Mutations and the age pattern of death.
Mutations and the age pattern of death.
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突变和死亡年龄模式。
DOI：
10.1073/pnas.1307921110
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发表时间：
2013
影响因子：
11.1
通讯作者：
Tuljapurkar,Shripad
中科院分区：
文献类型：
--
作者：
Tuljapurkar,Shripad
死亡的年龄模式是生物学家和人口学家在考虑死亡(或永生)时所考虑的问题。众所周知，在过去的一个世纪里，人类的平均寿命几乎翻了一番，然而，随着人们年龄超过40岁，人类死亡率仍然以指数级的速度增长(图1)。毫不奇怪，老年人的健康现在是一个主要问题(2)，往往侧重于影响健康的生物、经济和社会等直接因素(3-5)。然而，一个更深层次的问题是，进化如何塑造了死亡率的年龄模式？特别是，老年死亡率的上升是由有害等位基因(即对你有害的)等位基因数量和频率的增加推动的吗？在PNAS中，Wachter等人(6)展示了如何在一个庞大的、年龄结构的和遗传异质性的种群中计算有害突变等位基因的平衡分布。他们的分析比以前关于这个问题的工作(7，8)有了很大的进步。Wachter等人(6)考虑的问题是群体遗传学中的一个普遍问题。在任何种群中，每个个体都经历了持续不断的小速率突变，几乎所有的突变都是有害的。在一个基因上出现有害突变等位基因的携带者具有选择性劣势，最终会被扫除。重复突变可以重复引入突变等位基因，因此在种群中，通过选择和突变之间的平衡，突变等位基因的频率保持在零以上。还有其他过程，有时(例如，在某些组合中)赋予选择性劣势的等位基因可以在种群中保持不变；这并不总是一件坏事，因为进化需要变异。然而，当然，任何这样的过程都意味着群体中包含的基因类型比其他人更不适合，因此平均适合度并不像它可能的那样高。平均适应度的降低称为遗传负荷(9)。一个有害的突变等位基因可以在注入新副本的突变和删除旧副本的选择之间保持平衡。平衡频率取决于突变携带者经历的适应度损失，而这种损失取决于突变如何影响个体。对于大多数动植物来说，适合度取决于繁殖和存活的年龄模式，适合度是通过长期增长率来衡量的，对于保持在一定限度的种群来说，适宜性是通过净繁殖率来衡量的。汉密尔顿(7)取得了重大突破，回答了这样一个问题：具有特定年龄效应的突变导致的健康损失是什么，即只在一个年龄时降低存活率或提高生育率？他的主要结论之一是，随着年龄的增长，这种减少的效果会逐渐减弱。查尔斯沃思(8)从这些结果开始计算每个年龄段突变的均衡分布。他假设选择是线性的--一个突变的三个副本的选择劣势是单个副本的三倍--并预测有害突变的频率会随着年龄的增长而上升，如果每个突变影响的是多个年龄，而不是一个年龄，最终可能会导致稳定。他当之无愧的有影响力的结果为老年死亡率的模式提供了一个进化的理由(图1)。这一结果从表面上看是令人满意的，但也提出了至少两个需要回答的问题。例如，当我们将一个携带三个有害等位基因(不必相同)的个体与另一个携带一个有害等位基因的个体进行比较时，假设线性选择合理吗？而且，因为突变是随机发生的，我们不应该分析一个异质群体，在这个群体中，个体携带的突变等位基因的数量和种类不同吗？这就是瓦切特对…的看法
The age pattern of death is what biologists and demographers think about when they consider mortality (or immortality). As everyone knows, human lives on average have nearly doubled in length over the past century (1), yet human mortality still increases exponentially fast (Fig. 1) as people age past 40. Not surprisingly, the health of older people is now a major concern (2), often focused on proximate factors, biological, economic and social, that affect health (3–5). However, a deeper question is, how did evolution shape the age pattern of mortality? In particular, is the rise in old-age mortality driven by an increase in the number and frequency of deleterious (ie, bad for you) alleles? In PNAS, Wachter et al.(6) show how to compute the equilibrium distribution of deleterious mutant alleles in a large, age-structured, and genetically heterogeneous population. Their analysis is a significant advance over previous work on this question (7, 8). The problem that Wachter et al.(6) consider is a general one in population genetics. In any population, every individual experiences a continuing flux of mutations at a small rate, almost all deleterious in effect. The carrier of a deleterious mutant allele arising at one gene has a selective disadvantage and is eventually swept away. Recurrent mutation can repeatedly introduce a mutant allele so that, in the population, the frequency of the mutant allele is kept above zero by the balance between selection and mutation. There are other processes (9) by which alleles that sometimes (eg, in some combinations) confer a selective disadvantage can be maintained in a population; this is not always a bad thing because evolution requires variation. However, any such process means, of course, that the population contains genotypes that are less fit than others, and so on the average fitness is not as high as it could be. The reduction in average fitness is called the genetic load (9). A single deleterious mutant allele can be held in a balance between mutation that injects new copies and selection that removes old ones. The equilibrium frequency depends on the fitness loss experienced by carriers of the mutation, and that loss depends on how the mutation affects individuals. For most plants and animals, fitness depends on the age pattern of reproduction and survival, and fitness is measured by the long-run growth rate or, for a population held at some limits, by the net reproductive rate. Hamilton (7) made a major breakthrough by answering the question: what is the loss in fitness produced by a mutation that has age-specific effect, ie, reduces survival or increases fertility at just one age? One of his main conclusions was that such reductions had declining effect with age. Charlesworth (8) started from these results to compute the equilibrium distribution of mutations at each age. He assumed linearity of selection—the selective disadvantage of three copies of a mutation is three times that of a single copy—and predicted a rise in the frequency of deleterious mutations with age, as well as an eventual leveling-off that can result if every mutation affects many ages, not just one. His deservedly influential results provide an evolutionary reason for the pattern of old-age mortality (Fig. 1). This result is satisfying on the face of it but raises at least two questions that need answering.Is it reasonable to assume linear selection when, for example, we compare an individual carrying say three deleterious alleles (which need not be the same) to another with just one? And, because mutations strike at random, shouldn’t we analyze a heterogeneous population in which individuals differ by the number and kind of mutant alleles they carry? This is where Wachter …