Replication Stress Induces Genome-wide Copy Number Changes in Human Cells that Resemble Polymorphic and Pathogenic Variants
Replication Stress Induces Genome-wide Copy Number Changes in Human Cells that Resemble Polymorphic and Pathogenic Variants
复制标题
DOI：
10.1016/j.ajhg.2009.01.024
复制
发表时间：
2009-03-13
影响因子：
9.8
通讯作者：
Glover, Thomas W.
中科院分区：
文献类型：
--
作者：
Arlt, Martin F.;Mulle, Jennifer G.;Glover, Thomas W.
拷贝数变异（CNV）是人类和其他哺乳动物基因组变异的重要组成部分。现在已知类似的从头删除和重复或复制数字变化（CNC）是遗传和发育障碍的主要原因，并且在许多癌症中都会出现。导致CNV和与疾病相关的CNC的主要机制是减数分裂不平等的过境或非平行性同源重组（NAHR），是由侧翼重复序列或节段性重复介导的。其他似乎涉及非同源末端连接（NHEJ）或异常复制表明有丝分裂细胞的起源。在这里，我们表明，蚜虫蛋白诱导的正常人细胞中的复制应激导致在人类基因组中的数千千碱基的CNC高频，与CNV非常相似，与疾病相关的CNC非常相似。大多数删除和重复断点连接的特征是短（
Copy number variants (CNVs) are an important component of genomic variation in humans and other mammals. Similar de novo deletions and duplications, or copy number changes (CNCs), are now known to be a major cause of genetic and developmental disorders and to arise somatically in many cancers. A major mechanism leading to both CNVs and disease-associated CNCs is meiotic unequal crossing over, or nonallelic homologous recombination (NAHR), mediated by flanking repeated sequences or segmental duplications. Others appear to involve nonhomologous end joining (NHEJ) or aberrant replication suggesting a mitotic cell origin. Here we show that aphidicolin-induced replication stress in normal human cells leads to a high frequency of CNCs of tens to thousands of kilobases across the human genome that closely resemble CNVs and disease-associated CNCs. Most deletion and duplication breakpoint junctions were characterized by short (