Understanding how developmental systems compensate for and are affected by change

描述（由申请人提供）：动物的发育对遗传、环境或随机起源的变异具有很强的抵抗力。人们普遍认为，复杂系统的进化是为了缓冲变异，因为无补偿变异的后果对生物体是严重有害的，就像在发育过程中由于遗传或环境扰动而产生的无数人类先天性疾病一样。尽管使开发健壮的系统很重要，但对它们的理解仍然很差。例如，我们对稳健性水平和表型严重程度之间的关系知之甚少，如果稳健性失败的话。可以说，在动物发育过程中遇到的最常见的大规模遗传变异形式是性染色体剂量。在我的研究中，我使用雄性和雌性果蝇性染色体剂量差异的后果和反应作为理解基因剂量变化如何影响发育的一般模型。我最近开发了从单个果蝇胚胎中测序mRNA的方法，这使我发现许多在果蝇胚胎模式中起重要作用的x连锁基因在标准果蝇剂量补偿系统被激活之前几乎以相同的水平表达。这表明存在一种未表征的，但广泛使用的，早期胚胎剂量补偿系统。下一步，我将a .1)确定早期合子剂量补偿的机制，a .2)在一个新近获得性染色体的物种中表征剂量补偿，以鉴定具有强烈补偿需求的基因，a .3)在转基因黑腹龙中操纵基因剂量，以表征早期发育变化如何影响成年表型。最后一个目标将允许解剖变异在发展过程中是如何传播或抑制的，并形成我的研究计划的独立阶段的基础。

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.