The Rate and Molecular Spectrum of Spontaneous Mutations

自发突变的速率和分子谱

• 批准号: 7492562
• 负责人: Michael R LYNCH
• 金额: $ 8.38万
• 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/7492562
• 关键词: Applied Genetics; Area; Base Composition; Biological Preservation; Biology; Caenorhabditis elegans; Code; Codon Nucleotides; Crows; DNA Sequence; DNA Transposable Elements; Daphnia; Dependency; Depth; Detection; Elements; Emerging Technologies; Evaluation; Evolution; Excision; Free Radicals; Future; Generations; Genes; Genetic; Genetic Load; Genetic Polymorphism; Genetic Recombination; Genetic Transcription; Genome; Genomics; Goals; Hereditary Disease; Human; Introns; Meiotic Recombination; Methods; Modeling; Molecular; Molecular Evolution; Molecular Models; Mutation; Natural Selections; Nematoda; Nucleotides; Numbers; Paramecium tetraurelia; Pattern; Phylogenetic Analysis; Population; Process; Property; Proteins; Range; Rate; Recurrence; Replication Error; Reporter; Research; Research Personnel; Resources; Role; Running; Saccharomyces cerevisiae; Site; Spottings; Surveys; System; Tandem Repeat Sequences; Techniques; Thinking; Time; Untranslated Regions; Variant; Work; Y Chromosome; Yeast Model System; analytical method; base; behavior observation; duplicate genes; expectation; fluidity; insertion/deletion mutation; insight; programs; research study; size

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.

突变过程最终定义了所有人群的遗传特征，因此具有 与进化遗传学，遗传和遗传疾病的全部问题有关。 尽管突变是生物学的中心地位，但强大的技术障碍却限制了我们的 了解突变发生的速率及其作用的分子光谱。我们将 使用新的紧急技术进行高效的基因组测序，以定义这些功能的四个功能 模型系统：酿酒酵母酵母菌，线虫秀丽隐杆线虫， Microcrustacean洗发症Pulex和纤毛脱发三尿尿尿。有发达的基因组 每个系统的资源，每个系统都有一组长期突变利用线 哪些自发突变已经以中立的方式积累了很长时间。 从这些实验中的每一个中，我们将表征几个平行的整体或大部分 线，产生各种基础基本变化，插入的大小频谱和 删除，各种形式的重复DNA的流动性从均聚物运行到串联 重复中等大小以及移动元件的插入/切除率。上下文依赖性 这些功能将在相邻基量组成，转录和 复制活动和减数分裂重组率。除了取决于突变基础 遗传疾病，结果将与进化遗传学中的一系列未解决的问题有关， 包括：突变引起基因组扩张与收缩，突变热的程度（或 存在冷斑，蛋白质编码基因，内含子和其他非编码位点的静音位点在 选择。通过充当基因组变化的无效模型，前所未有的无偏见 这项研究产生的突变效应还将为未来研究提供永久资源 在这些精心研究的物种中，分子水平的自然变异。