosomes are similar for highly expressed genes. However, comparison of differentially located one-to-one orthologs between C. elegans and P. pacificus indicates lower expression of X-linked orthologs, arguing against X upregulation. These contradicting observations may be reconciled if X upregulation is not a global mechanism but instead acts locally on a subset of tissues and X-linked genes that are dosage sensitive.

How to include chromosome X in your genome-wide association study.

Abstract: In current genome-wide association studies (GWAS), the analysis is usually focused on autosomal variants only, and the sex chromosomes are often neglected. Recently, a number of technical hurdles have been described that add to a reluctance of including chromosome X in a GWAS, including complications in genotype calling, imputation, and selection of test statistics. To overcome this, we provide a "how to" guide for analyzing X chromosomal data within a standard GWAS. Following a general pipeline for GWAS, we highlight the steps in which the X chromosome requires specific attention, and we give tentative advice for each of these. Through this, we show that by selection of sensible algorithms and parameter settings, the inclusion of chromosome X in GWAS is manageable. Closing this gap is expected to further elucidate the genetic background of complex diseases, especially of those with sex-specific features.

Variable escape from X‐chromosome inactivation: Identifying factors that tip the scales towards expression

Abstract: In humans over 15% of X-linked genes have been shown to ‘escape’ from X-chromosome inactivation (XCI): they continue to be expressed to some extent from the inactive X chromosome Mono-allelic expression is anticipated within a cell for genes subject to XCI, but random XCI usually results in expression of both alleles in a cell population Using a study of allelic expression from cultured lymphoblasts and fibroblasts, many of which showed substantial skewing of XCI, we recently reported that the expression of genes lies on a contiunuum between those that are subject to inactivation, and those that escape We now review allelic expression studies from mouse, and discuss the variability in escape seen in both humans and mice in genic expression levels, between X chromosomes and between tissues We also discuss current knowledge of the heterochromatic features, DNA elements and three-dimensional topology of the inactive X that contribute to the balance of expression from the otherwise inactive X chromosome

Sex chromosome turnover contributes to genomic divergence between incipient stickleback species.

Abstract: Sex chromosomes turn over rapidly in some taxonomic groups, where closely related species have different sex chromosomes. Although there are many examples of sex chromosome turnover, we know little about the functional roles of sex chromosome turnover in phenotypic diversification and genomic evolution. The sympatric pair of Japanese threespine stickleback (Gasterosteus aculeatus) provides an excellent system to address these questions: the Japan Sea species has a neo-sex chromosome system resulting from a fusion between an ancestral Y chromosome and an autosome, while the sympatric Pacific Ocean species has a simple XY sex chromosome system. Furthermore, previous quantitative trait locus (QTL) mapping demonstrated that the Japan Sea neo-X chromosome contributes to phenotypic divergence and reproductive isolation between these sympatric species. To investigate the genomic basis for the accumulation of genes important for speciation on the neo-X chromosome, we conducted whole genome sequencing of males and females of both the Japan Sea and the Pacific Ocean species. No substantial degeneration has yet occurred on the neo-Y chromosome, but the nucleotide sequence of the neo-X and the neo-Y has started to diverge, particularly at regions near the fusion. The neo-sex chromosomes also harbor an excess of genes with sex-biased expression. Furthermore, genes on the neo-X chromosome showed higher non-synonymous substitution rates than autosomal genes in the Japan Sea lineage. Genomic regions of higher sequence divergence between species, genes with divergent expression between species, and QTL for inter-species phenotypic differences were found not only at the regions near the fusion site, but also at other regions along the neo-X chromosome. Neo-sex chromosomes can therefore accumulate substitutions causing species differences even in the absence of substantial neo-Y degeneration.

