X inactivation Xplained

Random inactivation of one of the two female X chromosomes establishes dosage compensation between XY males and XX females in placental mammals. X inactivation is controlled by the X inactivation center (Xic). Recent advances in genome sequencing show that the Xic has evolved from an ancestral vertebrate gene cluster in placental mammals and has undergone separate rearrangements in marsupials. The Xic ensures that all but one X chromosome per diploid genome are inactivated. Which chromosome remains active is randomly chosen. Pairing of Xic loci on the two X chromosomes and alternate states of the X chromosomes before inactivation have recently been implicated in the mechanism of random choice. Chromosome-wide silencing is then initiated by the noncoding Xist RNA, which evolved with the mammalian Xic and covers the inactive X chromosome.     

Mammalian X Chromosome Dosage Compensation: Perspectives From the Germ Line

Sex chromosomes are advantageous to mammals, allowing them to adopt a genetic rather than environmental sex determination system. However, sex chromosome evolution also carries a burden, because it results in an imbalance in gene dosage between females (XX) and males (XY). This imbalance is resolved by X dosage compensation, which comprises both X chromosome inactivation and X chromosome upregulation. X dosage compensation has been well characterized in the soma, but not in the germ line. Germ cells face a special challenge, because genome wide reprogramming erases epigenetic marks responsible for maintaining the X dosage compensated state. Here we explain how evolution has influenced the gene content and germ line specialization of the mammalian sex chromosomes. We discuss new research uncovering unusual X dosage compensation states in germ cells, which we postulate influence sexual dimorphisms in germ line development and cause infertility in individuals with sex chromosome aneuploidy.     

Random X Inactivation and Extensive Mosaicism in Human Placenta Revealed by Analysis of Allele-Specific Gene Expression along the X Chromosome

Imprinted inactivation of the paternal X chromosome in marsupials is the primordial mechanism of dosage compensation for X-linked genes between females and males in Therians. In Eutherian mammals, X chromosome inactivation (XCI) evolved into a random process in cells from the embryo proper, where either the maternal or paternal X can be inactivated. However, species like mouse and bovine maintained imprinted XCI exclusively in extraembryonic tissues. The existence of imprinted XCI in humans remains controversial, with studies based on the analyses of only one or two X-linked genes in different extraembryonic tissues. Here we readdress this issue in human term placenta by performing a robust analysis of allele-specific expression of 22 X-linked genes, including XIST, using 27 SNPs in transcribed regions. We show that XCI is random in human placenta, and that this organ is arranged in relatively large patches of cells with either maternal or paternal inactive X. In addition, this analysis indicated heterogeneous maintenance of gene silencing along the inactive X, which combined with the extensive mosaicism found in placenta, can explain the lack of agreement among previous studies. Our results illustrate the differences of XCI mechanism between humans and mice, and highlight the importance of addressing the issue of imprinted XCI in other species in order to understand the evolution of dosage compensation in placental mammals.     

Sex chromosome homology and incomplete, tissue-specific X-inactivation suggest that monotremes represent an intermediate stage of mammalian sex chromosome evolution

Female mammals have two X chromosomes and males have a single X and a smaller, male-determining Y chromosome. The dosage of X-linked gene products is equalized between the sexes by the genetic inactivation of one X chromosome in females. The characteristics of the mechanism of X-chromosome inactivation differ in eutherian and metatherian mammals, and it has been suggested that the metatherian system represents a more primitive stage. The present study of monotreme sex chromosomes and X-chromosome inactivation suggests that the prototherian mammals may represent an even more primitive stage. There is extensive G-band homology between the monotreme X and Y chromosomes, and differences in the patterns of replication of the two X chromosomes in females suggest that X inactivation is tissue specific and confined to the unpaired segment of the X. On the basis of these results, we propose a model for the differentiation of mammalian sex chromosomes and the evolution of the mechanism of X-chromosome inactivation. This model involves a gradual reduction of the Y chromosome and an accompanying gradual recruitment of (newly unpaired) X-linked loci under the control of a single inactivation center.     

Independent Evolution of Transcriptional Inactivation on Sex Chromosomes in Birds and Mammals

X chromosome inactivation in eutherian mammals has been thought to be tightly controlled, as expected from a mechanism that compensates for the different dosage of X-borne genes in XX females and XY males. However, many X genes escape inactivation in humans, inactivation of the X in marsupials is partial, and the unrelated sex chromosomes of monotreme mammals have incomplete and gene-specific inactivation of X-linked genes. The bird ZW sex chromosome system represents a third independently evolved amniote sex chromosome system with dosage compensation, albeit partial and gene-specific, via an unknown mechanism (i.e. upregulation of the single Z in females, down regulation of one or both Zs in males, or a combination). We used RNA-fluorescent in situ hybridization (RNA-FISH) to demonstrate, on individual fibroblast cells, inactivation of 11 genes on the chicken Z and 28 genes on the X chromosomes of platypus. Each gene displayed a reproducible frequency of 1Z/1X-active and 2Z/2X-active cells in the homogametic sex. Our results indicate that the probability of inactivation is controlled on a gene-by-gene basis (or small domains) on the chicken Z and platypus X chromosomes. This regulatory mechanism must have been exapted independently to the non-homologous sex chromosomes in birds and mammals in response to an over-expressed Z or X in the homogametic sex, highlighting the universal importance that (at least partial) silencing plays in the evolution on amniote dosage compensation and, therefore, the differentiation of sex chromosomes.     

