Data from: Dietary stress unmasks cryptic genetic variation regulating lifespan in outbred Drosophila

Evolutionary theory suggests that lifespan-associated alleles should be purged from the gene pool, and yet decades of GWAS and model organism studies have shown they persist. Here, we address one potential explanation, the idea that the alleles that regulate lifespan do so only in certain contexts. We exposed thousands of outbred Drosophila to a standard and a high sugar diet. We then sequenced over 10,000 individuals and track genome-wide allele frequency changes over time, as these populations aged. We mapped thousands of lifespan-altering alleles, some associated with early- vs late-life tradeoffs, late-onset effects, and genotype-by-environment interactions. We find that lifespan-reducing alleles are most likely to be recently derived and have stronger effects on a high-sugar diet, consistent with the hypothesis that historically neutral or beneficial alleles can become detrimental in novel conditions. We also show that the gene midway, a regulator of lipid storage and ortholog of the lifespan-associated gene DGAT1 in mice, also regulates lifespan in Drosophila. Our results provide insight into the highly polygenic and context-dependent genetic architecture of lifespan, as well as the evolutionary processes that shape this key trait.

进化论指出，与寿命相关的等位基因（alleles）应当从基因库中被清除，但数十年来的全基因组关联研究（Genome-Wide Association Study, GWAS）与模式生物研究均表明，这类等位基因依然存续。本研究针对这一现象提出一种潜在解释：调控寿命的等位基因仅在特定情境下发挥作用。我们将数千只远交系果蝇分别置于标准饲料与高糖饲料环境中饲养，随后对超过10000只个体进行测序，追踪这些种群随衰老进程的全基因组等位基因频率变化。我们定位了数千个影响寿命的等位基因，其中部分与早期生命与晚期生命的权衡、迟发性效应以及基因型-环境互作相关。我们发现，缩短寿命的等位基因大多为新近衍生而来，且在高糖饲料环境中效应更强，这与“历史上为中性或有益的等位基因，在新型环境中可能产生有害影响”的假说相符。我们还证实，果蝇的midway基因——一种脂质储存调控因子，同时也是小鼠寿命相关基因DGAT1的同源基因——同样能够调控果蝇的寿命。本研究结果为理解寿命调控的高度多基因性与情境依赖型遗传结构，以及塑造这一关键性状的进化过程提供了新见解。