Spatial separation of Xist RNA and polycomb proteins revealed by superresolution microscopy

Abstract: In female mammals, one of the two X chromosomes is transcriptionally silenced to equalize X-linked gene dosage relative to XY males, a process termed X chromosome inactivation. Mechanistically, this is thought to occur via directed recruitment of chromatin modifying factors by the master regulator, X-inactive specific transcript (Xist) RNA, which localizes in cis along the entire length of the chromosome. A well-studied example is the recruitment of polycomb repressive complex 2 (PRC2), for which there is evidence of a direct interaction involving the PRC2 proteins Enhancer of zeste 2 (Ezh2) and Supressor of zeste 12 (Suz12) and the A-repeat region located at the 5′ end of Xist RNA. In this study, we have analyzed Xist-mediated recruitment of PRC2 using two approaches, microarray-based epigenomic mapping and superresolution 3D structured illumination microscopy. Making use of an ES cell line carrying an inducible Xist transgene located on mouse chromosome 17, we show that 24 h after synchronous induction of Xist expression, acquired PRC2 binding sites map predominantly to gene-rich regions, notably within gene bodies. Paradoxically, these new sites of PRC2 deposition do not correlate with Xist-mediated gene silencing. The 3D structured illumination microscopy was performed to assess the relative localization of PRC2 proteins and Xist RNA. Unexpectedly, we observed significant spatial separation and absence of colocalization both in the inducible Xist transgene ES cell line and in normal XX somatic cells. Our observations argue against direct interaction between Xist RNA and PRC2 proteins and, as such, prompt a reappraisal of the mechanism for PRC2 recruitment in X chromosome inactivation.

MOF-associated complexes ensure stem cell identity and Xist repression

Abstract: Gene expression is controlled by a complicated network of mechanisms involving a wide range of enzymes and protein complexes. Many of these mechanisms are identical in males and females, but some are not. Female mammals, for example, carry two X chromosomes, whereas males have one X and one Y chromosome. Since the two X chromosomes in females contain essentially the same set of genes, one of them undergoes silencing to prevent the overproduction of certain proteins. This process, which is called X-inactivation, occurs during different stages of development and it must be tightly controlled. An enzyme called MOF was originally found in flies in two distinct complexes—the male-specific lethal (MSL) complex, which forms only in males, and the non-specific lethal (NSL) complex, which is ubiquitous in both males and females. These complexes are evolutionary conserved and are also found in mammals. While mammalian MOF is reasonably well understood, the MSL and NSL complexes are not, so Chelmicki, Dundar et al. have used various sequencing techniques, in combination with biochemical experiments, to investigate their roles in embryonic stem cells and neuronal progenitor cells in mice. These experiments show that MSL and NSL complexes engage in the regulation of thousands of genes. Although the two complexes often show different gene preferences, they often regulate the same cellular processes. The MSL/NSL-dependent regulation of X chromosome inactivation is a prime example of this phenomenon. The MSL complex reduces the production of an RNA molecule called Xist, which is responsible for the inactivation of one of the two X chromosomes in females. The NSL complex, meanwhile, ensures the production of multiple proteins that are crucial for the development of embryonic stem cells, and are also involved in the repression of X inactivation. This analysis sheds light on how different complexes can cooperate and complement each other in order to reach the same goal in the cell. The knowledge gained from this study will pave the way towards better understanding of complex processes such as embryonic development, organogenesis and the pathogenesis of disorders like cancer.

