人类基因组DNA复制动态特征的解析及在CNV突变中的作用

DNA replication errors can cause copy number variation (CNV; including deletion and duplication) in the human genome. CNV is of vital importance to human health. Our newly published work indicates the connection between DNA replication dynamics (including replication timing and replication rate) and CNV mutagenesis. However, its molecular basis remains to be elucidated. To further investigate the DNA replication dynamics of the human genome and its roles in CNV mutagenesis, we will generate genome-wide profiles of DNA replication dynamics for human embryonic stem cells, spermatogonial stem cells and various somatic cells. These data can help reveal the relative contributions of DNA replication error to CNV mutations in these cells/tissues. We will also study the tissue-specific properties of common fragile sites (CFS) and their potential association with tissue-specific patterns of DNA replication dynamics. Furthermore, our proposed study will investigate the variance of replication timing between individuals in the Chinese populations. After further identifying the genetic variants (CNVs or SNPs) responsible for timing variances, we will employ the genome editing technologies and cell models for functional assays. Our proposed study aims at the relationship and interaction between CNV mutagenesis and DNA replication dynamics, which may also help inspire the studies on CNV-associated disorders and genome instability in cancers.

人类基因组DNA的错误复制可以产生拷贝数变异（CNV），表现为DNA大片段的缺失或重复。CNV是重要的遗传致病因素。本团队的最新研究成果显示：基因组DNA复制动态（包括复制时相和复制速率）与CNV突变密切相关，但其内在机制尚不明确。为深入探索人类基因组DNA复制动态特征的调控机制及在CNV突变中的作用这一关键科学问题，本项目拟针对精原干细胞、胚胎干细胞及不同体细胞，分别构建DNA复制时相和复制速率图谱；深入分析CNV突变与基因组复制动态特征的相关性，研究生殖发育不同环节对于CNV遗传多样性的贡献度；从常见脆性位点CFS角度，探讨体细胞基因组不稳定性与DNA复制动态的内在联系；分析中国人群中DNA复制时相的个体间差异，并利用基因组编辑技术和细胞模型探索基因组复制调控的遗传学机制。本项目可揭示CNV等遗传变异与基因组复制动态之间的互作关系，协助对CNV致病、肿瘤基因组进化等相关热点问题的解答。

基因组DNA的错误复制可以产生拷贝数变异（CNV），表现为DNA大片段的缺失或重复。CNV是重要的遗传致病因素。基因组DNA复制动态（包括复制时相和复制速率）与CNV突变密切相关，但其内在机制尚不明确。本团队致力于探索人类基因组DNA复制动态特征的调控机制及在CNV突变中的作用这一关键科学问题。本项目针对不同个体构建了人类基因组DNA复制时相和复制速率图谱，发现了DNA复制时相的个体间差异，验证了SNP等遗传变异能影响DNA复制时相。此外，我们还发现DNA复制错误诱发的TBX6基因重复是导致先天性脊柱侧凸等出生缺陷的重要原因。我们也研发了CNV断点分析新技术——ALN-walking，构建了中国人群CNV遗传图谱和数据库CNVBase。本项目揭示了遗传变异与基因组复制动态之间的互作关系，并再次确认了CNV在生殖与发育疾病中的重要致病作用。

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