Evolutionary Causes and Consequences of Variation in the Rate of Mutation

描述(申请人提供)：所有生物都会发生突变。要了解任何生物体的生物学，无论是过去的还是未来的，都需要了解突变过程。这项拟议研究的最终目标是了解突变率变异背后的遗传和环境因素。这些因素可能包括特定物种和个人固有的特性。这一建议的具体目的是：(1)表征自发突变的速率和分子谱在物种内和物种间的差异，(2)确定基因组突变率是否在不同的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)在没有自然选择的情况下积累突变250代的现有Rhabditid线虫种群将在100Kb的随机基因组DNA上进行测序。为了达到目标(2)，将使用历史上的异交线虫进行类似的突变累积实验，以与自我繁殖的线虫进行对比。自交和异交分类群在新突变的速率和/或影响方面的显著差异将提供证据，证明基因组突变率受到自然选择的“微调”。AIM(3)是由代谢率和进化率之间的明显正相关所驱动的。这种关系似乎可以归因于代谢副产物产生的氧自由基造成的DNA损伤，但也有几种不同的解释。 有证据表明，随机选择的任何两种蠕虫的突变率可能相差十倍，潜在的分子突变率实际上可能比人们通常认为的高十倍。如果这些结果被证明是普遍的，那么对于理解人类如何发生突变以及复杂遗传因素引起的疾病的性质将产生重要的后果。也许更重要的是，这项拟议的工作对目前用于推断任何生物体的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.