X chromosome aneuploidy in the Alzheimer’s disease brain

Abstract: Although the link between brain aging and Alzheimer’s disease (AD) is a matter of debate, processes hallmarking cellular and tissue senescence have been repeatedly associated with its pathogenesis. Here, we have studied X chromosome aneuploidy (a recognized feature of aged cell populations) in the AD brain. Extended molecular neurocytogenetic analyses of X chromosome aneuploidy in 10 female AD as well as 10 age and sex matched female control postmortem brain samples was performed by multiprobe/quantitative FISH. Additionally, aneuploidy rate in the brain samples of 5 AD and as 5 age and sex matched control subjects were analyzed by interphase chromosome-specific multicolor banding (ICS-MCB). Totally, 182,500 cells in the AD brain and 182,500 cells in the unaffected brain were analyzed. The mean rate of X chromosome aneuploidy in AD samples was approximately two times higher than in control (control: mean - 1.32%, 95% CI 0.92- 1.71%; AD: mean - 2.79%, 95% CI 1.88-3.69; P = 0.013). One AD sample demonstrated mosaic aneuploidy of chromosome X confined to the hippocampus affecting about 10% of cells. ICS-MCB confirmed the presence of X chromosome aneuploidy in the hippocampal tissues of AD brain (control: mean - 1.74%, 95% CI 1.38- 2.10%; AD: mean - 4.92%, 95% CI 1.14-8.71; P < 0.001). Addressing X chromosome number variation in the brain, we observed that somatically acquired (post-zygotic) aneuploidy causes large-scale genomic alterations in neural cells of AD patients and, therefore, can be involved in pathogenesis of this common neurodegenerative disorder. In the context of debates about possible interplay between brain aging and AD neurodegeneration, our findings suggest that X chromosome aneuploidy can contribute to both processes. To this end we conclude that mosaic aneuploidy in the brain is a new non-heritable genetic factor predisposing to AD.

Genetic and pharmacological reactivation of the mammalian inactive X chromosome

Abstract: X-chromosome inactivation (XCI), the random transcriptional silencing of one X chromosome in somatic cells of female mammals, is a mechanism that ensures equal expression of X-linked genes in both sexes. XCI is initiated in cis by the noncoding Xist RNA, which coats the inactive X chromosome (Xi) from which it is produced. However, trans-acting factors that mediate XCI remain largely unknown. Here, we perform a large-scale RNA interference screen to identify trans-acting XCI factors (XCIFs) that comprise regulators of cell signaling and transcription, including the DNA methyltransferase, DNMT1. The expression pattern of the XCIFs explains the selective onset of XCI following differentiation. The XCIFs function, at least in part, by promoting expression and/or localization of Xist to the Xi. Surprisingly, we find that DNMT1, which is generally a transcriptional repressor, is an activator of Xist transcription. Small-molecule inhibitors of two of the XCIFs can reversibly reactivate the Xi, which has implications for treatment of Rett syndrome and other dominant X-linked diseases. A homozygous mouse knockout of one of the XCIFs, stanniocalcin 1 (STC1), has an expected XCI defect but surprisingly is phenotypically normal. Remarkably, X-linked genes are not overexpressed in female Stc1(-/-) mice, revealing the existence of a mechanism(s) that can compensate for a persistent XCI deficiency to regulate X-linked gene expression.

Molecular cytogenetic characterization of the dioecious Cannabis sativa with an XY chromosome sex determination system.

Abstract: Hemp (Cannabis sativa L.) was karyotyped using by DAPI/C-banding staining to provide chromosome measurements, and by fluorescence in situ hybridization with probes for 45 rDNA (pTa71), 5S rDNA (pCT4.2), a subtelomeric repeat (CS-1) and the Arabidopsis telomere probes. The karyotype has 18 autosomes plus a sex chromosome pair (XX in female and XY in male plants). The autosomes are difficult to distinguish morphologically, but three pairs could be distinguished using the probes. The Y chromosome is larger than the autosomes, and carries a fully heterochromatic DAPI positive arm and CS-1 repeats only on the less intensely DAPI-stained, euchromatic arm. The X is the largest chromosome of all, and carries CS-1 subtelomeric repeats on both arms. The meiotic configuration of the sex bivalent locates a pseudoautosomal region of the Y chromosome at the end of the euchromatic CS-1-carrying arm. Our molecular cytogenetic study of the C. sativa sex chromosomes is a starting point for helping to make C. sativa a promising model to study sex chromosome evolution.

