Collaborative Research: Risk and reward of high mutation rate: why large populations favor mutators while small populations inhibit them

合作研究：高突变率的风险和回报：为什么大群体青睐突变体，而小群体抑制突变体

• 批准号: 1556168
• 负责人: Paul Sniegowski
• 金额: $ 8.84万
• 依托单位: University of Pennsylvania
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1556168&HistoricalAwards=false
• 关键词: Collaborative; Research; Risk; reward; mutation

Genetic variation, the raw material for evolution, is ultimately generated by mutation. The rate of mutation is influenced by particular genes, e.g. for DNA replication and repair enzymes, which can themselves be altered by mutations. Some variants of those genes, known as mutators, increase the genomic rate of mutation. Even when mutators have no direct effect on survival and reproduction of the individual, they can experience indirect selection via genetic linkage to beneficial and deleterious mutations that occur elsewhere in the genome. This proposal explores a novel hypothesis that population size may have an effect on indirect selection experienced by mutators. Understanding the role of population size and spatial structure in shaping the evolution of mutation rate may resolve a longstanding empirical puzzle: why mutators frequently emerge in well-mixed microbial laboratory populations, yet are only sporadically found in nature. This project has important implications for understanding both natural and directed genetic changes in basic, health, conservation, and agriculture research. For example, this research may illuminate the role of mutators during disease progression of cancer tumors. The investigators will also work directly with K-12 teachers and students to improve their understanding of genetics and scientific inquiry. Building on several of their previous publications, the applicants present preliminary calculations and experimental results suggesting that large populations enrich for mutators and small populations inhibit them. In specific aim 1, the applicants propose to extend their calculations by developing computer simulations and mathematical analysis to model the evolution of mutators in complex and realistic scenarios, including spatially structured environments. In specific aim 2 the applicants propose to experimentally test their predictions in the laboratory by competing mutator and non-mutator strains of Saccharomyces cerevisiae yeast. Competitions will be monitored by fluorescence and conducted across a range of population sizes and spatial structures.

遗传变异是进化的原材料，最终是由突变产生的。突变速率受特定基因的影响，例如用于DNA复制和修复酶，它们本身可以通过突变改变。这些基因的某些变体（称为突变器）增加了突变的基因组速率。即使突变器对个体的生存和繁殖没有直接影响，它们也可以通过与基因组其他地方发生的有益和有害突变的遗传联系而间接选择。 该提案探讨了一个新的假设，即种群规模可能会影响突变器所经历的间接选择。了解种群规模和空间结构在塑造突变率演变中的作用可能会解决一个长期存在的经验拼图：为什么突变器经常在混合良好的微生物实验室种群中出现，而在自然界中只发现了突变器。该项目对理解基本，健康，保护和农业研究的自然遗传变化具有重要意义。例如，这项研究可能会阐明突变器在癌症疾病进展中的作用。研究人员还将直接与K-12教师和学生合作，以提高他们对遗传学和科学探究的理解。申请人在以前的几个出版物的基础上，提出了初步计算和实验结果，这表明大量人群富含突变器和少数人群会抑制它们。在特定目标1中，申请人建议通过开发计算机模拟和数学分析来扩展计算，以模拟在复杂和现实的场景中（包括空间结构化的环境）中突变器的演变。在特定的目标2中，申请人建议通过酿酒酵母酵母的竞争突变器和非突变器菌株在实验室中测试其预测。竞争将通过荧光监测，并在各种人口大小和空间结构上进行。