Understanding how developmental systems compensate for and are affected by change

了解发展系统如何补偿变化并受变化影响

• 批准号: 8516159
• 负责人: Susan E Lott
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-11 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516159
• 关键词: Accounting; Adult; Affect; Aneuploidy; Animals; Autistic Disorder; Behavior; Biochemical; Buffers; California; Complex; Congenital Abnormality; Congenital Disorders; Data; Development; Developmental Process; Diploidy; Disease; Dissection; Dosage Compensation (Genetics); Dose; Drosophila genus; Drosophila melanogaster; Embryo; Female; Financial compensation; Gene Dosage; Gene Expression; Gene Transfer Techniques; Genes; Genetic; Genetic Variation; Genome; Genomics; Growth; Human; Lead; Link; Measures; Mentorship; Messenger RNA; Methods; Modeling; Molecular; Morphology; Organism; Outcome; Pattern; Phenotype; Play; Process; Proteins; Research; Research Personnel; Role; Severities; Sex Chromosomes; Source; Spontaneous abortion; Staging; Stereotyping; System; Techniques; Testing; Time; Transgenic Organisms; Universities; Variant; Y Chromosome; abstracting; base; dosage; follow-up; male; mutant; programs; response; sex; skills

Project Abstract Animal development is remarkably robust to variation, be it of genetic, environmental, or stochastic origin. It is widely believed that complex systems have evolved to buffer against variation because the consequences of uncompensated variation are severely deleterious to the organism, as in the myriad human congenital disorders that arise because of genetic or environmental perturbations in development. Despite the importance of the systems that make development robust, they remain poorly understood. Little is known, for example, about relationship between the level of robustness and the severity of the phenotype were the robustness to fail. Arguably the most common form of large-scale genetic variation encountered in animal development is sex chromosome dosage. In my research, I use the consequences of and response to differences in sex chromosome dose between males and females of Drosophila melanogaster as a general model for understanding how variation in the gene dose can affect development. I recently developed methods to sequence the mRNA from single Drosophila embryos, which allowed me to discover that many X-linked genes that play an important role in patterning the Drosophila embryo are expressed at nearly identical levels before the canonical Drosophila dosage compensation system is activated. This demonstrated the existence of an uncharacterized, yet widely used, system of dosage compensation in the early embryo. Moving forward, I will A.1) determine the mechanism of early zygotic dosage compensation, A.2) characterize dosage compensation in a species with recently derived sex chromosomes to identify genes with a strong requirement for compensation, and A.3) manipulate gene dose in transgenic D. melanogaster to characterize how variation in early development affects adult phenotypes. The last aim will allow dissection of how variation is propagated or suppressed during development, and form the basis of the independent stage of my research program.

项目摘要 动物的发育对变异具有显著的鲁棒性，无论是遗传的、环境的还是随机的。 人们普遍认为，复杂系统的进化是为了缓冲变化，因为 未经补偿的变异对生物体是严重有害的，就像在无数的人类先天性 由于发育过程中的遗传或环境干扰而引起的疾病。尽管重要性 在使发展稳健的系统中，人们对这些系统的了解仍然很少。例如，我们所知甚少， 关于稳健性水平与表型严重程度之间的关系， 失败可以说，动物发育过程中最常见的大规模遗传变异形式是性别 染色体剂量在我的研究中，我使用性别差异的后果和反应， 黑腹果蝇雌雄间染色体剂量的一般模型 了解基因剂量的变化如何影响发育。我最近发明了一种方法 对单个果蝇胚胎的mRNA进行测序，这让我发现许多X连锁基因 在形成果蝇胚胎的模式中起重要作用的蛋白质， 典型的果蝇剂量补偿系统被激活。这表明存在一个 在早期胚胎中的剂量补偿系统的未表征，但广泛使用。向前看，我会 A.1）确定早期合子剂量补偿的机制，A.2）表征剂量补偿 在一个最近衍生出性染色体的物种中，以确定对以下方面有强烈需求的基因： A.3）控制转基因D.黑腹动物来描述 早期发育影响成体表型。最后一个目标将允许解剖变异是如何传播的， 在发展过程中被抑制，并形成我的研究计划的独立阶段的基础。