Understanding how developmental systems compensate for and are affected by change

项目摘要 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。 人们普遍认为，复杂系统已经进化为对变化的缓冲，因为 无偿变异对生物体是严重有害的，就像无数人类先天的 由于发育过程中的遗传或环境干扰而引起的疾病。尽管重要的是 在使发展变得强劲的系统中，人们对它们的理解仍然很少。例如，人们对此知之甚少， 关于健壮性水平和表型严重程度之间的关系是健壮性 失败了。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有性 染色体剂量。在我的研究中，我使用了性别差异的后果和反应 黑腹果蝇雌雄之间染色体剂量的一般模型 了解基因剂量的变化如何影响发育。我最近开发了一些方法来 对单个果蝇胚胎的mRNA进行测序，这让我发现许多X连锁的基因 在形成果蝇胚胎模式方面发挥重要作用的基因在以前的表达水平几乎相同 经典的果蝇剂量补偿系统被激活。这证明了存在一个 在早期胚胎中没有特征但广泛使用的剂量补偿系统。向前看，我会 A.1)确定受精卵早期剂量补偿的机制，a2)表征剂量补偿 在具有新近衍生的性染色体的物种中，以识别具有强烈要求的基因 补偿，以及A.3)操纵转基因黑腹果蝇的基因剂量，以表征如何在 早期发育会影响成体表型。最后一个目标将允许剖析变异是如何传播的或 在发展过程中被压制，并形成了我独立阶段的研究计划的基础。

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.