Prediction of complex phenotypes using the Drosophila melanogaster metabolome

Understanding the genotype-phenotype map and how variation at different levels of biological organization is associated are central topics in modern biology. Fast developments in sequencing technologies and other molecular omic tools enable researchers to obtain detailed information on variation at DNA level and on intermediate endophenotypes, such as RNA, proteins and metabolites. This can facilitate our understanding of the link between genotypes and molecular and functional organismal phenotypes. Here, we use the Drosophila melanogaster Genetic Reference Panel and nuclear magnetic resonance (NMR) metabolomics to investigate the ability of the metabolome to predict organismal phenotypes. We performed NMR metabolomics on four replicate pools of male flies from each of 170 different isogenic lines. Our results show that metabolite profiles are variable among the investigated lines and that this variation is highly heritable. Second, we identify genes associated with metabolome variation. Third, using the metabolome gave better prediction accuracies than genomic information for four of five quantitative traits analyzed. Our comprehensive characterization of population-scale diversity of metabolomes and its genetic basis illustrates that metabolites have large potential as predictors of organismal phenotypes. This finding is of great importance, e.g., in human medicine, evolutionary biology and animal and plant breeding.

解析基因型-表型图谱（genotype-phenotype map），并阐明不同层级生物组织的变异间的关联机制，乃是现代生物学的核心研究主题。测序技术与其他分子组学工具的飞速发展，使研究者能够获取DNA层面的变异信息，以及RNA、蛋白质、代谢物等中间内表型（endophenotype）的详细数据，这将助力我们深入解析基因型与生物体分子层面及功能层面表型之间的内在关联。本研究依托黑腹果蝇遗传参考面板（Drosophila melanogaster Genetic Reference Panel）与核磁共振（NMR）代谢组学技术，探究代谢组预测生物体表型的能力。我们针对170个不同同基因品系的雄性果蝇，分别制备了4个重复混合样本并开展核磁共振代谢组学检测。研究结果显示：受试品系间的代谢物谱存在显著差异，且该差异具有高度可遗传性；其二，我们鉴定出与代谢组变异相关的基因；其三，针对本次分析的5个数量性状中的4个，基于代谢组的预测精度显著优于基因组信息。我们对种群尺度代谢组多样性及其遗传基础的全面解析表明，代谢物作为生物体表型预测因子具备巨大应用潜力。该发现具有重要价值，例如在人类医学、进化生物学以及动植物育种领域。