Evolutionary Causes and Consequences of Variation in the Rate of Mutation

突变率变化的进化原因和后果

• 批准号: 7096380
• 负责人: CHARLES F BAER
• 金额: $ 31万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096380
• 关键词: DNA damage; Nematoda; biochemical evolution; free radical oxygen; gene environment interaction; gene mutation; helminth genetics; metabolism; molecular genetics; nucleic acid sequence; species difference

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.

描述（由申请人提供）：所有生物体都会突变。了解任何生物体的生物学，无论过去还是未来，都需要了解突变过程。本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）表征自发突变率和分子谱的物种内和物种间变异，（2）确定不同生物体中基因组突变率是否已进化到不同的最佳值，以及（ 3）通过实验表征代谢率和突变率之间的关系。为了实现目标 (1)，将对现有的杆状线虫种群进行 100Kb 的随机基因组 DNA 测序，这些线虫在 250 代的自然选择缺乏的情况下已经积累了突变。为了实现目标（2），将使用历史上异型杂交的线虫来进行类似的突变积累实验，以与自花能育的线虫进行对比。自交和异交类群之间在新突变的发生率和/或影响方面的显着差异将提供证据表明基因组突变率受到自然选择的“微调”。目标（3）的动机是代谢率和进化率之间明显的正相关性。这种关系似乎是由于新陈代谢副产品产生的氧自由基引起的 DNA 损伤，但也存在几种替代解释。 有证据表明，任何两种随机选择的蠕虫的突变率可能相差十倍之多，并且潜在的分子突变率实际上可能比通常认为的高十倍。如果这些结果被证明具有普遍性，将对理解人类突变如何发生以及复杂遗传因素引起的疾病的本质产生重要影响。也许更重要的是，拟议的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。