MOLECULAR GENETICS OF GENE DOSAGE COMPENSATION AND SEX

基因剂量补偿和性别的分子遗传学

• 批准号: 3466274
• 负责人: ALAN C CHRISTENSEN
• 金额: $ 9.66万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3466274
• 关键词: autoradiography; complementary DNA; cytogenetics; developmental genetics; endonuclease; gel electrophoresis; gene dosage; gene expression; gene interaction; gene mutation; genetic manipulation; genetic regulation; genetic transcription; genetic translation; molecular cloning; molecular genetics; phosphogluconate dehydrogenase; sex chromosomes; sex determination

In Drosophila sex is determined by the ratio of the number of X chromosomes to the number of sets of autosomes. Cells with one X chromosome and two sets of automsomes are males and cells with 2 X chromosomes and two sets of autosomes are females. Since males have the same requirements for X-linked gene products as females, they respond by hyperactivating the X chromosome at the transcriptional level to compensate for the difference in gene dosage. This project is aimed at two questions: how do male cells double the transcription rate of virtually every gene on the X chromosome, and how do cells count the number of X chromosomes. The first question will be addressed by using the gene for 6-phosphogluconate dehydrogenase (Pgd) as a model gene for the X chromosome. In vitro manipulation of the gene and its promoter, followed by reintegration into the Drosophila genome, will be used to find the cis-acting regulatory site of the Pgd gene that is responsible for the dosage compensation response. Dosage compensation is an important topic in the study of gene regulation since it changes the expression levels of a large battery of genes by exactly two-fold. This subtle regulation may be controlled by a novel mechanism, or by novel application of conventional mechanisms. Understanding dosage compensation will be an important step in understanding the coordinated regulation of a large group of genes, which is also a significant facet of development and neoplasia. The question of how the X chromosomes are counted will be attacked by cloning the Tp1 gene either by a chromosome walk or transposon tagging, and then studying the expression of the gene. Tpl is a locus on chromosome 3 which is extremely dosage sensitive. Drosophila requires exaclty 2 doses of Tpl for survival. Individuals bearing 1 or 3 doses die as embryos. It has been suggested that Tpl is involved in counting the X chromosomes for two reasons. One would expect a gene that titrates the X chromosomes against itself to be dosage sensitive, and in addition, Tpl appears to interact with the X in aneuploids. If this hypothesis turns out be incorrect, then Tpl must perform a vital function in embryogenesis or cellular metabolism. In either case the study of Tpl has for-reaching implications for sex determination, the consequences of aneuploidy, and embryogenesis. Drosophila is one of very few organisms in which such a gene can be studied since it has a dominant lethal phenotype.

在果蝇中，性别是由X的数量之比决定的 染色体与常染色体组数之比。带一个的单元格 X染色体和两组自体是雄性和细胞 有两条X染色体和两组常染色体是雌性的。 因为男性对X连锁基因有同样的要求 作为女性的产品，它们的反应是过度激活X 在转录水平上的染色体以补偿 基因剂量的差异。该项目针对两个问题： 男性细胞是如何将几乎所有 X染色体上的基因，以及细胞如何计算 X染色体。第一个问题将使用 6-磷酸葡萄糖酸脱氢酶基因作为模型基因 用于X染色体。该基因及其相关基因的体外操作 启动子，然后重新融入果蝇基因组， 将用于寻找pgd基因的顺式作用调控位点 这是剂量补偿反应的主要原因。剂量 补偿是基因调控研究中的一个重要课题。 因为它改变了大量基因的表达水平 正好是两倍。这一微妙的规则可能由 一种新的机制，或者通过传统的新应用 机制。了解剂量补偿将是一个 理解协调监管的重要一步 一大组基因，这也是 发育和肿瘤。问题是X是如何 染色体被计数将受到克隆TP1的攻击 基因可以通过染色体行走或转座子标记，然后 研究该基因的表达情况。第三方物流是染色体上的一个基因座 3具有极强的剂量敏感性。果蝇需要 存活所需的TPL恰好为2剂。带1或3的个人 剂量会像胚胎一样死亡。有人认为，第三方物流参与了 计算X染色体有两个原因。人们会期待一个 将X染色体自身滴定为剂量的基因 敏感，此外，TPL似乎与X在 非整倍体。如果这一假设被证明是不正确的，那么第三方物流 必须在胚胎发生或细胞发育过程中发挥重要作用 新陈代谢。在任何一种情况下，第三方物流的研究都具有深远的意义 对性别决定的影响， 非整倍体和胚胎发生。果蝇是为数不多的 可以在其中研究这种基因的生物体，因为它具有 显性致死表型。