Analysis of Somatic Mutations in Longitudinal Whole-genome Sequencing Data

纵向全基因组测序数据中的体细胞突变分析

• 批准号: 10836613
• 负责人: Cody Steely
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10836613
• 关键词: Age; Aging; Algorithmic Software; Algorithms; Blood; Body mass index; Cancer Etiology; Cancer Patient; Cardiovascular Diseases; Cells; Collection; Copy Number Polymorphism; DNA; DNA Repair; Data; Data Set; Detection; Disease; Disease Outcome; Elements; Event; Family; Foundations; Frequencies; Generations; Genetic Polymorphism; Genome; Germ Cells; Germ-Line Mutation; Goals; Hematopoiesis; Human; Human Genome; Individual; Malignant Neoplasms; Measures; Mediating; Modeling; Mutation; Organoids; Phenotype; Play; Postdoctoral Fellow; Process; Research; Role; Sampling; Series; Short Tandem Repeat; Single Nucleotide Polymorphism; Somatic Mutation; Testing; Time; Tissues; Training; Universities; Utah; Variant; Work; career; career development; computational pipelines; design; experience; experimental study; genetic pedigree; genome sequencing; human tissue; improved; member; phenotypic data; programs; time use; variant detection; whole genome

PROJECT SUMMARY While recent efforts have focused on better understanding the germline mutation rate of different types of DNA variants, the dynamics of somatic mutations in the human genome are poorly understood. Somatic mutations are a well-known cause of cancer and may play a causative role in other diseases and aging. Analyses of somatic mutations have generally been limited to single-cell or low-coverage studies. To accurately assess the rate of somatic mutations over time would require a longitudinal, high coverage dataset. For ~450 individuals in the Utah CEPH (Centre d'Etude du Polymorphism Humain) pedigrees, blood was drawn at two timepoints approximately 15 years apart. This proposal describes experiments to determine the rate of somatic mutations throughout the human genome by utilizing high-coverage (720x) whole-genome sequencing data at both of these timepoints in a subset of CEPH individuals. The genomes included in this study will be used to determine the rate of somatic mutations and improve our understanding of differences in this rate between individuals. Building on previous work performed at the University of Utah, we will determine the relationship between the germline and somatic mutation rate. Further, using detailed phenotypic data collected for these individuals, experiments will be performed to determine how this rate is correlated with disease outcomes such as cancer and cardiovascular disease. From this work, a series of filtering algorithms will be produced to allow for comprehensive analysis of somatic mutations occurring between two timepoints in the same individual. This dataset provides me with a unique opportunity to study somatic mutations over time using high-quality data. This proposal builds upon my experience in analyzing mobile element-mediated somatic mutations in longitudinal whole-genome data of cancer patients, and my recent work analyzing germline short tandem repeat mutations in the CEPH pedigrees. The K99 portion of this project will focus on determining the rate of somatic mutations in longitudinal, high-coverage whole-genome sequencing data while creating filtering algorithms to improve our detection capabilities. The additional training I will receive during this period will lay the foundation of an independent research program that will determine the significance of somatic mutations in the human genome and how these relate to disease outcomes.

项目摘要 尽管最近的努力集中在更好地理解不同的种系突变率 DNA变异的类型，人类基因组中体细胞突变的动力学知之甚少。 体细胞突变是癌症的众所周知的原因，可能在其他疾病中起因作用 老化。体细胞突变的分析通常仅限于单细胞或低覆盖研究。 为了准确评估随着时间的推移的体突变速率，需要纵向高覆盖率 数据集。对于犹他州的约有450个人（中心d'Etude du多态性荷兰）的谱系， 在相隔大约15年的两个时间点上抽血。该建议描述了实验 通过利用高覆盖范围（720X）来确定整个人类基因组的体细胞突变速率 在CEPH个体的一部分中，在这两个时间点上对全基因组进行了测序数据。基因组 本研究中包括将用于确定躯体突变的速率并改善我们的 了解个人之间这种速度的差异。建立在以前的工作 犹他大学，我们将确定种系与体细胞突变率之间的关系。 此外，使用为这些个体收集的详细表型数据，将进行实验 确定该率与癌症和心血管疾病等疾病结局的相关性。 从这项工作中，将产生一系列过滤算法，以允许对 在同一个人的两个时间点之间发生体细胞突变。这个数据集为我提供了 使用高质量数据随着时间的推移研究体细胞突变的独特机会。 该建议是基于我在分析移动元件介导的体细胞突变的经验的基础上的 在癌症患者的纵向全基因组数据中，以及我最近分析种系的工作 在Ceph谱系中串联重复突变。该项目的K99部分将着重于确定 在创建纵向高覆盖的全基因组测序数据中的体细胞突变速率 过滤算法以提高我们的检测功能。在此期间我将接受的额外培训 时期将奠定独立研究计划的基础，该计划将确定 人类基因组中的体细胞突变以及这些与疾病结局的关系。