Large-scale population study of human cell lines indicates that dosage compensation is virtually complete

X chromosome inactivation in female mammals results in dosage compensation of X-linked gene products between the sexes. In humans there is evidence that a substantial proportion of genes escape from silencing. We have carried out a large-scale analysis of gene expression in lymphoblastoid cell lines from four human populations to determine the extent to which escape from X chromosome inactivation disrupts dosage compensation. We conclude that dosage compensation is virtually complete. Overall expression from the X chromosome is only slightly higher in females and can largely be accounted for by elevated female expression of approximately 5% of X-linked genes. We suggest that the potential contribution of escape from X chromosome inactivation to phenotypic differences between the sexes is more limited than previously believed.     

X inactivation and disease

X inactivation is the mechanism by which mammals adjust the X-linked gene dosage between the sexes. The dosage difference between XX females and XY males is functionally equalized by silencing one of the two X chromosomes in female cells. This dosage-compensation mechanism is based on the long functional Xist RNA. Here, we review our understanding of dosage compensation and Xist function in the context of disease.     

X-chromosome inactivation: a hypothesis linking ontogeny and phylogeny

In mammals, sex is determined by differential inheritance of a pair of dimorphic chromosomes: the gene-rich X chromosome and the gene-poor Y chromosome. To balance the unequal X-chromosome dosage between the XX female and XY male, mammals have adopted a unique form of dosage compensation in which one of the two X chromosomes is inactivated in the female. This mechanism involves a complex, highly coordinated sequence of events and is a very different strategy from those used by other organisms, such as the fruitfly and the worm. Why did mammals choose an inactivation mechanism when other, perhaps simpler, means could have been used? Recent data offer a compelling link between ontogeny and phylogeny. Here, we propose that X-chromosome inactivation and imprinting might have evolved from an ancient genome-defence mechanism that silences unpaired DNA.     

Silence of the fathers: early X inactivation

X chromosome inactivation is the mammalian answer to the dilemma of dosage compensation between males and females. The study of this fascinating form of chromosome-wide gene regulation has yielded surprising insights into early development and cellular memory. In the past few months, three papers reported unexpected findings about the paternal X chromosome (X(p)). All three studies agree that the X(p) is imprinted to become inactive earlier than ever suspected during embryonic development. Although apparently incomplete, this early form of inactivation insures dosage compensation throughout development. Silencing of the X(p) persists in cells of extraembryonic tissues, but it is erased and followed by random X inactivation in cells of the embryo proper. These findings challenge several aspects of the current view of X inactivation during early development and may have profound impact on studies of pluripotency and epigenetics.     

哺乳动物性别分化的调控

哺乳动物性别分化调控的分子机制的研究特别是性别分化的层次调控、剂量补偿和性染色体进化这三个领域,已取得快速进展。已经发现Ｙ染色体性别决定区基因（ＳＲＹ）、Ｘ染色体ＤＳＳ－ＡＨＣ决定区基因１（ＤＡＸ－１）、甾类生成因子１基因（ＳＦ１）和Ｗｉｌｍｓ瘤抑制基因（ＷＴ－１）等与哺乳动物性别决定有关。ＳＲＹ启动睾丸分化,但胚胎发育成雄性的其余步骤由事丸分泌的激素控制。ＤＡＸ－１且编码一种女性特异功能的蛋白质,它在男性中被ＳＲＹ所抑制。ＳＦ－１和ＷＴ－１在ＳＲＹ开启之前作用于性腺和肾上腺发育的启动。哺乳动物通过随机失活雌性两条Ｘ染色体中的一条来使Ｘ连锁的基因在两性间的表达水平达到平衡（剂量补偿）。Ｘ染色体失活由Ｘ染色体失活中心（ＸＩＣ）控制。失活的Ｘ染色体专一转录基因（ＸＩＳＴ）是ＸＩＣ的强烈候选者,它可能参与Ｘ失活的启动。对有袋目和单孔目动物性染色体的研究为我们提供了其进化的信息。有证据支持性染色体起源于一对同源常染色体,而ＳＲＹ的祖先基因可能是ＳＯＸ－３。     

Evolution of Mammalian Sex Chromosomes: Cooperation of Genetic and Epigenetic Factors

The X and Y chromosomes of mammals, which significantly differ in structure and genetic composition, are thought to originate from a pair of autosomes. During evolution of sex chromosomes in placental mammals, the degradation of the Y chromosome and inactivation spreading along the X chromosome occurred gradually and in concert. Thus, at the molecular level, the genetic and epigenetic factors interacted toward greater differentiation of the X/Y pair. In this review, in context of a comparison permitting to trace this evolutionary pathway, we consider the structural features of mammalian sex chromosomes focusing on the X-chromosomal genes and the unique epigenetic mechanism of their regulation. Possible causes and consequences of the genes escaping X inactivation and aspects of molecular mechanism of X-chromosome inactivation are discussed. A number of hypotheses are considered on evolutionary relationships of X-chromosome inactivation and other molecular processes in mammals.     

