Genetic variation and evolution of translational control in Drosophila

项目摘要 大多数人类疾病和性状都是复杂的数量性状，涉及大量的基因、DNA 序列变异和环境因素，以及它们之间复杂的相互作用。尽管不同寻常 高分辨率遗传作图的进展，我们对序列变异如何导致表型的理解 变异仍然不完整。最近包括RNA在内的中间分子表型的研究， 蛋白质和代谢物的丰度促进了DNA之间联系的功能描述 人类和模式生物的变异和复杂的数量性状。然而，尽管mRNA翻译 是一个关键的生物学过程，自然序列变异如何导致翻译过程中的遗传变异 控制以及这一水平的监管差异如何有助于种群内和物种间 多样性仍有待理解。使用果蝇胚胎作为模型系统，我们建议通过以下方式来填补这一空白 1)量化和定位不同发育阶段胚胎间翻译效率的遗传变异 全序列和深表型黑腹果蝇种群近交系；2)作图 顺式或反式调节变异导致物种间翻译差异的基因 效率；以及3)建立大规模平行的报告分析系统地测试顺式调节的效果。 信使核糖核酸翻译变异。这些全面的研究，当与广泛的 使用研究人群，以前所未有的详细程度提供了基因-表型图谱的特征。 它们将极大地促进我们对DNA变异如何导致体内表型变异的理解 以及物种之间的差异，包括人类种群中个体之间疾病风险的差异。

Project Summary Most human diseases and traits are complex quantitative traits, involving a large number of genes, DNA sequence variants and environmental factors, and the complex interactions among them. Despite remarkable progress in high resolution genetic mapping, our understanding of how sequence variants cause phenotypic variation remains incomplete. Recent studies incorporating intermediate molecular phenotypes including RNA, protein, and metabolite abundances have facilitated functional delineation of associations between DNA variants and complex quantitative traits in humans and model organisms. However, although mRNA translation is a critical biological process, how natural sequence variation may lead to genetic variation in translational control and how this level of regulatory variation can contribute to within-population and between-species diversity remain to be understood. Using Drosophila embryos as a model system, we propose to fill this gap by 1) quantifying and mapping genetic variation of translation efficiency among embryos at multiple stages from inbred strains of a fully sequenced and deeply phenotyped Drosophila melanogaster population; 2) mapping genes whose cis or trans regulatory variation contributes to between-species divergence in translation efficiency; and 3) developing a massively parallel reporter assay to systematically test effects of cis regulatory variation on mRNA translation. These comprehensive studies, when integrated with existing data in the widely used study population, provide a characterization of the genotype-phenotype maps in unprecedented details. They will significantly advance our understanding of how DNA variants contribute to phenotypic variation within and between species, including variation in disease risks among individuals in human populations.