Understanding how developmental systems compensate for and are affected by change

描述(申请人提供)：动物的发育对变异有很强的抵抗力，无论是遗传的、环境的还是随机的起源。人们普遍认为，复杂系统的进化是为了缓冲变异，因为没有补偿的变异的后果对有机体是严重有害的，就像无数人类先天疾病一样，这些疾病是由于发育过程中的遗传或环境扰动而产生的。尽管使发展变得强劲的系统很重要，但人们对它们的了解仍然很少。例如，健壮性水平与失败后健壮性的严重程度之间的关系就知之甚少。可以说，在动物发育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，我使用雄性和雌性黑腹果蝇性别染色体剂量差异的后果和反应作为一个通用模型，以了解基因剂量的变化如何影响发育。我最近开发了对单个果蝇胚胎的mRNA进行测序的方法，这让我发现，在果蝇胚胎的模式形成过程中发挥重要作用的许多X连锁基因在典型的果蝇剂量补偿系统激活之前的表达水平几乎相同。这表明在早期胚胎中存在一种没有特征但被广泛使用的剂量补偿系统。下一步，我将：1)确定早期合子剂量补偿的机制；2)表征具有新近衍生的性染色体的物种的剂量补偿，以确定具有强烈补偿需求的基因；以及A.3)操纵转基因黑腹果蝇的基因剂量，以表征早期发育的变异如何影响成体表型。最后一个目标将允许剖析变化是如何在发展过程中传播或抑制的，并形成我研究计划的独立阶段的基础。 与公共卫生相关：动物发育是一个强大的过程，尽管遗传和环境存在差异，但仍能产生刻板印象的结果。然而，某些形式的变异是通过发育传播的，可能会产生严重的影响，导致流产和广泛的先天畸形。在这里，我建议研究发育过程抑制这种变异的机制，以及当这种抑制失败时，它是如何通过发育传播的，以及对表型的影响。

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.