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 动物发育对变异非常强大，无论是遗传，环境还是随机来源。 人们普遍认为，复杂的系统已经演变为缓冲剂，因为后果会带来变化 无偿差异对生物有严重有害，如无数人类先天性 由于发育中的遗传或环境扰动而引起的疾病。尽管很重要 在使开发稳健的系统中，它们仍然知之甚少。例如，鲜为人知 关于鲁棒性水平与表型的严重程度之间的关系是鲁棒性 失败。可以说，动物发育中遇到的大规模遗传变异的最常见形式是性 染色体剂量。在我的研究中，我利用性别差异的后果和反应 男性和果蝇的女性之间的染色体剂量作为一般模型 了解基因剂量的变异如何影响发育。我最近开发了 序列来自单个果蝇胚胎的mRNA，这使我能够发现许多X连锁基因 在对果蝇胚胎进行构图方面起着重要作用 典型的果蝇剂量补偿系统被激活。这表明了 早期胚胎中未表征但广泛使用的剂量补偿系统。前进，我会 A.1）确定早期合子剂量补偿的机制，A.2）剂量补偿的特征 在最近衍生的性染色体的物种中，鉴定具有很强要求的基因 补偿和A.3）操纵转基因的基因剂量D. melanogaster以表征如何变异 早期发展会影响成人表型。最后一个目标将允许解剖如何传播变异或 在开发过程中被抑制，并构成了我研究计划的独立阶段的基础。