The Genetic Architecture of Somatic Mutation Rate

体细胞突变率的遗传结构

• 批准号: 1021720
• 负责人: Daniel Promislow
• 金额: $ 66万
• 依托单位: University of Georgia Research Foundation Inc
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1021720&HistoricalAwards=false
• 关键词: Genetic; Architecture; Somatic; Mutation; Rate; Genetic; Architecture; Somatic; Mutation; Rate

Intellectual merit: DNA damage is important and costly enough that organisms devote scores of genes to its repair, but little is known about how individuals in natural populations vary in their underlying mutation rates, or in their ability to repair those mutations. Furthermore, little is understood about the identity of the genetic determinants of this variation, and whether these genes differ from those found in studies on laboratory organisms. This gap in knowledge seriously limits the ability to understand the mechanisms that maintain genome integrity, and to understand natural variation in mutation-dependent phenomena such as senescence. The long-term goal of this project is to understand the genetic and environmental factors that affect genome stability in nature. The central hypothesis of this project is that individuals vary in somatic mutation rate, and that this variation is caused by differences in gene sequences and gene expression. To test the central hypothesis, this project examines variation in somatic mutation rate in 40 inbred lines of Drosophila melanogaster derived from a natural population in North Carolina. Genome-wide expression and sequence data are available for these lines. The study is made possible by the recent creation of a transgenic model to measure somatic mutation rates in vivo in the fruit fly with a lacZ reporter gene. Aim 1 will involve experiments to test the hypothesis that genetic variation exists for somatic mutation rate by placing a lacZ reporter gene into the 40 inbred lines and measuring line-, sex- and tissue-specific variation for somatic mutation. This hypothesis is strongly supported by preliminary data showing heritable variation for somatic mutation rate. In Aim 2, genetic and regulatory factors associated with somatic mutation rate will be investigated. Genome-wide association studies of single nucleotide polymorphisms will be used to identify genes associated with somatic mutation rate. Expression data will be analyzed to search for networks of co-regulated genes whose expression levels correlate with somatic mutation rate. Aim 3 will determine whether genotypes with naturally high somatic mutation rate show relatively large increases in mutation frequency when exposed to paraquat, a herbicide that has been shown previously to increase the frequency of mutations in Drosophila. This project uses a creative combination of quantitative genetics, molecular genetics, and high-throughput genomics. In its focus on natural genetic variation, this work is expected to lead to the discovery of new genes that influence evolutionarily relevant variation in somatic mutation rates and to create a novel paradigm for understanding the genetic basis of somatic mutation rate. This new framework should provide better understanding of the evolution of genome stability and genome structure. Broader impacts: This proposal provides the first direct study of natural variation for somatic mutation rate, and should lead to the identification of novel genes associated with somatic mutation rate. All novel strains developed and all expression data collected during the course of this project will be made freely available to the research community. The project will provide continued hands-on research training for high school and undergraduate students, including students from underrepresented populations. Trainees will be given the opportunity to publish scientific articles and to attend national scientific meetings with the investigator.

智力优点：DNA损害很重要且昂贵，以至于生物体将数十种基因的修复投入，但是关于自然种群中的个体在其潜在的突变率或修复这些突变的能力方面鲜为人知。此外，对这种变异的遗传决定因素的身份以及这些基因是否与实验生物的研究中发现的基因有所不同。知识的这一差距严重限制了理解维持基因组完整性的机制，并了解依赖突变依赖现象（例如衰老）的自然变异的机制。该项目的长期目标是了解影响自然界基因组稳定性的遗传和环境因素。该项目的中心假设是个体在体细胞突变率上有所不同，并且这种变异是由基因序列和基因表达的差异引起的。为了检验中心假设，该项目研究了北卡罗来纳州自然人口的40种果蝇的近交系列体细胞突变率的变化。全基因组表达和序列数据可用于这些线。最近创建了转基因模型来测量使用LACZ报告基因的果蝇中体内体内的体体突变率，这项研究是可能的。 AIM 1将涉及实验，以检验以下假设：通过将LACZ报告基因放入40个近交系中，并测量线，性别和组织特异性变异的遗传变异，以进行体细胞突变率。该假设得到了初步数据的强烈支持。在AIM 2中，将研究与体细胞突变率相关的遗传和调节因素。单核苷酸多态性的全基因组关联研究将用于鉴定与体细胞突变率相关的基因。表达数据将进行分析，以搜索共同调节基因的网络，其表达水平与体细胞突变率相关。 AIM 3将确定自然较高的体细胞突变速率的基因型在暴露于Paraquat时是否表现出相对较大的突变频率，这是一种先前已显示以增加果蝇突变的频率。该项目使用定量遗传学，分子遗传学和高通量基因组学的创造性组合。在其对自然遗传变异的关注中，这项工作有望导致发现新基因，这些基因影响了体细胞突变率的进化相关变化，并创建了一种新的范式来理解体细胞突变率的遗传基础。这个新框架应更好地理解基因组稳定性和基因组结构的演变。 更广泛的影响：该提案提供了对体细胞突变率的自然变异的首次直接研究，并应导致鉴定与体细胞突变率相关的新基因。所有新型菌株都开发了，并且在该项目过程中收集的所有表达数据都将免费提供给研究社区。该项目将为高中和本科生提供继续进行动手研究培训，包括来自代表性不足的人群的学生。学员将有机会发表科学文章并与研究人员参加国家科学会议。