Evolutionary Causes and Consequences of Variation in the Rate of Mutation

描述（由申请人提供）：所有生物都会发生突变。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。这项研究的最终目的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。本提案的具体目标是：(1)表征物种内和物种间自发突变率和分子谱的变化；(2)确定基因组突变率在不同生物体中是否进化到不同的最佳值；(3)实验表征代谢率和突变率之间的关系。为了实现目标(1)，将对250代在没有自然选择的情况下积累了突变的现有横纹肌线虫种群进行100Kb随机基因组DNA测序。为了实现目标(2)，将使用历史异交线虫与自交线虫进行类似的突变积累实验。自交和异交类群在新突变率和/或影响上的显著差异将提供证据，证明基因组突变率受自然选择的“微调”影响。Aim(3)的动机是代谢率和进化率之间存在明显的正相关关系。这种关系似乎归因于代谢副产物氧自由基引起的DNA损伤，但存在几种其他解释。

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.