Program in Genetics, W. M. Keck Center for Behavioral Biology, Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, USA.
School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
Sci Rep. 2017 Jun 23;7(1):4109. doi: 10.1038/s41598-017-04530-x.
Longevity varies among individuals, but how natural genetic variation contributes to variation in lifespan is poorly understood. Drosophila melanogaster presents an advantageous model system to explore the genetic underpinnings of longevity, since its generation time is brief and both the genetic background and rearing environment can be precisely controlled. The bellwether (blw) gene encodes the α subunit of mitochondrial ATP synthase. Since metabolic rate may influence lifespan, we investigated whether alternative haplotypes in the blw promoter affect lifespan when expressed in a co-isogenic background. We amplified 521 bp upstream promoter sequences containing alternative haplotypes and assessed promoter activity both in vitro and in vivo using a luciferase reporter system. The AG haplotype showed significantly greater expression of luciferase than the GT haplotype. We then overexpressed a blw cDNA construct driven by either the AG or GT haplotype promoter in transgenic flies and showed that the AG haplotype also results in greater blw cDNA expression and a significant decrease in lifespan relative to the GT promoter haplotype, in male flies only. Thus, our results show that naturally occurring regulatory variants of blw affect lifespan in a sex-specific manner.
寿命在个体之间存在差异，但自然遗传变异如何导致寿命的变化还知之甚少。黑腹果蝇为探索长寿的遗传基础提供了一个有利的模型系统，因为它的世代时间很短，而且遗传背景和饲养环境都可以精确控制。风向标 (blw) 基因编码线粒体 ATP 合酶的α亚基。由于代谢率可能会影响寿命，我们研究了 blw 启动子中的替代单倍型是否会影响在共同基因背景下表达时的寿命。我们扩增了包含替代单倍型的 521bp 上游启动子序列，并使用荧光素酶报告系统在体外和体内评估了启动子活性。AG 单倍型的荧光素酶表达显著高于 GT 单倍型。然后，我们在转基因果蝇中过表达由 AG 或 GT 单倍型启动子驱动的 blw cDNA 构建体，并表明 AG 单倍型也会导致 blw cDNA 表达增加，以及与 GT 启动子单倍型相比，雄性果蝇的寿命显著缩短。因此，我们的结果表明，blw 的自然发生的调控变体以性别特异性的方式影响寿命。
