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: 8166004
• 负责人: Susan E Lott
• 金额: $ 9万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166004
• 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; base; dosage; follow-up; male; mutant; programs; response; sex; skills

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Animal development is a robust process, able to produce stereotyped outcomes despite genetic and environmental variation. Yet some forms of variation are propagated through development, and can have severe effects, leading to miscarriage and a wide range of congenital abnormalities. Here, I propose to investigate the mechanisms by which developmental processes suppress such variation, and when this suppression fails, how it is propagated through development, and to what phenotypic effect.

描述（由申请人提供）：无论是遗传，环境还是随机来源，动物发育都非常适合变异。人们普遍认为，复杂的系统已经演变为缓冲抗体的变化，因为无补偿变异的后果对生物体严重有害，就像由于发展中遗传或环境扰动而引起的无数人类先天性疾病。尽管这些系统的重要性使开发良好，但它们仍然知之甚少。例如，关于鲁棒性水平与表型的严重程度之间的关系知之甚少。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，我利用果蝇和女性之间性别染色体剂量差异的后果和响应果蝇剂量的差异作为一般模型，以了解基因剂量的变异如何影响发育。我最近开发了从单个果蝇胚胎中对mRNA进行测序的方法，这使我能够发现，在典型的果蝇剂量补偿系统之前，在几乎相同的水平上表达了许多在对果蝇胚胎构图中起重要作用的X连锁基因。这表明在早期胚胎中存在剂量补偿系统的未表征但广泛使用的系统。向前迈进，我将A.1）确定早期二剂剂量补偿的机制，A.2）表征具有最近衍生的性别染色体的物种中的剂量补偿，以鉴定具有强大补偿要求的基因，并且A.3）操纵基因剂量在转基因D. Melanogaster中，以表征早期发育的变异对成人的变异表征成人的变异。最后的目标将允许在开发过程中解剖如何繁殖或抑制变异，并构成我研究计划的独立阶段的基础。 公共卫生相关性：动物发展是一个强大的过程，尽管遗传和环境变化，但仍能够产生定型的结果。然而，某些形式的变异是通过发展传播的，并可能产生严重的影响，导致流产和多种先天性异常。在这里，我建议研究发展过程抑制这种变异的机制，以及这种抑制失败时，如何通过发育传播以及表型效应。