Dasmeh Pouria, Kepp Kasper P
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
Department of Biochemistry and Cedergren Center for Bioinformatics and Genomics, Faculty of Medicine, University of Montreal, 2900 Edouard-Montpetit, Montreal, QC, H3T 1J4, Canada.
Cell Mol Life Sci. 2017 Aug;74(16):3023-3037. doi: 10.1007/s00018-017-2519-8. Epub 2017 Apr 7.
Positive (adaptive) selection has recently been implied in human superoxide dismutase 1 (SOD1), a highly abundant antioxidant protein with energy signaling and antiaging functions, one of very few examples of direct selection on a human protein product (exon); the molecular drivers of this selection are unknown. We mapped 30 extant SOD1 sequences to the recently established mammalian species tree and inferred ancestors, key substitutions, and signatures of selection during the protein's evolution. We detected elevated substitution rates leading to great apes (Hominidae) at ~1 per 2 million years, significantly higher than in other primates and rodents, although these paradoxically generally evolve much faster. The high evolutionary rate was partly due to relaxation of some selection pressures and partly to distinct positive selection of SOD1 in great apes. We then show that higher stability and net charge and changes at the dimer interface were selectively introduced upon separation from old world monkeys and lesser apes (gibbons). Consequently, human, chimpanzee and gorilla SOD1s have a net charge of -6 at physiological pH, whereas the closely related gibbons and macaques have -3. These features consistently point towards selection against the malicious aggregation effects of elevated SOD1 levels in long-living great apes. The findings mirror the impact of human SOD1 mutations that reduce net charge and/or stability and cause ALS, a motor neuron disease characterized by oxidative stress and SOD1 aggregates and triggered by aging. Our study thus marks an example of direct selection for a particular chemical phenotype (high net charge and stability) in a single human protein with possible implications for the evolution of aging.
正向（适应性）选择最近被认为与人类超氧化物歧化酶1（SOD1）有关，SOD1是一种高度丰富的抗氧化蛋白，具有能量信号传导和抗衰老功能，是人类蛋白质产物（外显子）上极少的直接选择实例之一；这种选择的分子驱动因素尚不清楚。我们将30个现存的SOD1序列映射到最近建立的哺乳动物物种树上，并推断了该蛋白质进化过程中的祖先、关键替代和选择特征。我们检测到在大约每200万年有一个导致类人猿（人科）的替代率升高，这显著高于其他灵长类动物和啮齿动物，尽管这些动物通常进化得更快，这似乎自相矛盾。高进化速率部分是由于一些选择压力的放松，部分是由于类人猿中SOD1的独特正向选择。然后我们表明，与旧世界猴和小猿（长臂猿）分离后，在二聚体界面选择性地引入了更高的稳定性和净电荷以及变化。因此，人类、黑猩猩和大猩猩的SOD1在生理pH值下的净电荷为-6，而密切相关的长臂猿和猕猴的净电荷为-3。这些特征一致地表明，针对长寿类人猿中SOD1水平升高的有害聚集效应进行了选择。这些发现反映了人类SOD1突变的影响，这些突变会降低净电荷和/或稳定性并导致肌萎缩侧索硬化症（ALS），这是一种以氧化应激和SOD1聚集体为特征并由衰老引发的运动神经元疾病。因此，我们的研究标志着在单一人类蛋白质中针对特定化学表型（高净电荷和稳定性）进行直接选择的一个例子，这可能对衰老的进化产生影响。
