关于Lyon假说的理解

剂量补偿是表观遗传中的一类,它是使性染色体上的连锁基因在表达水平上达到平衡的过程,其机制多种多样。1961年提出的Lyon假说认为雌性哺乳动物在胚胎早期发育过程中,会随机的将体细胞中的一条X性染色体去活化形成巴尔氏体,并传递给后代细胞,从而弥补与雄性哺乳动物X性染色体数量上的缺陷。1963年三位科学家通过对X性染色体上的基因编码的G-6-PD进行凝胶电泳并对条带进行分析,证实了Lyon假说。尽管Lyon假说沿用至今,但仍存在很大局限性。     

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。     

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。     

X染色体失活——一种特殊方式的基因调控

剂量补偿是使Ｘ连锁基因的表达水平在两性间达到平衡的过程。生物界实现剂量补偿的策略有很多种,真兽亚纲哺乳动物是随机失活雌性的一条Ｘ染色体。Ｘ失活开始于ＸＩＣ,然后传播到整条染色体。ＸＩＳＴ基因定位于ＸＩＣ中,参与Ｘ失活的启动,可能是Ｘ失活决定基因。最近在人和小鼠中发现了逃避Ｘ失活的基因。探讨这些基因逃避Ｘ失活的机制有助于理解Ｘ染色体失活是如何对基因表达进行调控的。人和小鼠中有一些基因的Ｘ失活状态不同,提示了性染色体的持续不断的进化改变 。     

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。     

棉铃虫剂量补偿相关基因Hamsl1的鉴定与功能分析

【目的】棉铃虫Helicoverpa armigera的剂量补偿(dosage compensation, DC)分子机制尚不清楚。本研究旨在通过克隆棉铃虫雄性特异性致死(male specific lethal, msl) 基因Hamsl1,利用RNA干扰技术明确其是否参与调控棉铃虫剂量补偿。【方法】利用RT-PCR同源克隆棉铃虫Hamsl1基因全长cDNA; 利用qPCR技术研究Hamsl1基因在棉铃虫不同发育时期的表达谱;通过显微注射Hamsl1 siRNA到棉铃虫3龄幼虫中对Hamsl1基因进行RNA干扰后,利用qPCR技术检测15个Z染色体基因的表达情况,分析Hamsl1是否调控Z染色体基因剂量。【结果】成功克隆了棉铃虫Hamsl1基因的cDNA序列,鉴定出Hamsl1基因mRNA存在2种剪接体,分别命名为Hamsl1a(GenBank登录号: MK564008)和Hamsl1b(GenBank登录号: MK564009)。功能域分析发现HaMSL1含有典型的PEHE和coiled-coil功能域,具有MSL1蛋白的特征。qPCR分析表明,Hamsl1基因位于棉铃虫Z染色体上;棉铃虫Hamsl1a与Hamsl1b基因表达均具有发育时期特异性,在成虫期表达量最高,且雌雄化蛹后基因表达量差异显著,具有性别特异性。通过同源比对和qPCR分析,在DNA水平鉴定了15个Z染色体候选基因。显微注射Hamsl1 siRNA于3龄幼虫体内72 h,干扰效率为36.01%~64.27%,并未发生雄性致死现象;与对照组相比,Hamsl1 RNAi处理组中棉铃虫15个Z染色体基因在雄性个体中整体呈现表达量上调趋势,而在雌性个体中平均表达水平差异不显著。【结论】本研究初步探明Hamsl1基因位于棉铃虫Z染色体上,且该基因可能通过抑制雄性棉铃虫Z染色体基因表达,调控棉铃虫Z染色体剂量补偿。本研究为深入研究棉铃虫剂量补偿分子机制和绿色防控棉铃虫提供了理论基础。     

欧斑鸠的染色体组型及G、C带研究

本文研究了繁殖于新疆的欧斑鸠的染色体组型,其2n=80,NF=110,和以报道的山斑鸠与灰斑鸠的染色体组型差异显著。通过G、C带的比较观测,雌性大染色体为30条,雄性大染色体为31条（其中第6对为不配对单体）,雄性性染色体为ZW,雄性性染色体为Z0,其去均为微小染色体。雄性染色体组型的形成和遗传机制有待进一步研究。     

