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.
Differences in disease risks among individuals in human populations can be characterized as quantitative traits with a complex genetic basis. However, our understanding of how DNA variation causes phenotypic variation remains incomplete. The proposed studies will reveal how DNA variation can lead to variation in the efficiency of mRNA translation, improving our knowledge about the genetic basis of complex quantitative traits, including human diseases.