剂量补偿和MSL复合物研究进展

剂量补偿效应(Dosage compensation effect)广泛存在于两性真核生物,是基于性别决定、平衡不同性别间基因转录水平的遗传效应。MSL复合物(Male-specific lethal complex)是果蝇剂量补偿机制的核心,它乙酰化雄性果蝇X染色体上一些特定的位点,双倍激活X连锁活跃基因的转录,从而弥补雄性果蝇只具有单一条X染色体的不足。目前,已对果蝇MSL复合物各主要成分进行了结构分析,大体了解了各组分间的相互作用位点,并对该复合物的识别机制进行了大量的研究。与果蝇不同,哺乳动物是通过雌性个体一条X染色体的失活来实现剂量补偿。虽然哺乳动物MSL复合物的组成已被鉴定,但对其功能的研究还处于初步阶段。迄今为止,对硬骨鱼类剂量补偿及MSL复合物的研究极少。文章概括了线虫、果蝇和哺乳动物各物种剂量补偿机制的异同,综述了果蝇MSL复合物及其剂量补偿机制作用机理的研究进展,并提出有待解决的问题,同时利用同线性分析发现了不同鱼类msl3基因的多样性,为今后继续研究各物种的剂量补偿机制提供基础资料和研究方向。     

Evolution of mammalian sex chromosomes: cooperation of genetic and epigenetic factors

The X and Y chromosomes of mammals, which significantly differ in structure and genetic composition, are thought to originate from a pair of autosomes. During evolution of sex chromosomes in placental mammals, the degradation of the Y chromosome and inactivation spreading along the X chromosome occurred gradually and in concert. Thus, at the molecular level, the genetic and epigenetic factors interacted toward greater differentiation of the X/Y pair. In this review, in context of a comparison permitting to trace this evolutionary pathway, we consider the structural features of mammalian sex chromosomes focusing on the X-chromosomal genes and the unique epigenetic mechanism of their regulation. Possible causes and consequences of the genes skipping inactivation and aspects of molecular mechanism of X-chromosome inactivation are discussed. A number of hypotheses are considered on evolutionary relationships of X-chromosome inactivation and other molecular processes in mammals.     

剂量补偿和MSL复合物研究进展

剂量补偿效应(Dosage compensation effect)广泛存在于两性真核生物, 是基于性别决定、平衡不同性别间基因转录水平的遗传效应。MSL复合物(Male-specific lethal complex)是果蝇剂量补偿机制的核心, 它乙酰化雄性果蝇X染色体上一些特定的位点, 双倍激活X连锁活跃基因的转录, 从而弥补雄性果蝇只具有单一条X染色体的不足。目前, 已对果蝇MSL复合物各主要成分进行了结构分析, 大体了解了各组分间的相互作用位点, 并对该复合物的识别机制进行了大量的研究。与果蝇不同, 哺乳动物是通过雌性个体一条X染色体的失活来实现剂量补偿。虽然哺乳动物MSL复合物的组成已被鉴定, 但对其功能的研究还处于初步阶段。迄今为止, 对硬骨鱼类剂量补偿及MSL复合物的研究极少。文章概括了线虫、果蝇和哺乳动物各物种剂量补偿机制的异同, 综述了果蝇MSL复合物及其剂量补偿机制作用机理的研究进展, 并提出有待解决的问题, 同时利用同线性分析发现了不同鱼类msl3基因的多样性, 为今后继续研究各物种的剂量补偿机制提供基础资料和研究方向。     

Sexual antagonism and X inactivation--the SAXI hypothesis

X inactivation has evolved in the soma of mammalian females so that both sexes have the same ratio of X:autosomal gene expression. The X chromosome in the germ cells of XY males is also precociously inactivated for reasons that remain unclear. Unlike X inactivation in the soma, this germline X inactivation is not restricted to mammals but has evolved independently in several animal phyla. Thus, germline X inactivation might have been the precursor of somatic X inactivation in mammals. We now propose a hypothesis for the evolution of germline X inactivation. The hypothesis predicts a redistribution of late spermatogenic genes from the X chromosome to the autosomes, leading eventually to germline X inactivation as the X chromosome becomes 'demasculinized'. Sexual antagonism could be the mechanism driving this redistribution. Recent expression and genetic studies in mammals, nematodes and Drosophila support this hypothesis, and expression data on taxa that have not evolved germline X inactivation, such as birds and butterflies, should shed further light on it.