人类胚胎发育过程中体细胞突变特征、热点及组织特异性分析

Somatic mutations widely distribute across the human genome. Studies based on tumor and normal tissues suggest that the factors associated with mutation occurrence include the nucleotide composition of DNA sequences, the epigenetic status of the mutation sites, and intracellular environment. Embryonic stage is very crucial in human growth and development, but our knowledge on somatic mutations in this stage is still limited. The dissection of somatic mutation patterns in the embryonic stage and the dynamic changes during tissue development will give us more clues to explore the molecular mechanism underlying both common and rare genetic diseases, and also improve our understanding on the maintenance of tissue functions..This project will perform whole exome sequencing at deep coverage on samples from 5 embryonic tissues, including placenta, germ cells, brain, heart and liver, from 3 aborted fetuses with no chromosome abnormal or genetic disorder. This will provide a thorough profile of embryonic somatic mutations, giving sights on mutation hotspots in multiple tissues and their epigenetic changes during development..Here, we will focus on the somatic mutation pattern in embryogenesis, and provide more new evidence for the theory of human somatic mutation, and the data will also be crucial for us to understand the mutation pattern, their impacts on gene functions, and their roles in pathogenesis of human diseases.

体细胞突变广泛存在于人类基因组中。对肿瘤及健康组织的体细胞突变研究提示，体细胞突变的发生与DNA碱基组成、基因组表观修饰状态、细胞内部环境等密切相关。胚胎发育是生命周期中的重要过程，目前对期间体细胞突变状态的研究存在不足。阐明体细胞突变模式在胚胎发育过程中的变化规律，不仅能够为遗传及罕见疾病发生的分子生物学研究提供方向，还可为理解组织环境相关的功能提供参考。本项目拟对3例无染色体畸变及大片段结构变异的人类人工流产胚胎的包括胎盘，生殖细胞，大脑、心脏、肝脏等5种不同胚层来源的代表性组织进行外显子组深度测序，以建立体细胞突变分布图谱，从而确定点突变热点区域并探讨其组织特异性分布规律及其与胚胎发育中表观基因组动态的关联。本项目关注胚胎发育过程中体细胞点突变规律，对人类基因组体细胞突变的理论体系提供新的数据补充，为了解突变产生规律，体细胞突变的功能影响及其与疾病的关联提供可靠的实验及数据基础。