The evolution and diversity of mutation, molecular fidelity, and genome structure

项目摘要摘要 突变是所有进化新颖性和多样性的来源，塑造着 基因组。随着进化时间的推移，基因组结构和内容的变化与大量 物种间和物种内的表型变化。在有机体的整个生命周期中，单个细胞 积累体细胞突变，也可以赋予选择优势。我们的实验室感兴趣的是 突变的出现以及基因组序列和结构的这些变化是如何维持和作用的 选择。我们试图在细胞和生物体水平上理解细胞类型、基因型别、选择性 压力和进化史影响着基因组的结构和序列。最终，我们的 研究将进一步加深我们对特定细胞类型为什么 以及基因组结构如何影响内部和之间的表型多样性 物种。在癌症基因组的背景下，体细胞突变的模式已经被广泛研究 其中克隆扩张将突变信号放大到可检测的水平。然而，人们对此了解的要少得多 关于“正常”细胞如何随时间累积突变，以及这些动态如何受 如细胞类型和基因等因素。此外，体细胞突变已被证明具有鉴定的挑战性。 由于标准测序方法的错误率相对较高。我们建议使用新的基因组 方法研究不同形式的体细胞突变是如何积累的以及体细胞突变是如何发生的 过程受到遗传基因变异的影响。除了识别个人在哪些情况下 细胞积累突变，我们建议确定基因组结构是如何在 不同的进化史、选择压力和生活史策略。虽然它的大小和结构 真核生物的基因组在脊椎动物中有三个数量级的巨大差异，进化 而这种变异的机制基础仍不清楚。我们建议研究基因组的进化 岩鱼爆炸性适应性辐射中的建筑，以了解寿命的极端变化如何 影响突变过程和遗传多样性。我们进一步建议研究人类的结构是如何 黑猩猩的基因组已经被当地的适应和选择的力量所塑造。识别 结构可变(SV)基因座的选择和适应的特征一直是具有挑战性的，部分原因是 SVS倾向于出现在基因组的复杂重复区域。我们建议使用基于长期阅读的 基因组学方法和新的计算方法来评估这些基因座。最终，我们的研究将 进一步了解内部和外部的突变、多样性和基因组结构多样性 物种之间以及有机体的单个细胞之间也是如此。

Project Summary Abstract Mutation is the source of all evolutionary novelty and diversity shaping both the structure and sequence of genomes. Over evolutionary timescales changes to genome structure and content are associated with vast phenotypic changes between and within species. Throughout the lifetime of an organism individual cells accumulate somatic mutations that can also confer selective advantages. Our lab is interested in how mutations emerge and how these changes to genome sequence and structure are maintained and acted on by selection. We seek to understand at both the cellular and organismal level how cell-type, genotype, selective pressures, and evolutionary histories influence the structure and sequence of the genome. Ultimately, our research will further our understanding of the mechanisms underlying why specific cell types are more susceptible to disease as well as how genome structure influences phenotypic diversity within and between species. Patterns of somatic mutation have been extensively studied in the context of cancer tumor genomes in which clonal expansions amplify the signals of mutation to detectable levels. Far less is understood however about how “normal” cells accumulate mutations through time and how these dynamics are influenced by factors such as cell type and genotype. Furthermore, somatic mutations have proven challenging to identify due to the comparably high error rate of standard sequencing approaches. We propose to use novel genomic methods to investigate how different forms of somatic mutation accumulate and how somatic mutational processes are impacted by inherited genetic variation. In addition to discerning the contexts in which individual cells accumulate mutations, we propose to determine how genome structures have evolved in the context of different evolutionary histories, selective pressures, and life history strategies. While the size and structure of eukaryotic genomes varies tremendously spanning three orders of magnitude in vertebrates, the evolutionary and mechanistic bases of this variation remain unknown. We propose to study the evolution of genome architectures in the explosive adaptive radiation of rockfish to understand how extreme variation in lifespan can impact mutational processes and genetic diversity. We further propose to study how the structures of human and chimpanzee genomes have been shaped by local adaptations and the forces of selection. Identifying signatures of selection and adaption at structurally variable (SV) loci has been challenging in part due the tendency of SVs to emerge in complex repetitive regions of the genome. We propose to use long-read based genomics approaches and novel computational methods to assess these loci. Ultimately, our research will further our understanding of mutation, diversity, and genome structural diversity both within and between species as well as among the individual cells of organisms.