体细胞突变的积累过程及与表型的关联性是遗传与基因组学的重要内容。目前研究多通过对肿瘤基因组的体细胞突变频率关系进行间接推断，缺乏直接特别是对正常细胞突变积累过程的研究。阐明体细胞突变积累过程及与表型的关联，将为包括肿瘤在内的疾病发生发展研究提供基础数据。 项目拟利用细胞模型传代可控的优势分析体细胞突变积累过程。通过对淋巴母细胞及脐带内皮细胞进行50代培养，对终末及中间若干代次进行全基因组、转录组、组蛋白H3K4mer3测序和DNA甲基化芯片分析，确定传代过程体细胞突变的动态变化和所引起的表观遗传学修饰改变及基因表达改变。 本项目关注体细胞突变研究热点问题，将首次利用今年2月推出的最新高通量较低成本测序体系，通过大规模基因组学研究方法，实现对体细胞突变在细胞模型中的积累过程的描述，并初步确定该过程与细胞分子表型变化的关联，将为后续更深层次揭示体细胞突变产生的原因及造成的结果的重要基础。

The accumulation of somatic mutations and their relationship with phenotypes is a fundamental question of the human genetics and genomics. Previous research were mainly based on indirect speculation from frequencies of somatic mutations in cancer genomes. Dissecting the accumulation process and the correlation with phenotypes will provide new insights in the genesis of disease and tumor. Here, we attempt to directly characterize the accumulation process of the somatic mutation using human cell models, in which each generation of cell populations can be obtained. In selected generations of human lymphoblastoid cells and endothelial cells of human umbilical vein, we will conduct the sequencing analyses of the whole genome, transcriptome, and H3K4mer3 ChIP DNA, as well as array analysis of DNA methylation. By the integration of these omics data, we will be able to uncover the dynamic changes of during the process of somatic mutation accumulation, and to learn their correlations with epigenetic modification and gene expression. This project focuses on the critical questions regarding the effect of somatic mutation. By these omics analyses, it will, for the first time, reveal the accumulation of mutations in cell models, and correlate mutations with cellular phenotype at the molecular level. It will provide fundamental data for more insights on the mechanisms contributing to the somatic mutation occurrence and crucial consequences.