The Rate and Molecular Spectrum of Spontaneous Mutations

自发突变的速率和分子谱

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：突变过程最终定义了所有人群的遗传特征，因此与进化遗传学，遗传和遗传疾病的全部问题有关。然而，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对突变发生率和作用的分子光谱的理解。我们将使用新的新兴技术进行高效的基因组测序，以定义四个模型系统的这些特征：酵母糖酵母酿酒酵母，线虫秀丽隐杆线虫，微质量秀丽隐杆线虫，微质量达西亚paphnia pulex和ciliate parmecium parmecium parmecium parmecium tetraurelia。这些系统中的每一个都有发达的基因组资源，每个系统都有一组长期突变 - 蓄积线，其中自发突变以中立的方式积累了很长时间。从这些实验中的每一个中，我们都将表征几条平行线的整体或很大一部分，从而产生各种基础机构变化，插入和缺失的尺寸频谱，各种形式的重复性DNA的流动性，从同性聚合物运行到均匀的尺寸到中等尺寸和插入式移动元素的均匀尺寸，以及插入式移动元素的重复。这些特征的上下文依赖性将根据相邻基本组成，转录和复制活性以及减数分裂重组率进行评估。除了基于遗传疾病的突变基础外，结果还将与进化遗传学中的一系列未解决的问题有关，包括：突变导致基因组扩张与收缩，突变热（或冷的（或冷）存在，以及蛋白质编码基因的沉默位点，蛋白质编码基因，内含物，以及其他未编码的位置。通过作为基因组变化的无效模型，这项研究出现的前所未有的突变效应频谱还将为这些经过良好的物种中分子水平的自然变异进行永久性资源。