棕色田鼠的细胞遗传学研究

本次首次报告棕色田鼠（Microtus mandarinus)的核型,核型公式为2n=50=2(M,T) 2SM 44T XX(M,SM),XY(SM,ST),发现第一对常染色体及X性染色体存在多态现象,在所研究的15只雌性个体中有7只雌性个体的细胞只有1条X性染色体,性染色体组成为XO型,核型公式为2n=49=2(M,ST) 2SM 44T＋XO,。其中X性染色体不同于雄性中的X（SM）,为M类型,本文提出的综色田鼠3种核型与Brown等人（1964）提出的Microtus oregoni的3种核型（XO,YO,XY）有异,本文还阐述了染色体多态产生的机制和探讨了XO型个体发生的机理及其繁殖。     

植物性染色体进化及性别决定基因研究进展

植物性染色体起源于1对常染色体, 其在不同雌雄异株植物中多次起源并独立演变, 是研究性染色体起源和进化机制的理想材料。过去的研究在一定程度上阐明了植物性染色体的起源和演化动力; 且性染色体遗传退化、性别决定基因以及剂量补偿效应正逐渐成为研究的热点。近年来, 关于植物性染色体进化及性别决定基因的研究取得了一些重要进展。该文综述了植物性染色体的起源、进化、遗传退化、剂量补偿效应以及性别决定基因等, 并对植物性染色体进化研究发展趋势进行了展望。     

两栖动物性染色体的多样性及其 进化机制的研究进展

两栖动物性别决定类型和性染色体具有多样性的特点。在已发现异形性染色体两栖动物中,大部分物种Y或W染色体大于其对应的X或Z染色体,少数物种具有高度分化的Y或W染色体。同时两栖动物类群内基因组大小差异大,性染色体间分子水平上也存在差异。高频转换、偶然重组和染色体重排可能是两栖动物性染色体进化过程中的关键机制。本综述通过对两栖动物性染色体进化的深入探讨,揭示其遗传性别决定的机理,有助于对两栖动物性别人工调控的进一步探索。     

Dosage Compensation in Mammals

Many organisms show major chromosomal differences between sexes. In mammals, females have two copies of a large, gene-rich chromosome, the X, whereas males have one X and a small, gene-poor Y. The imbalance in expression of several hundred genes is lethal if not dealt with by dosage compensation. The male–female difference is addressed by silencing of genes on one female X early in development. However, both males and females now have only one active X chromosome. This is compensated by twofold up-regulation of genes on the active X. This complex system continues to provide important insights into mechanisms of epigenetic regulation.     

Dosage compensation in birds

The Z and W sex chromosomes of birds have evolved independently from the mammalian X and Y chromosomes [1]. Unlike mammals, female birds are heterogametic (ZW), while males are homogametic (ZZ). Therefore male birds, like female mammals, carry a double dose of sex-linked genes relative to the other sex. Other animals with nonhomologous sex chromosomes possess "dosage compensation" systems to equalize the expression of sex-linked genes. Dosage compensation occurs in animals as diverse as mammals, insects, and nematodes, although the mechanisms involved differ profoundly [2]. In birds, however, it is widely accepted that dosage compensation does not occur [3-5], and the differential expression of Z-linked genes has been suggested to underlie the avian sex-determination mechanism [6]. Here we show equivalent expression of at least six of nine Z chromosome genes in male and female chick embryos by using real-time quantitative PCR [7]. Only the Z-linked ScII gene, whose ortholog in Caenorhabditis elegans plays a crucial role in dosage compensation [8], escapes compensation by this assay. Our results imply that the majority of Z-linked genes in the chicken are dosage compensated.     

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.     

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.     

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.     

Re-evaluation of the function of the male specific lethal complex in Drosophila

A set of proteins and noncoding RNAs,referred to as the male specific lethal (MSL) complex,is present on the male X chromosome in　Drosophila and has been postulated to be responsible for dosage compensation of this chromosome - the up-regulation of its expression to be　equal to that of two X chromosomes in females.This hypothesis is evaluated in view of lesser known aspects of dosage compensation such as the　fact that metafemales with three X chromosomes also have equal expression to normal females,which would require a down-regulation of each　gene copy.Moreover,when this complex is ectopically expressed in females or specifically targeted to a reporter in males,there is no increase in　expression of the genes or targets with which it is associated.These observations are not consistent with the hypothesis that the MSL complex　conditions dosage compensation.A synthesis is described that can account for these observations.