High-Resolution Sex-Specific Linkage Maps of the Mouse Reveal Polarized Distribution of Crossovers in Male Germline

Abstract: Since the publication of the first comprehensive linkage map for the laboratory mouse, the architecture of recombination as a basic biological process has become amenable to investigation in mammalian model organisms. Here we take advantage of high-density genotyping and the unique pedigree structure of the incipient Collaborative Cross to investigate the roles of sex and genetic background in mammalian recombination. Our results confirm the observation that map length is longer when measured through female meiosis than through male meiosis, but we find that this difference is modified by genotype at loci on both the X chromosome and the autosomes. In addition, we report a striking concentration of crossovers in the distal ends of autosomes in male meiosis that is absent in female meiosis. The presence of this pattern in both single- and double-recombinant chromosomes, combined with the absence of a corresponding asymmetry in the distribution of double-strand breaks, indicates a regulated sequence of events specific to male meiosis that is anchored by chromosome ends. This pattern is consistent with the timing of chromosome pairing and evolutionary constraints on male recombination. Finally, we identify large regions of reduced crossover frequency that together encompass 5% of the genome. Many of these "cold regions" are enriched for segmental duplications, suggesting an inverse local correlation between recombination rate and mutation rate for large copy number variants.

miRNA gene counts in chromosomes vary widely in a species and biogenesis of miRNA largely depends on transcription or post-transcriptional processing of coding genes

Abstract: MicroRNAs target specific mRNA(s) to silence its expression and thereby regulate various cellular processes. We have investigated miRNA gene counts in chromosomes for 20 different species and observed wide variation. Certain chromosomes have extremely high number of miRNA gene compared with others in all the species. For example, high number of miRNA gene in X chromosome and the least or absence of miRNA gene in Y chromosome was observed in all species. To search the criteria governing such variation of miRNA gene counts in chromosomes, we have selected three parameters- length, number of non-coding and coding genes in a chromosome. We have calculated Pearson’s correlation coefficient of miRNA gene counts with length, number of non-coding and coding genes in a chromosome for all 20 species. Major number of species showed that number of miRNA gene was not correlated with chromosome length. 85% of species under study showed strong positive correlation coefficient (r≥0.5) between the numbers of miRNA gene vs non-coding gene in chromosomes as expected because miRNA is a sub-set of non-coding genes. 55% species under study showed strong positive correlation coefficient (r≥0.5) between numbers of miRNA gene vs coding gene. We hypothesize biogenesis of miRNA largely depends on coding genes, an evolutionary conserved process. Chromosomes having higher number of miRNA genes will be most likely playing regulatory roles in several cellular processes including different disorders. In humans, cancer and cardiovascular disease associated miRNAs are mostly intergenic and located in Chromosome 19, X, 14 and 1.

X Chromosome Control of Meiotic Chromosome Synapsis in Mouse Inter-Subspecific Hybrids

Abstract: Hybrid sterility (HS) belongs to reproductive isolation barriers that safeguard the integrity of species in statu nascendi. Although hybrid sterility occurs almost universally among animal and plant species, most of our current knowledge comes from the classical genetic studies on Drosophila interspecific crosses or introgressions. With the house mouse subspecies Mus m. musculus and Mus m. domesticus as a model, new research tools have become available for studies of the molecular mechanisms and genetic networks underlying HS. Here we used QTL analysis and intersubspecific chromosome substitution strains to identify a 4.7 Mb critical region on Chromosome X (Chr X) harboring the Hstx2 HS locus, which causes asymmetrical spermatogenic arrest in reciprocal intersubspecific F1 hybrids. Subsequently, we mapped autosomal loci on Chrs 3, 9 and 13 that can abolish this asymmetry. Combination of immunofluorescent visualization of the proteins of synaptonemal complexes with whole-chromosome DNA FISH on pachytene spreads revealed that heterosubspecific, unlike consubspecific, homologous chromosomes are predisposed to asynapsis in F1 hybrid male and female meiosis. The asynapsis is under the trans- control of Hstx2 and Hst1/Prdm9 hybrid sterility genes in pachynemas of male but not female hybrids. The finding concurred with the fertility of intersubpecific F1 hybrid females homozygous for the Hstx2Mmm allele and resolved the apparent conflict with the dominance theory of Haldane's rule. We propose that meiotic asynapsis in intersubspecific hybrids is a consequence of cis-acting mismatch between homologous chromosomes modulated by the trans-acting Hstx2 and Prdm9 hybrid male sterility genes.

