Source data Fig 1B.

Nutrition is a primary determinant of health, but responses to nutrition vary with genotype. Epistasis between mitochondrial and nuclear genomes may cause some of this variation, but which mitochondrial loci and nutrients participate in complex gene-by-gene-by-diet interactions? Furthermore, it remains unknown whether mitonuclear epistasis is involved only in the immediate responses to changes in diet, or whether mitonuclear genotype might modulate sensitivity to variation in parental nutrition, to shape intergenerational fitness responses. Here, in Drosophila melanogaster, we show that mitonuclear epistasis shapes fitness responses to variation in dietary lipids and amino acids. We also show that mitonuclear genotype modulates the parental effect of dietary lipid and amino acid variation on offspring fitness. Effect sizes for the interactions between diet, mitogenotype, and nucleogenotype were equal to or greater than the main effect of diet for some traits, suggesting that dietary impacts cannot be understood without first accounting for these interactions. Associating phenotype to mtDNA variation in a subset of populations implicated a C/T polymorphism in mt:lrRNA, which encodes the 16S rRNA of the mitochondrial ribosome. This association suggests that directionally different responses to dietary changes can result from variants on mtDNA that do not change protein coding sequence, dependent on epistatic interactions with variation in the nuclear genome.

营养是健康的核心决定因素，但机体对营养的应答会随基因型的不同而存在差异。线粒体与细胞核基因组间的上位性（epistasis）或许是造成这种个体差异的部分原因，但究竟哪些线粒体基因座与营养物质参与了复杂的基因-基因-膳食互作？此外，目前尚不明确线粒体核上位性（mitonuclear epistasis）是否仅参与膳食改变的即时应答，抑或线粒体核基因型是否可调控亲本营养变异的敏感性，进而塑造代际间的适合度应答。本研究以黑腹果蝇（Drosophila melanogaster）为实验材料，证实线粒体核上位性可调控机体对膳食脂质与氨基酸变异的适合度应答；同时发现，线粒体核基因型可调控膳食脂质与氨基酸变异对子代适合度的亲本效应。针对部分性状而言，膳食、线粒体基因型与细胞核基因型间互作的效应量等于甚至大于膳食的主效应，这表明若不先考量这些互作关系，便无法阐明膳食的影响机制。通过将表型与部分种群的线粒体DNA（mtDNA）变异进行关联分析，本研究锁定了mt:lrRNA基因中的一处C/T多态性——该基因编码线粒体核糖体的16S rRNA。该关联结果表明，膳食改变的方向性应答差异可源自不改变蛋白质编码序列的线粒体DNA变异，且这种差异依赖于与细胞核基因组变异间的上位性互作。