The Rate and Molecular Spectrum of Spontaneous Mutations

突变过程最终定义了所有种群的遗传特征，因此具有 涉及进化遗传学、遗传和遗传障碍的一系列问题。然而， 尽管突变是生物学的中心，但强大的技术壁垒限制了我们的 了解突变发生的速度及其影响的分子光谱。我们会 使用新出现的高效基因组测序技术来定义以下四个特征 模式系统：酵母酿酒酵母，线虫秀丽线虫， 微型甲壳类、草履虫和纤毛虫。有发育良好的基因组 资源，并且每个系统都有一组长期的突变-累积线 这些自发突变已经以中性方式积累了很长一段时间。 从每个实验中，我们将描述几个平行实验的整体或很大一部分 线条，产生碱基-置换变化的全谱，插入的大小谱和 缺失，各种形式的重复DNA的流动性，从均聚体运行到串联 中等大小的重复，以及移动元素的插入/删除率。语境依赖 这些特征中的一个将根据邻近碱基组成、转录和 复制活性和减数分裂重组率。除了在突变的基础上产生 遗传障碍，结果将与进化遗传学中一系列悬而未决的问题相关， 包括：突变导致基因组扩张与收缩、突变热(或 冷)点存在，蛋白质编码基因、内含子和其他非编码区的沉默位点在 选择。通过作为基因组变化的零模型，史无前例的和公正的光谱 这项研究中出现的突变效应也将为未来的研究提供永久的资源 这些经过充分研究的物种在分子水平上的自然变异。

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.