How Do Y-Chromosomes Modulate Genome-Wide Epigenetic States: Genome Folding, Chromatin Sinks, and Gene Expression

Abstract: The Y chromosomes of Drosophila melanogaster and D. simulans contain only a handful of protein-coding genes, which are related to sperm mobility and reproductive fitness. Despite low or absent protein coding polymorphism, the Drosophila Y chromosome has been associated with natural phenotypic variation, including variation in the expression of hundreds to thousands of genes located on autosomes and on the X chromosome. Polymorphisms present in the large blocks of heterochromatin and consisting of differences in the amounts and kinds of sequences for satellite DNA and transposable elements may be the source of this modulation. Here we review the evidence and discuss mechanisms for global epigenetic regulation by repetitious elements in the Y chromosome. We also discuss how the discovery of this new function impacts the current knowledge about Y chromosome origin, its current dynamics, and future fate.

The number of X chromosomes influences protection from cardiac ischaemia/reperfusion injury in mice: one X is better than two.

Abstract: Aim Sex differences in coronary heart disease have been attributed to sex hormones, whereas the potential role of the sex chromosomes has been ignored so far. Here, we investigated the role of the sex chromosomes in causing sex differences in myocardial ischaemia/reperfusion (I/R) injury. Methods and results We used two unique mouse models, the ‘four core genotypes’ [XX mice with ovaries (XXF) or testes (XXM) and XY mice with ovaries (XYF) or testes (XYM)] and XY* (gonadal male or female mice with one or two X chromosomes). All mice were gonadectomized (GDX). In vivo or isolated Langendorff-perfused hearts were subjected to I/R injury. The in vivo infarct size in XY mice was significantly smaller than XX mice regardless of their gonadal type (24.5 ± 4.1% in XYF and 21.8 ± 3.3% in XYM vs. 37.0 ± 3.2% in XXF and 35.5 ± 2.1% in XXM, P < 0.01). Consistent with the results in vivo , the infarct size was markedly smaller and cardiac functional recovery was significantly better in XY mice compared with XX ex vivo . The mitochondrial calcium retention capacity was significantly higher in XY compared with XX mice (nmol/mg protein: XXF = 126 ± 9 and XXM = 192 ± 45 vs. XYF = 250 ± 56 and XYM = 286 ± 51 , P < 0.05). In XY* mice, mice with 2X chromosomes had larger infarct size (2X females = 41.4 ± 8.9% and 2X males = 46.3 ± 9.5% vs. 1X females = 23.7 ± 3.9% and 1X males = 26.6 ± 6.9%, P < 0.05) and lower heart functional recovery, compared with those with 1X chromosome. Several X genes that escape X inactivation ( Eif2s3x , Kdm6a , and Kdm5c ) showed higher expression in XX than in XY hearts. Conclusion XX mice have higher vulnerability to I/R injury compared with XY mice, which is due to the number of X chromosomes rather than the absence of the Y chromosome.

The Social Behavioral Phenotype in Boys and Girls with an Extra X Chromosome (Klinefelter Syndrome and Trisomy X): A Comparison with Autism Spectrum Disorder

Abstract: The present study aimed to gain more insight in the social behavioral phenotype, and related autistic symptomatology, of children with an extra X chromosome in comparison to children with ASD. Participants included 60 children with an extra X chromosome (34 boys with Klinefelter syndrome and 26 girls with Trisomy X), 58 children with ASD and 106 controls, aged 9 to 18 years. We used the Autism Diagnostic Interview, Social Responsiveness Scale, Social Anxiety Scale and Social Skills Rating System. In the extra X group, levels of social dysfunction and autism symptoms were increased, being in between controls and ASD. In contrast to the ASD group, the extra X group showed increased social anxiety. The effects were similar for boys and girls with an extra X chromosome.