An Evolutionary Genome Scan for Longevity-Related Natural Selection in Mammals
An Evolutionary Genome Scan for Longevity-Related Natural Selection in Mammals
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DOI：
10.1093/molbev/msp293
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发表时间：
2010-04-01
影响因子：
10.7
通讯作者：
Galtier, Nicolas
中科院分区：
文献类型：
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作者：
Jobson, Richard W.;Nabholz, Benoit;Galtier, Nicolas
衰老被认为是通过影响DNA、蛋白质和脂质的生化损伤的积累而发生的。细胞损伤的主要来源涉及在电子传递链的线粒体呼吸活动中产生的活性氧物种。从模式生物的实验研究来看，能量代谢、抗氧化过程、基因组维持和细胞周期是最常见的与衰老有关的细胞功能。这些实验对于自然界中与长寿相关的选择性限制的意义尚不清楚。在这里，我们采用了系统基因组学的方法来确定哺乳动物延长寿命的自然选择的遗传目标。通过比较25个物种中近570万个密码子的非同义和同义进化，我们识别出密码子和基因在长寿的谱系中显示出比短期的谱系更强的氨基酸保守水平。我们发现，在长寿物种中，涉及脂质组成和(胶原相关)维生素C结合的基因共同经历了更大的选择压力，而涉及DNA复制/修复或抗氧化的基因则没有。大多数实验上与衰老相关的候选基因(如Polg、Sod、FOXO)在哺乳动物的长寿进化中没有起到明显的作用。目前大量的医学研究旨在发现如何延长人类寿命。在这项研究中，我们揭示了自然选择在哺乳动物进化过程中完成这一任务的方式。细胞膜和细胞外胶原组成，而不是基因组的完整性，显然是优化的特征。
Aging is thought to occur through the accumulation of biochemical damage affecting DNA, proteins, and lipids. The major source of cellular damage involves the generation of reactive oxygen species produced during mitochondrial respiratory activity of the electron transport chain. Energetic metabolism, antioxidative processes, genome maintenance, and cell cycle are the cellular functions most commonly associated with aging, from experimental studies of model organisms. The significance of these experiments with respect to longevity-related selective constraints in nature remains unclear. Here we took a phylogenomic approach to identify the genetic targets of natural selection for elongated life span in mammals. By comparing the nonsynonymous and synonymous evolution of similar to 5.7 million codon sites across 25 species, we identify codons and genes showing a stronger level of amino acid conservation in long-lived than in short-lived lineages. We show that genes involved in lipid composition and (collagen associated) vitamin C binding have collectively undergone increased selective pressure in long-lived species, whereas genes involved in DNA replication/repair or antioxidation have not. Most of the candidate genes experimentally associated with aging (e.g., PolG, Sod, Foxo) have played no detectable role in the evolution of longevity in mammals. A large body of current medical research aims at discovering how to increase longevity in human. In this study, we uncovered the way natural selection has completed this task during mammalian evolution. Cellular membrane and extracellular collagen composition, not genome integrity, have apparently been the optimized features.