Evolutionary Causes and Consequences of Variation in the Rate of Mutation

描述（由申请人提供）：所有生物体都会发生突变。了解任何生物体的生物学，无论是过去还是未来，都需要了解突变过程。拟议研究的最终目标是了解突变率变化背后的遗传和环境因素。这些因素可能包括特定物种和个体固有的特性。该提案的具体目标是：（1）表征自发突变的速率和分子谱的种内和种间变化，（2）确定基因组突变速率是否在不同生物体中进化到不同的最佳值，以及（3）实验表征代谢率和突变率之间的关系。为了实现目标（1），将在100 Kb的随机基因组DNA下对在不存在自然选择的情况下积累突变250代的现有杆状线虫种群进行测序。为了实现目标（2），将使用历史上异交的线虫进行类似的突变累积实验，以与自交能育的线虫进行对比。自交和异交类群之间的显着差异的速度和/或新的突变的影响将提供证据表明，基因组突变率受到“微调”的自然选择。目的（3）是由代谢率和进化率之间明显的正相关性激发的。这种关系可能归因于代谢副产物产生的氧自由基引起的DNA损伤，但存在几种替代解释。 有证据表明，任意两种随机选择的蠕虫的突变率可能相差10倍，而潜在的分子突变率实际上可能比通常认为的高10倍。如果这些结果被证明是普遍的，那么对于理解突变如何在人类中发生以及复杂遗传因素引起的疾病的性质将产生重要影响。也许更重要的是，这项工作为目前用于推断任何生物体突变率的方法提供了关键的验证。

DESCRIPTION (provided by applicant): All living organisms mutate. Understanding the biology of any organism, past and future, requires understanding the mutational process. The ultimate objective of the proposed research is to understand the genetic and environmental factors underlying variation in the mutation rate. Those factors potentially include properties intrinsic to particular species and individuals. The specific aims of this proposal are: (1) characterize within- and between-species variation in the rate and molecular spectrum of spontaneous mutations, (2) determine if the genomic mutation rate has evolved to different optimal values in different organisms, and (3) experimentally characterize the relationship between metabolic rate and mutation rate. To achieve aim (1) existing stocks of Rhabditid nematodes that have accumulated mutations in the absence of natural selection for 250 generations will be sequenced at 100Kb of random genomic DNA. To achieve aim (2) a similar mutation accumulation experiment will be performed using historically outcrossing nematodes to contrast to self-fertile nematodes. Significant differences between selfing and outcrossing taxa in the rate and/or effects of new mutations will provide evidence that the genomic mutation rate is subject to "fine-tuning" by natural selection. Aim (3) is motivated by the apparent positive correlation between metabolic rate and rate of evolution. The relationship is plausibly attributed to DNA damage caused by oxygen radicals generated as by-products of metabolism, but several alternative explanations exist. Evidence suggests that any two randomly chosen worms may vary by as much as ten-fold in their mutation rate, and that the underlying molecular mutation rate may actually be ten times higher than is generally thought. If those results prove general, there would be important consequences fort the understanding of how mutations occur in humans, and on the nature of disease caused by complex genetic factors. Perhaps of even more importance, the proposed work provides a critical validation of the methods currently used to infer mutation rate in any organism.