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

遗传变异是进化的原料，最终是由突变产生的。突变率受特定基因的影响，例如DNA复制和修复酶，它们本身可因突变而改变。这些基因的一些变体，被称为突变体，增加了基因组的突变率。即使突变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中其他地方发生的有益或有害突变的遗传联系进行间接选择。这一提议探讨了一个新的假设，即群体大小可能对突变体所经历的间接选择有影响。了解种群规模和空间结构在塑造突变率进化中的作用可能会解决一个长期存在的经验难题：为什么突变体经常出现在混合良好的微生物实验室种群中，而在自然界中只偶尔发现。该项目对了解基础、健康、保护和农业研究中的自然和定向遗传变化具有重要意义。例如，这项研究可能阐明突变体在癌症肿瘤疾病进展中的作用。调查人员还将直接与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。基于他们之前发表的几篇文章，申请人提出了初步的计算和实验结果，表明大种群丰富了突变体，而小种群抑制了它们。在具体目标1中，申请人建议通过开发计算机模拟和数学分析来扩展他们的计算，以模拟复杂和现实场景中的突变体进化，包括空间结构环境。在具体目标2中，申请人提议在实验室中通过竞争的酿酒酵母突变株和非突变株来实验验证他们的预测。比赛将通过荧光监测，并在一系列人口规模和空间结构中进行。

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.