The Rate and Molecular Spectrum of Spontaneous Mutations

自发突变的速率和分子谱

• 批准号: 7151001
• 负责人: Michael R LYNCH
• 金额: $ 63.01万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151001
• 关键词: Branchiopoda; Saccharomyces cerevisiae; animal breeding; arthropod genetics; bacterial genetics; biochemical evolution; computer simulation; fertility; fungal genetics; gene mutation; genetic models; genetic screening; genetic strain; helminth genetics; inbreeding; microorganism culture; microorganism genetics; microorganism growth; natural selections

DESCRIPTION (provided by applicant): The mutation process ultimately defines the genetic features of all populations, and hence has a bearing on the full range of issues in evolutionary genetics, inheritance, and genetic disorders. Yet, despite the centrality of mutation to biology, formidable technical barriers have constrained our understanding of the rate at which mutations arise and the molecular spectrum of their effects. We will use newly emergent technology for highly efficient genomic sequencing to define these features for four model systems: the yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, the microcrustacean Daphnia pulex, and the ciliate Paramecium tetraurelia. There are well-developed genomic resources for each of these systems, and each has a set of long-term mutation-accumulation lines in which spontaneous mutations have been accumulated for extensive periods of time in a neutral fashion. From each of these experiments, we will characterize the entirety or a large fraction of several parallel lines, yielding the full spectrum of base-substitutional changes, the size spectrum of insertions and deletions, the fluidity of various forms of repetitive DNAs ranging from homopolymeric runs to tandem repeats of moderate size, and the insertion/excision rates of mobile elements. The contextual dependency of these features will be evaluated with respect to neighboring-base composition, transcription and replication activity, and meiotic recombination rate. In addition to bearing on the mutational basis of genetic disorders, the results will be relevant to a broad array of unsolved issues in evolutionary genetics, including the extent to which: mutation causes genomic expansion vs. contraction, mutational hot (or cold) spots exist, and silent sites in protein-coding genes, introns, and other noncoding sites are under selection. By serving as a null model for genomic change, the unprecedented and unbiased spectrum of mutational effects that emerges from this study will also provide a permanent resource for future studies on natural variation at the molecular level in these well-studied species.

描述（申请人提供）：突变过程最终定义了所有人群的遗传特征，因此对进化遗传学、遗传和遗传疾病的所有问题都有影响。然而，尽管突变是生物学的中心，但巨大的技术障碍限制了我们对突变发生的速度及其影响的分子谱的理解。我们将使用新出现的技术进行高效的基因组测序，以确定这些功能的四个模型系统：酵母酿酒酵母，线虫，微甲壳动物水蚤pulex，和纤毛虫草履虫tetraurelia。这些系统中的每一个都有发达的基因组资源，并且每一个都有一组长期突变积累系，其中自发突变以中性方式积累了很长一段时间。从这些实验中的每一个，我们将表征几个平行线的整体或大部分，产生碱基取代变化的全谱，插入和缺失的大小谱，各种形式的重复DNA的流动性，从均聚运行到中等大小的串联重复序列，以及移动的元素的插入/切除率。这些特征的上下文依赖性将根据相邻碱基组成、转录和复制活性以及减数分裂重组率进行评估。除了与遗传疾病的突变基础有关外，这些结果还与进化遗传学中一系列尚未解决的问题有关，包括：突变导致基因组扩张与收缩的程度，突变热点（或冷点）的存在，蛋白质编码基因中的沉默位点，内含子和其他非编码位点正在选择中。通过作为基因组变化的零模型，这项研究中出现的前所未有的和无偏见的突变效应谱也将为这些研究充分的物种在分子水平上的自然变异的未来研究提供永久的资源。