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: 8532934
• 负责人: Susan E Lott
• 金额: $ 23.26万
• 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/8532934
• 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 动物发育对变异的抵抗力非常强，无论是遗传的、环境的还是随机的。 人们普遍认为，复杂系统已经进化到可以缓冲变化，因为其后果 无补偿的变异对有机体是严重有害的，就像无数的人类先天性变异一样 由于发育过程中的遗传或环境扰动而引起的疾病。尽管很重要 对于使开发稳健的系统，人们仍然知之甚少。鲜为人知的是，例如 关于稳健性水平和表型严重程度之间的关系是稳健性 失败。可以说，动物发育中遇到的大规模遗传变异最常见的形式是性别 染色体剂量。在我的研究中，我利用了性别差异的后果和反应 黑腹果蝇雄性和雌性之间的染色体剂量作为一般模型 了解基因剂量的变化如何影响发育。我最近开发了方法 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 在果蝇胚胎模式中发挥重要作用的基因在之前以几乎相同的水平表达 典型的果蝇剂量补偿系统被激活。这证明了存在一个 早期胚胎中未表征但广泛使用的剂量补偿系统。往前走，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 在最近衍生出性染色体的物种中，以识别对性染色体有强烈要求的基因 补偿，以及 A.3) 操纵转基因黑腹果蝇中的基因剂量来表征 早期发育影响成年表型。最后一个目标将允许剖析变异如何传播或 在发展过程中受到抑制，并构成我的研究计划的独立阶段的基础。