Discovering the spectrum of natural somatic mosaicism in human skin fibroblasts

发现人类皮肤成纤维细胞中天然体细胞嵌合的光谱

• 批准号: 9119794
• 负责人: ALEXEJ ABYZOV
• 金额: $ 8.13万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-03 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119794
• 关键词: Address; Aging; Appearance; B-Cell Lymphomas; Breast; Cancer Etiology; Cataloging; Catalogs; Cell Line; Cells; Child; Clinic; Clinical Research; Clonal Expansion; DNA Sequence; Data; Data Analyses; Development; Diagnostic; Disease; Effectiveness; Fibroblasts; Foundations; Frequencies; Future; Gene Frequency; Genes; Genome; Genomics; Genotype; Goals; Health; Human; Human body; Individual; Inherited; Malignant Neoplasms; Methods; Monitor; Mosaicism; Mutation; Mutation Spectra; Normal Cell; Nucleotides; Oligonucleotides; Organism; Parents; Persons; Phenotype; Population; Predisposition; Prevention; Process; Protocols documentation; Regulatory Element; Reporting; Research; Research Project Grants; Sequence Analysis; Skin; Somatic Cell; Somatic Mutation; Techniques; Time; Tissues; Variant; age group; analytical tool; base; cancer type; carcinogenesis; epigenomics; exome sequencing; experience; genetic variant; genome analysis; genome sequencing; induced pluripotent stem cell; insight; medulloblastoma; personalized medicine; predictive modeling; prevent; single cell analysis; single cell sequencing; stem; targeted sequencing; whole genome

 DESCRIPTION (provided by applicant): Emerging evidence suggests that, contrary to previous assumptions, not all cells of the human body have an identical DNA sequence, a phenomenon known as somatic variation. Somatic variations have been shown to cause cancer and several other diseases, but the extent of this phenomenon in the human body remains unknown, in part because somatic mutations often occur in a small proportion of cells and may not be detected in the whole population. Therefore, studying this phenomenon has fundamental importance to our understanding of how the human body functions, what causes/predisposes us to various diseases, and how we can avoid and/or cure them. This proposal describes the development of computation methods and experimental approaches for the analysis of single cell's genomes, as well as how to apply these methods and approaches to study somatic mosaicism in human skin fibroblasts. The proposal first suggests developing a sophisticated, comprehensive approach for somatic variation discovery based on single cell clonal expansion. Then, this approach will be applied to uncover somatic mosaicism in human skin fibroblasts cells and will result in a reference set of somatic variants in this tissue. The result of completig the project will be new computational and experimental analytical approaches for single cell sequencing analysis. These approaches can be used in various single cell studies (somatic mosacism, organism development, etc.) and in the clinic (e.g., for cancer monitoring). Moreover, the result will provide a better understanding of genome variations in human body, which ultimately is relevant in: i) understanding and preventing the susceptibility of different people t different diseases; i) estimating the effectiveness of different treatments for each particular person; and, iii) creating the foundation for personalized medicine.

 描述(申请人提供)：新出现的证据表明，与之前的假设相反，并不是所有人体细胞都有相同的DNA序列，这种现象被称为体细胞变异。体细胞变异已被证明会导致癌症和其他几种疾病，但这种现象在人体内的程度尚不清楚，部分原因是体细胞突变通常发生在一小部分细胞中，可能无法在整个人群中检测到。因此，研究这一现象对于我们理解人体是如何运作的，是什么导致/使我们患上各种疾病，以及我们如何避免和/或治愈这些疾病具有重要的意义。该提案描述了单细胞基因组分析的计算方法和实验方法的发展，以及如何将这些方法和方法应用于研究人皮肤成纤维细胞的体细胞嵌合体。该提案首先建议开发一种基于单细胞克隆扩增的复杂、全面的体细胞变异发现方法。然后，这一方法将被应用于揭示人类皮肤成纤维细胞中的体细胞嵌合体，并将在该组织中产生一组体细胞变异的参考集。该项目的完成将为单细胞测序分析提供新的计算和实验分析方法。这些方法可用于各种单细胞研究(体细胞镶嵌、生物体发育等)。以及在临床上(例如，用于癌症监测)。此外，研究结果将更好地了解人体内的基因组变异，这最终与以下方面有关：i)了解和预防不同人对不同疾病的易感性；i)估计针对每个特定人的不同治疗方法的有效性；以及iii)为个性化医疗奠定基础。