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: 3466277
• 负责人: ALAN C CHRISTENSEN
• 金额: $ 12.31万
• 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/3466277
• 关键词: Drosophilidae; autoradiography; complementary DNA; cytogenetics; developmental genetics; endonuclease; gel electrophoresis; gene dosage; gene expression; gene interaction; gene mutation; genetic manipulation; genetic promoter element; genetic regulation; genetic transcription; genetic translation; molecular cloning; molecular genetics; nucleic acid hybridization; nucleic acid probes; phosphogluconate dehydrogenase; sex chromosomes; sex determination; transcription factor

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染色体数目的比例决定的。 染色体的数目与常染色体的数目成正比。 细胞与一 X染色体和两套常染色体为雄性和细胞 有两条X染色体和两套常染色体的是雌性。 由于男性对X连锁基因的要求相同， 产品作为女性，他们的反应是过度激活X 染色体在转录水平，以弥补 基因剂量的差异。 该项目旨在解决两个问题： 雄性细胞是如何将几乎所有的 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 作为模型基因的6-磷酸葡萄糖酸脱氢酶（Pgd）基因 X染色体。 基因的体外操作及其 启动子，然后重新整合到果蝇基因组中， 将用于寻找Pgd基因的顺式作用调控位点 负责剂量补偿反应。 剂量 代偿是基因调控研究的重要课题 因为它改变了大量基因的表达水平 整整两倍 这种微妙的调节可能是由 一个新的机制，或通过新的应用，传统的 机制等 了解剂量补偿将是一个 这是理解协调监管的重要一步， 这也是一个重要的方面， 发育和瘤形成。 问题是X 染色体计数将受到攻击的克隆Tp 1 通过染色体步移或转座子标记， 研究基因的表达。 Tpl是染色体上的一个位点 3、对剂量非常敏感。 果蝇需要 为了生存，需要精确的2个剂量的Tpl。 轴承1或3的个体 剂量作为胚胎死亡。 有人认为TPL参与了 计数X染色体有两个原因。 人们会期望 使X染色体对抗自身的基因 敏感，此外，Tpl似乎与X相互作用， 非整倍体 如果这个假设是不正确的，那么Tpl 必须在胚胎发生或细胞发育中发挥重要作用 新陈代谢. 无论哪种情况，对第三人称代词的研究都具有深远的意义 对性别决定的影响， 非整倍性和胚胎发生。 果蝇是极少数 这种基因可以被研究的生物，因为它有一个 显性致死表型