The Rate and Molecular Spectrum of Spontaneous Mutations

突变过程最终确定了所有种群的遗传特征，因此具有 与进化遗传学、遗传和遗传疾病的所有问题有关。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的研究。 了解突变发生的速率及其影响的分子谱。我们将 使用新出现的技术进行高效的基因组测序，以确定这些特征的四个 模型系统：酵母酿酒酵母，线虫秀丽隐杆线虫， 微甲壳动物蚤状水蚤和纤毛草履虫。有发达的基因组 这些系统中的每一个都有一组长期的突变积累线， 这些自发突变已经以中性方式积累了很长一段时间。 从这些实验中的每一个，我们将描述几个平行的整体或大部分， 线，产生碱基取代变化的全谱，插入的大小谱， 缺失，各种形式的重复DNA的流动性，从均聚运行到串联 中等大小的重复序列和移动的元件的插入/切除率。所述前后关系依赖性 这些功能将评估相对于相邻的基础组成，转录和 复制活性和减数分裂重组率。除了与突变基础有关外， 遗传疾病，其结果将与进化遗传学中一系列未解决的问题有关， 包括在何种程度上：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位点中的沉默位点被抑制。 选择.作为基因组变化的零模型， 从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 在分子水平上对这些被充分研究的物种的自然变异进行研究。

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.