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

突变的进化和多样性、分子保真度和基因组结构

• 批准号: 10463776
• 负责人: Peter Heshedahl Sudmant
• 金额: $ 40.13万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-06 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463776
• 关键词: Architecture; Cell physiology; Cells; Clonal Expansion; Complex; Computing Methodologies; Disease; Evolution; Genetic Variation; Genome; Genomic approach; Genomics; Genotype; Goals; Human; Individual; Inherited; Longevity; Malignant Neoplasms; Methods; Molecular; Mutation; Normal Cell; Organism; Pan Genus; Pattern; Phenotype; Process; Radiation; Recording of previous events; Repetitive Sequence; Research; Shapes; Signal Transduction; Somatic Cell; Somatic Mutation; Source; Structure; Time; Variant; Vertebrates; base; cancer genome; cell type; interest; life history; novel; pressure

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.

项目摘要 突变是所有进化的新奇和多样性的来源，它们塑造了生物的结构和序列。 基因组在进化的时间尺度上，基因组结构和内容的变化与巨大的 物种间和物种内的表型变化。在生物体的整个生命周期中， 积累体细胞突变，也可以赋予选择优势。我们的实验室很感兴趣 基因组序列和结构的这些变化是如何被维持和作用的。 选择.我们试图在细胞和生物体水平上了解细胞类型、基因型、选择性 压力和进化历史影响基因组的结构和序列。最终，我们 研究将进一步了解为什么特定的细胞类型比其他细胞类型更容易被感染的机制。 以及基因组结构如何影响表型多样性 物种体细胞突变的模式已经在癌症肿瘤基因组的背景下被广泛研究 其中克隆扩增将突变信号放大到可检测的水平。然而， 关于“正常”细胞如何随着时间积累突变，以及这些动态如何受到 例如细胞类型和基因型。此外，体细胞突变已被证明具有挑战性， 这是由于标准测序方法的错误率非常高。我们建议使用新的基因组 研究不同形式的体细胞突变如何积累以及体细胞突变如何 这些过程受到遗传变异的影响。除了辨别个人所处的环境之外， 细胞积累突变，我们建议确定基因组结构是如何在 不同的进化历史、选择压力和生活史策略。虽然规模和结构的 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，进化的 这种变化的机制基础仍然未知。我们建议研究基因组的进化 在岩鱼的爆炸性适应性辐射的架构，以了解如何极端变化的寿命， 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如何 而黑猩猩的基因组是由局部适应和选择的力量塑造的。识别 在结构可变（SV）基因座处的选择和适应的特征一直是具有挑战性的，部分原因是 SV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 进一步了解突变，多样性和基因组结构多样性，无论是内部和之间 物种之间以及生物体的单个细胞之间。